Pharmacological interventions for pruritus in adult palliative care patients

Abstract

Background

This is the second update of the original Cochrane review published in 2013 (issue 6), which was updated in 2016 (issue 11). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is a burdening symptom. It can cause considerable discomfort and negatively affect patients' quality of life.

Objectives

To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients.

Search methods

For this update, we searched CENTRAL (the Cochrane Library), MEDLINE (OVID) and Embase (OVID) up to 6 July 2022. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data.

Selection criteria

We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients.

Data collection and analysis

Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta‐analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE and created 13 summary of findings tables.

Main results

 In total, we included 91 studies and 4652 participants in the review. We added 42 studies with 2839 participants for this update. Altogether, we included 51 different treatments for pruritus in four different patient groups.

The overall risk of bias profile was heterogeneous and ranged from high to low risk. The main reason for giving a high risk of bias rating was a small sample size (fewer than 50 participants per treatment arm). Seventy‐nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains; the remaining studies had an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%).

Using GRADE criteria, we judged that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa‐opioid agonists compared to placebo and moderate for GABA‐analogues compared to placebo. Certainty of evidence was low for naltrexone, fish‐oil/omega‐3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. We downgraded the certainty of the evidence mainly due to serious study limitations regarding risk of bias, imprecision, and inconsistency.

For participants suffering from uraemic pruritus (UP; also known as chronic kidney disease (CKD)‐associated pruritus (CKD‐aP)), treatment with GABA‐analogues compared to placebo likely resulted in a large reduction of pruritus (visual analogue scale (VAS) 0 to 10 cm): mean difference (MD) −5.10, 95% confidence interval (CI) −5.56 to −4.55; five RCTs, N = 297, certainty of evidence: moderate. Treatment with kappa‐opioid receptor agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduced pruritus slightly (VAS 0 to 10 cm, MD −0.96, 95% CI −1.22 to −0.71; six RCTs, N = 1292, certainty of evidence: high); thus, this treatment was less effective than GABA‐analogues. Treatment with montelukast compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (two studies, 87 participants): SMD −1.40, 95% CI −1.87 to ‐0.92; certainty of evidence: very low. Treatment with fish‐oil/omega‐3 fatty acids compared to placebo may result in a large reduction of pruritus (four studies, 160 observations): SMD −1.60, 95% CI −1.97 to ‐1.22; certainty of evidence: low. Treatment with cromolyn sodium compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (VAS 0 to 10 cm, MD ‐3.27, 95% CI −5.91 to −0.63; two RCTs, N = 100, certainty of evidence: very low). Treatment with topical capsaicin compared with placebo may result in a large reduction of pruritus (two studies; 112 participants): SMD −1.06, 95% CI −1.55 to ‐0.57; certainty of evidence: low. Ondansetron, zinc sulphate and several other treatments may not reduce pruritus in participants suffering from UP.

In participants with cholestatic pruritus (CP), treatment with rifampicin compared to placebo may reduce pruritus, but the evidence is very uncertain (VAS: 0 to 100, MD −42.00, 95% CI −87.31 to 3.31; two RCTs, N = 42, certainty of evidence: very low). Treatment with flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain (RR > 1 favours treatment group; RR 2.32, 95% CI 0.54 to 10.1; two RCTs, N = 69, certainty of evidence: very low). Treatment with the opioid antagonist naltrexone compared to placebo may reduce pruritus (VAS: 0 to 10 cm, MD −2.42, 95% CI −3.90 to −0.94; two RCTs, N = 52, certainty of evidence: low). However, effects in participants with UP were inconclusive (percentage of difference −12.30%, 95% CI −25.82% to 1.22%, one RCT, N = 32).

In palliative care participants with pruritus of a different nature, the treatment with the drug paroxetine (one study), a selective serotonin reuptake inhibitor, compared to placebo may reduce pruritus slightly by 0.78 (numerical analogue scale from 0 to 10 points; 95% CI −1.19 to −0.37; one RCT, N = 48, certainty of evidence: low).

Most adverse events were mild or moderate. Two interventions showed multiple major adverse events (naltrexone and nalfurafine).

Authors' conclusions

Different interventions (GABA‐analogues, kappa‐opioid receptor agonists, cromolyn sodium, montelukast, fish‐oil/omega‐3 fatty acids and topical capsaicin compared to placebo) were effective for uraemic pruritus. GABA‐analogues had the largest effect on pruritus. Rifampin, naltrexone and flumecinol tended to be effective for cholestatic pruritus. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta‐analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.

Plain language summary

What are the benefits and risks of pharmacological interventions for itch in adult palliative care patients?

cPruritus or itch is one of the most puzzling symptoms in advanced incurable diseases and can cause considerable discomfort in patients. Pruritus is multifactorial in origin and can be a symptom of diverse pathophysiologies. Particularly over the last decade, clinical observation and controlled trials have done much to aid the understanding and treatment of pruritus, especially in liver disease, uraemia and other kinds of chronic pruritus. Therefore, this review aimed to systematically collect and evaluate the evidence for adequate treatment of pruritus in the field of palliative care.

Key messages

‐ for pruritus (itch) associated with kidney disease we found a reduction of pruritus for the following pharmacological interventions compared to placebo: GABA‐analogues (gabapentin, pregabalin) likely result in a large reduction of pruritus, kappa‐opioid agonists (difelikefalin, nalbuphine, nalfurafine) reduce pruritus slightly, cromolyn sodium, fish‐oil/omega‐3 fatty acids, and topical capsaicin may result in a large reduction of pruritus, and montelukast may result in a large reduction of pruritus, but the evidence is very uncertain.

‐ for pruritus (itch) associated with liver disease we found that rifampicin and flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain.

‐ research in palliative care is challenging and often limited to a restricted period of time at the end of life. More high‐quality studies on preventing and treating pruritus (itch) are needed.

What is pruritus?

Pruritus is the medical term for itching. This symptom can be a big problem in palliative care because it reduces quality of life. Pruritus may occur in association with different illnesses as chronic kidney disease, liver disease or cancer.

How is pruritus treated?

Depending on the cause, pruritus can be treated by pharmacological, non‐pharmacological and topical interventions.

What did we want to find out?

We wanted to find out if pharmacological interventions were better than placebo or another active control intervention to improve pruritus. We also wanted to find out if pharmacological interventions were associated with any unwanted effects.

What did we do? 
We searched for high‐quality clinical trials of drugs for preventing or treating pruritus in palliative care. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 91 studies testing 51 different drugs/applications in 4652 people with pruritus. The biggest study was in 373 people and the smallest study was in eight people. The studies took place in different countries in Europe, North America and Asia. Most studies lasted for around four to eight weeks. Pharmaceutical companies funded 17 (19%) of the 91 studies.

An ideal antipruritic therapy is currently lacking. However, there were enough studies to point out effects for particular causes of itch. GABA‐analogues (gabapentin, pregabalin), kappa‐opioid agonists (difelikefalin, nalbuphine, nalfurafine), montelukast, fish‐oil/omega‐3 fatty acids, cromolyn sodium, and topical capsaicin (all compared to placebo) improved itch associated with chronic kidney disease, and rifampicin (compared to placebo or active control) and flumecinol (compared to placebo) improved itch associated with liver problems. Overall, most of the drugs caused few and mild side effects. Naltrexone showed by far the most side effects.

What are the limitations of the evidence?

There were several limitations of the evidence. Most importantly, it is possible that people in the studies were aware of what treatment they were getting. Furthermore, the studies were done in different types of people and assessed different ways of delivering an intervention.

How up‐to‐date is this evidence?

This review updates our previous review. The evidence is up‐to‐date to July 2022.

Summary of findings

Summary of findings 1. Summary of findings table ‐ GABA‐analogues versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus.

GABA‐analogues versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus
Patient or population: health problem or population Setting: outpatients with short‐term hospitalisation during dialyses Intervention: GABA‐analogues Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with GABA‐analogues
Pruritus assessed with: VAS [cm] Scale from: 0 to 10	The mean pruritus ranged from 0.8 to 2.0 cm lower than pre‐treatment scores	MD 5.1 lower (5.65 lower to 4.55 lower)	‐	297 (5 RCTs)	⊕⊕⊕⊝ Moderatea	Compare analysis 1.1.; risk of placebo: range of pre/post‐difference; lower scores on VAS indicate less severe pruritus.
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not reported	‐	‐	‐	‐	‐
Risk for at least one adverse event per patient	29 per 100	75 per 100 (22 to 100)	RR 2.63 (0.76 to 9.05)	15 (1 RCT)	⊕⊕⊝⊝ Lowb	Gunal 2004, Naini 2007, Naghibi 2007, Nofal 2016 gave no numbers of patients with adverse events and Yue 2015 did not report adverse events for the placebo group; results from Bergasa (2006).1
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426842918272297787.

^a Certainty of evidence was downgraded by one level due to serious imprecision caused by fewer than 400 participants.
^b Certainty of evidence was downgraded by two levels due to very serious imprecision: Very wide 95% CI that crosses 1; fewer than 400 participants.
¹ Bergasa NV, McGee M,Ginsburg IH,Engler D. Gabapentin in patients with the pruritus of cholestasis: a double‐blind, randomized, placebo‐controlled trial. Hepatology; 2006.

Summary of findings 2. Summary of findings table ‐ Gabapentin versus pregabalin for patients with chronic kidney disease (CKD)‐associated pruritus.

Gabapentin versus pregabalin for patients with chronic kidney disease (CKD)‐associated pruritus
Patient or population: patients with chronic kidney disease (CKD) pruritus Setting: outpatients with short‐term hospitalisation during dialyses Intervention: gabapentin Comparison: pregabalin
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with pregabalin	Risk with gabapentin
Pruritus assessed with: VAS [cm] Scale from: 0 to 10	The mean pruritus ranged from 4.4 to 5.3 cm	MD 0.23 cm lower (1.29 lower to 0.83 higher)	‐	100 (2 RCTs)	⊕⊕⊝⊝ Lowa,b	Compare analysis 2.1; risk with pregabalin: post‐treatment scores; lower scores on VAS indicate less severe pruritus.
Quality of life ‐ not reported	‐	‐	‐	‐	‐
Patient satisfaction ‐ not reported	‐	‐	‐	‐	‐
Depression ‐ not reported	‐	‐	‐	‐	‐
Risk for at least one adverse event per patient	28 per 100	100 per 100 (6 to 100)	RR 4.70 (0.21 to 104.14)	122 (2 RCTs)	⊕⊝⊝⊝ Very lowa,c,d	Compare analysis 2.2.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426843454979632057.

^a Certainty of the evidence was downgraded by one level due to serious risk of bias in both studies (lack of blinding, small study size).
^b Certainty of evidence was downgraded by one level due to serious imprecision caused by fewer than 400 participants. 
^c Certainty of the evidence was downgraded by two levels due to very serious inconsistency: Meta‐analysis shows I square of 80% (substantial/considerable heterogeneity) and mean differences vary seriously. 
^d Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a very wide range and crosses 1; fewer than 300 participants.

Summary of findings 3. Summary of findings table ‐ Kappa‐opioid agonists versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus.

Kappa‐opioid agonists versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus
Patient or population: patients with chronic kidney disease (CKD) pruritus Setting: outpatients with short‐term hospitalisation during dialyses Intervention: kappa‐opioid agonists Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with kappa‐opioid agonists
Pruritus assessed with: VAS [cm] Scale from: 0 to 10	The mean pruritus ranged from 1.27 to 2.8 cm lower than pre‐treatment scores	MD 0.96 lower (1.22 lower to 0.71 lower)	‐	1292 (6 RCTs)	⊕⊕⊕⊕ High	Compare analysis 3.1.; risk of placebo: range of pre/post‐difference; Wikström 2005: data from study 1 and period 1 of study 2; lower scores on VAS indicate less severe pruritus.
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not measured	‐	‐	‐	‐	‐
Risk for at least one adverse drug reaction (ADR) per patient	345 per 1000	597 per 1000 (414 to 856)	RR 1.73 (1.20 to 2.48)	1344 (5 RCTs)	⊕⊕⊝⊝ Lowa,b	Compare analysis 3.3. ADR was chosen to enable pooled analysis.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426855302427772535.

^a Certainty of the evidence was downgraded by one level due to serious inconsistency: I square (72%) indicates substantial heterogeneity.
^b Certainty of the evidence was downgraded by one level due to serious imprecision: Wide 95% CI.

Summary of findings 4. Summary of findings table ‐ Ondansetron versus placebo for patients with chronic kidney disease (CKD) and cholestatic (CP)‐associated pruritus.

Ondansetron versus placebo for patients with chronic kidney disease (CKD) and cholestatic (CP)‐associated pruritus
Patient or population: patients with chronic kidney disease (CKD) pruritus Setting: outpatients with short‐term hospitalisation during dialyses Intervention: ondansetron Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with ondansetron
Pruritus assessed with: VAS [cm] Scale from: 0 to 10 follow‐up: range 2 weeks to 12 weeks	The mean pruritus ranged from 4.0 to 5.7 cm	MD 0.06 cm lower (0.71 lower to 0.58 higher)	‐	202 (4 RCTs)	⊕⊕⊝⊝ Lowa,b	Compare analysis 4.2; risk of placebo: range of post‐treatment scores; lower scores on VAS indicate less severe pruritus.
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not measured	‐	‐	‐	‐	‐
Risk for at least one adverse event per patient follow‐up: range 2 weeks to 12 weeks	6 per 100	15 per 100 (2 to 100)	RR 2.54 (0.38 to 16.78)	174 (3 RCTs)	⊕⊝⊝⊝ Very lowc,d	Compare analysis 4.5.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426855888282912419.

^a Certainty of the evidence was downgraded by one level due to serious inconsistency: Meta‐analysis shows I square of 62% (substantial heterogeneity).
^b Certainty of evidence was downgraded by one level due to serious imprecision caused by fewer than 400 participants.
^c Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a very wide range and crosses 1; fewer than 400 participants. 
^d Certainty of the evidence was downgraded by one level due to serious risk of bias: possible adverse events of placebo group not given (Murphy 2003).

Summary of findings 5. Summary of findings table ‐ Montelukast versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus.

Montelukast versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus
Patient or population: patients with chronic kidney disease (CKD) pruritus Setting: outpatients with short‐term hospitalisation during dialyses Intervention: montelukast Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with montelukast
Pruritus assessed with: % reduction Duo Score/VAS	‐	SMD 1.4 SD lower (1.87 lower to 0.92 lower)	‐	87 (2 RCTs)	⊕⊝⊝⊝ Very lowa,b,c	Compare analysis 5.1; risk of placebo: the mean pruritus difference (pre/post) was ‐0.53 (VAS 0‐10 cm, Mahmudpour 2017) and ‐7.1 (% reduction Duo Score: scale ranged from 0 to 45, Nasrollahi 2007); as suggested by Cohen an SMD of 0.2 is small, 0.5 is moderate and 0.8 is large.
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
depression ‐ not measured	‐	‐	‐	‐	‐
Risk for at least one adverse event per participant ‐ not measured	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; SMD: standardised mean difference
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426910471013294726.

^a Certainty of the evidence was downgraded by one level due to serious risk of bias: blinding and small study size.
^b Certainty of the evidence was downgraded by one level due to serious inconsistency: homogeneity was difficult to assess (due to well validated but different itch scoring methods).
^c Certainty of evidence was downgraded by one level due to serious imprecision caused by fewer than 400 participants.

Summary of findings 6. Summary of findings table ‐ Fish‐oil/omega‐3 fatty acids versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus.

Fish‐oil/omega‐3 fatty acids versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus
Patient or population: chronic kidney disease (CKD) pruritus Setting: outpatients with short‐term hospitalisation during dialyses Intervention: fish‐oil/omega‐3 fatty acids Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with fish‐oil/omega‐3 fatty acids
Prurits assessed with: VAS/Duo Scale	‐	SMD 1.6 SD lower (1.97 lower to 1.22 lower)	‐	212 (4 RCTs)	⊕⊕⊝⊝ Lowa,b	Compare analysis 6.1; risk of placebo: the mean pruritus difference (pre/post) was 0.06 (VAS 0‐10 cm, Forouhari 2022), ‐0.43 (VAS 0‐10 cm, Lahiji 2018), ‐2.6 (Duo Score: scale ranged from 0 to 45, Ghanei 2012) and ‐0.63 (5‐D itch scale questionnaire: scale range from 1 to 5, Shayanpour 2019; as suggested by Cohen an SMD of 0.2 is small, 0.5 is moderate and 0.8 is large.
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not measured	‐	‐	‐	‐	‐
Adverse events ‐ not measured	‐	‐	‐	‐	‐
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; SMD: standardised mean difference
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_427082502502358835.

^a Certainty of the evidence was downgraded by one level due to serious risk of bias with high risk of bias caused by lacking random sequence generation in one study (Ghanei 2012) and concerns about differences in baseline‐values in another study (Lahiji 2018).
^b Certainty of evidence was downgraded by one level due to serious imprecision caused by fewer than 400 participants.

Summary of findings 7. Summary of findings table ‐ Zinc sulphate versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus.

Zinc sulphate versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus
Patient or population: patients with chronic kidney disease (CKD) pruritus Setting: inpatients Intervention: zinc sulphate Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with zinc sulphate
Pruritus assessed with: VAS and Duo Scale follow‐up: range 4 weeks to 12 weeks	‐	SMD 0.13 SD lower (0.58 lower to 0.32 higher)	‐	76 (2 RCTs)	⊕⊕⊝⊝ Lowa	Compare analysis 7.1; risk of placebo: the mean pruritus post‐treatment was 10.7 (Duo score 0‐45, Mapar 2015) and 4.25 (VAS 0‐10, Najafabadi 2012); as suggested by Cohen an SMD of 0.2 is small, 0.5 is moderate and 0.8 is large.
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not measured	‐	‐	‐	‐	‐
Risk for at least one adverse event per participant follow‐up: range 4 weeks to 12 weeks	0 per 1000	0 per 1000 (0 to 0)	Not estimable	160 (2 RCTs)	‐	none observed for zinc sulfate; not stated for placebo
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; SMD: standardised mean difference
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426858151320161710.

^a Certainty of the evidence was downgraded by two levels due to very serious imprecision: Wide 95% CI that overlaps the line of no effect; fewer than 400 participants.

Summary of findings 8. Summary of findings table ‐ Cromolyn sodium versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus.

Cromolyn sodium versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus
Patient or population: patients with chronic kidney disease (CKD) pruritus Setting: inpatients Intervention: cromolyn sodium Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with cromolyn sodium
Pruritus assessed with: VAS (values from Feily (2012) multiplied by factor 2 since presented on VAS 0‐5 scale) Scale from: 0 to 10	The mean pruritus ranged from 2.6 to 5.6 cm	MD 3.27 cm lower (5.91 lower to 0.63 lower)	‐	100 (2 RCTs)	⊕⊝⊝⊝ Very lowa,b	Compare analysis 8.1.; risk of placebo: range of post‐treatment scores 5.6 (VAS 0‐10 cm; Vessal 2010:") and 1.3 (VAS 0‐5 cm; Feily 2012).
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not measured	‐	‐	‐	‐	‐
Risk for at least one adverse event per patient	10 per 100	13 per 100 (0 to 100)	RR 1.28 (0.02 to 106.52)	122 (2 RCTs)	⊕⊝⊝⊝ Very lowc,d	Oral administration (Vessal 2010); topical use (Feily 2012).
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426858292673187285.

^a Certainty of the evidence was downgraded by one level due to serious inconsistency: Meta‐analysis shows an I square of 81% (substantial/considerable) heterogeneity). The 95% CIs do not overlap each other mean differences.
^b Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a very wide range; fewer than 400 participants.
^c Certainty of the evidence was downgraded by two levels due to very serious inconsistency: Meta‐analysis shows I square of 84% (substantial/considerable heterogeneity) and mean differences are contrary. 
^d Certainty of the evidence was downgraded by one level due to serious imprecision: The 95% CI has a very wide range and crosses 1; fewer than 400 participants.

Summary of findings 9. Summary of findings table ‐ Topical capsaicin versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus.

Topical capsaicin versus placebo for patients with chronic kidney disease (CKD)‐associated pruritus
Patient or population: patients with chronic kidney disease (CKD) pruritus Setting: outpatients with short‐term hospitalisation during dialyses Intervention: topical capsaicin Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with topical capsaicin
Pruritus assessed with: different scales	‐	SMD 1.06 SD lower (1.55 lower to 0.57 lower)	‐	112 (2 RCTs)	⊕⊕⊝⊝ Lowa	Compare analysis 9.1.; risk with placebo: −0.88 (4‐point scale (1‐4), Cho 1997) and −4.70 (Duo scale (0‐30), Makhlough 2010) ; both favour topical capsaicin; as suggested by Cohen an SMD of 0.2 is small, 0.5 is moderate and 0.8 is large.
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not measured	‐	‐	‐	‐	‐
Risk for at least one adverse event per patient	9 per 100	32 per 100 (10 to 100)	RR 3.69 (1.17 to 11.67)	116 (3 RCTs)	⊕⊕⊝⊝ Lowb	Compare analysis 9.4. Breneman 1992a, Makhlough 2010, Tarng 1996: Mainly skin burning which is, however, a physiological mechanism of capsaicin. Makhlough 2010: only patients with moderate and severe skin burning included in RR calculation.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio; SMD: standardised mean difference
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426856837531502877.

^a Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a wide range and includes large and moderate effects; fewer than 400 participants.
^b Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a very wide range but does not cross 1; fewer than 400 participants.

Summary of findings 10. Summary of findings table ‐ Naltrexone versus placebo for patients with cholestatic pruritus (CP).

Naltrexone versus placebo for patients with cholestatic pruritus (CP)
Patient or population: patients with cholestatic pruritus (CP) Setting: inpatient Intervention: Naltrexone Comparison: Placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with Placebo	Risk with Naltrexone
Pruritus Scale from: 0 to 10	The mean pruritus ranged from 5.18‐5.34 cm	MD 2.49 cm lower (3.9 lower to 0.94 lower)	‐	52 (2 RCTs)	⊕⊕⊝⊝ Lowa,b	Compare analysis 10.1; lower scores on VAS indicate less severe pruritus.
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not measured	‐	‐	‐	‐	‐
Risk for at least one adverse event per patient	30 per 100	80 per 100 (40 to 100)	RR 2.67 (1.32 to 5.39)	40 (1 RCT)	⊕⊕⊝⊝ Lowc	Compare analysis 10.7.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426855648437405319.

^a Certainty of the evidence was downgraded by one level due to serious inconsistency: Meta‐analysis shows I square of 55% (substantial heterogeneity) and mean differences vary seriously. Though, 95% CIs overlap and do not cross 0. 
^b Certainty of evidence was downgraded by one level due to serious imprecision caused by fewer than 400 participants.
^c Certainty of the evidence was downgraded by two levels due to very serious imprecision: Wide 95% CI; fewer than 400 participants.

Summary of findings 11. Summary of findings table ‐ Rifampin/rifampicin versus placebo for patients with cholestatic pruritus (CP).

Rifampin/rifampicin versus placebo for patients with cholestatic pruritus (CP)
Patient or population: patients with cholestatic pruritus (CP) Setting: inpatients Intervention: Rifampin/rifampicin Comparison: Placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with Placebo	Risk with Rifampin/rifampicin
Pruritus assessed with: VAS [mm] Scale from: 0 to 100	The mean pruritus ranged from 54‐68 mm	MD 42 mm lower (87 lower to 3 higher)	‐	42 (2 RCTs)	⊕⊝⊝⊝ Very lowa,b	Compare analysis 11.1.; risk of placebo: range of post‐treatment scores; only 14 participants could be used for analysis because of carryover effects in the cross‐over design of Podesta 1991a; lower scores on VAS indicate less severe pruritus.
Quality of life ‐ not measured	‐	‐	‐	‐	‐
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not measured	‐	‐	‐	‐	‐
Risk for at least one adverse event per patient	17 per 100	5 per 100 (0 to 42)	RR 0.29 (0.03 to 2.51)	39 (1 RCT)	⊕⊝⊝⊝ Very lowc,d	Results from Bachs (1989): rifampin versus phenobarbitone
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426857299413240995.

^a Certainty of the evidence was downgraded by two levels due to very serious inconsistency: Meta‐analysis shows I square of 95% (considerable heterogeneity) and mean differences vary seriously.
^b Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a very wide range; fewer than 400 participants.
^c Certainty of the evidence was downgraded by one level due to serious risk of bias: Random sequence generation and allocation concealment unclear; no blinding.
^d Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a very wide range and crosses 1; fewer than 400 participants.

Summary of findings 12. Summary of findings table ‐ Flumecinol versus placebo for patients with cholestatic pruritus (CP).

Flumecinol versus placebo for patients with cholestatic pruritus (CP)
Patient or population: patients with cholestatic pruritus (CP) Setting: outpatient Intervention: Flumecinol Comparison: Placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with Placebo	Risk with Flumecinol
Pruritus: significant improvement assessed with: yes/no	31 per 100	73 per 100 (17 to 100)	RR 2.32 (0.54 to 10.10)	69 (2 RCTs)	⊕⊝⊝⊝ Very lowa,b	Compare analysis 12.1.; RR > 1 indicates more improvement in patients treated with flumecinol.
Pruritus assessed with: VAS (mm) Scale from: 0 to 100		median 8 lower (2.1 higher to 20.8 lower)	‐	50 (1 RCT)	⊕⊕⊝⊝ Lowc	Lower scores on VAS indicate less severe pruritus; results from Turner 1994a; Turner 1994b (n = 19): placebo: median: 47 mm, median difference: 19.8 mm, 95% CI 3.3 to 40.7 mm.
Quality of life assessed with: VAS (mm) Scale from: 0 to 100		median 5 lower (0.4 lower to 13 lower)	‐	50 (1 RCT)	⊕⊕⊝⊝ Lowd	VAS: 0 = able to cope with normal activities, to 100 = completely incapacitated;Results from Turner 1994a; Turner 1994b (n = 19): placebo: median: 44 mm, median difference: 3.5 mm, 95% CI −5.9 to 24.9 mm
Patient satisfaction ‐ not measured	‐	‐	‐	‐	‐
Depression ‐ not measured	‐	‐	‐	‐	‐
Risk for at least one adverse event per patient ‐ not measured	‐	‐	‐	‐	‐	No adverse events attributable to the trial medication" (Turner 1994a; Turner 1994b); no other adverse events stated or documented.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_426857509914873186.

^a Certainty of the evidence was downgraded by one level due to serious inconsistency: The meta‐analysis shows an I square of 59% (moderate/substantial heterogeneity).
^b Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a wide range and covers a large as well as a very small effect; fewer than 300 participants.
^c Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a wide range and crosses zero; fewer than 400 participants.
^d Certainty of the evidence was downgraded by two levels due to very serious imprecision: The 95% CI has a wide range and covers a large as well as a very small effect; fewer than 400 participants.

Background

This is the second update of the original Cochrane review published in 2013 (Xander 2013), which was updated 2016 (Siemens 2016), on “pharmacological interventions for pruritus in adult palliative care patients”. Pruritus, derived from the Latin word prurire, which means 'to itch', is defined as “an unpleasant sensation associated with the desire to scratch”. This definition of pruritus was introduced in 1660 by the German physician Samuel Hafenreffer (Haffenreffer 1660; Misery 2010; Proske 2010). In modern medicine, the term pruritus is generally used to refer to a pathological condition in which the sensations of itch are intense and often generalised and trigger repeated scratching in an attempt to relieve the discomfort. Pruritus is not a disease, but rather a common and still poorly understood symptom of both localised and systemic disorders that may accompany many conditions (Bernhard 2005; Summey 2009; Zylicz 2004). Pruritus is a prevalent symptom in many skin conditions. However, much less is known about pruritus that is not associated with primary skin disease. This latter problem is of major relevance to many medical specialities, and notably to palliative care. Pruritus or itch is not the most prevalent but a burdening symptom in advanced incurable diseases, and it can cause considerable discomfort in patients receiving treatment for cancer or other non‐malignant terminal illnesses. In addition to social embarrassment, the vicious cycle of itch‐scratch‐itch damages skin integrity, decreases resistance to infections, and impairs quality of life similarly to pain.

Prevalence of pruritus

Pruritus and malignant diseases

Pruritus may be associated with virtually any malignancy (Chiang 2011). Some neoplasms, particularly haematologic malignancies, are frequently related to pruritus. Amongst patients with polycythaemia vera, 48% to 70% have aquagenic pruritus. About 30% of people with Hodgkin's disease also suffer from pruritus (Krajnik 2001b). The incidence and significance of pruritus in other lymphomas and leukaemia are unknown, but investigators have reported its presence in approximately 3% of patients with non‐Hodgkin's lymphoma (Lober 1988). Solid tumours can be associated with paraneoplastic pruritus, which in fact might be a presenting symptom that precedes the diagnosis by months or years. The pathophysiology is not well understood, but it appears to involve an immunologic reaction to tumour‐specific antigens (Seccareccia 2011). Pruritus is also frequent in cutaneous lymphomas (Ahern 2012). Additionally, it is a common symptom in malignancies of the biliary tract. Retrospective studies have revealed that malignant diseases are present in 2% to 11% of chronic itch cases (Weisshaar 2009).

Pruritus and non‐malignant internal diseases

Many internal diseases other than cancer may be associated with pruritus. Pruritus has been reported to herald the onset of thyroid disease, renal insufficiency, liver disease, iron deficiency, diabetes mellitus, paraproteinaemia, Sjögren's syndrome, and other conditions. In internal diseases, itch has been best studied in chronic kidney disease associated pruritus (CKD‐aP), also called uraemic pruritus (UP), and cholestatic pruritus (CP) (Metz 2010; Wang 2010; Weisshaar 2009). About one third of uraemic patients treated without dialysis exhibit UP, and on maintenance haemodialysis, the incidence of uraemic itching is even higher. Although the prevalence of UP could be decreased over the past decades, possibly due to improved dialysis modalities, moderate to severe pruritus is experienced by up to 42% of haemodialysis patients (Bencini 1985; Pisoni 2006). In one of the largest trials conducted in patients suffering from UP, moderate to severe pruritus was associated with a markedly increased likelihood of fatigue, poor sleep quality, and depression (Pisoni 2006). 61% of the patients with UP reported having difficulties falling asleep and 44% were awakened frequently or occasionally by pruritus (Zucker 2003). Therefore, pruritus has been declared a research priority by patients (Manns 2014).

CP affects 100% of patients with biliary cirrhosis and is the initial symptom in almost half of the patients with this disease (Bergasa 2008). Furthermore, the prevalence of pruritus in patients with end‐stage HIV is over 20% (Smith 1997b; Uthayakumar 1997).

Pruritus in palliative care in general

In advanced diseases, as seen in palliative care units, the prevalence of severe pruritus is not too high, but pruritus is a distressing symptom for palliative care patients and may be difficult to manage. A specific problem in palliative medicine involves systemic pruritus in terminal illnesses because pruritus is often a result of changing organ functions in this phase of illness (Twycross 2001; Twycross 2004). In this case, the itch is multifactorial, associated with both liver and kidney function deterioration and increased anxiety (Yosipovitch 2003). Additionally, in the field of palliative care, pruritus is a well‐known adverse effect of opioid administration. Even though the incidence is low (approximately 1% after systemic administration), pruritus as an adverse effect must be kept in mind (Krajnik 2001a).

Challenges in study design

Pruritus measurement is problematic because of its subjective nature and poor localisation. In addition, itch has multidimensional aspects (for example severity, duration, frequency, spatial distribution, and quality). Although several authors have suggested that VAS is subjective and represents an inadequate and unreliable method of assessing pruritus (Jones 1999), more sophisticated and objective methods pose several practical difficulties since the main goal of pruritus treatment is to improve patients' well‐being and quality of life. It is only possible to measure these aspects subjectively, as pruritus is primarily based on the subjective perception of the patient. Therefore, in the assessment of itching, we rely on the subjective evaluation of the symptom by the patient themselves and must assume that the participants are able to accurately describe their experiences.

Description of the condition

In the field of palliative care, pruritus is a symptom occurring in patients with disparate underlying diseases and is caused by different pathologic mechanisms. The pathogenesis of pruritus is complex and not fully elucidated, but it is known that central and peripheral nerves and specific brain regions are involved (Langner 2009). For a long time, itch was regarded as a variant of pain; however, the neural transmission associated with pruritus follows distinct neuronal pathways and causes unique sensations (Ikoma 2006; Schmelz 1997). The pathogenesis of itch is diverse and involves a complex network of cutaneous and neuronal cells. Mediators of pruritus presumably act on nerve fibres or lead to a cascade of mediator release, resulting in nerve stimulation and the sensation of pruritus. The group of potential chemical mediators is large and is steadily increasing. It contains amines (e.g. histamine, serotonin), proteases (e.g. tryptases), neuropeptides (e.g. substance P (SP), calcitonin gene‐related peptide (CGRP), bradykinin), opioids (e.g. morphine, beta‐, met‐, leu‐enkephalin), eicosanoids, growth factors and cytokines (Weisshaar 2003). The identification of different itch‐specific mediators and receptors, such as interleukin‐31, gastrin‐releasing peptide receptor or histamine H₄ receptor, is increasing, and the characterisation of itch‐specific neurons is taking shape. The physiological basis of pruritus includes multiple mechanisms that are quite variable. Pruritus is initiated by the stimulation of unmyelinated C‐fibres in the dermal‐epidermal junction (Krajnik 2001a; Steinhoff 2006). Mediators of pruritus include histamine through H₁receptors and serotonin through 5‐HT₂ and 5‐HT₃ receptors (Jones 1999; Krajnik 2001a; Yamaguchi 1999). The actual sensation may depend on special temporal patterns of neural excitation and location of receptors (Seiz 1999). The perception of pruritus leads to a motor response to scratch, which stimulates myelinated A‐delta sensory fibres and temporarily blocks the sensation.

Description of the intervention

Due to the complex physiology of pruritus, many of the underlying mechanisms are still poorly understood (Krajnik 2001b). Modulations by serotonergic and enkephalinergic systems take place on all levels of the 'pruritus tract'. Additionally, opioid receptors seem to be of particular importance, which is not surprising considering the involvement of almost identical mediators for pain and itch (Moore 2019). This implies that various completely different pathologic mechanisms may form the basis of pruritus, making it difficult to find an effective medication for managing the symptom. Until now, no universally valid therapeutic concept has been developed. For the treatment of pruritus, researchers have tested the efficacy of several substance classes. Amongst these, our review includes trials on antiphlogistic substances, psychotropic drugs, antagonistic drugs, anaesthetics, adsorbent substances and topical treatments.

How the intervention might work

For this update, we identified 87 trials studying 50 drugs from different classes. Below we have listed drug classes and individual pharmacological interventions included in this review.

• GABA‐analogues are used to prevent or reduce the severity and frequency of seizures (Duley 2010; Ratilal 2013; Wiffen 2014). Gabapentin and pregabalin, which are H₁acid analogues, were originally developed as antiepileptics and may hinder the transmission of nociceptive sensations to the brain, thereby also suppressing pruritus.

• Serotonergic drugs: Pruritus sensations may arise from the superficial layers of the skin, which contain clustered nerve endings at 'itch points' close to the dermoepidermal junction, as well as the mucous membranes and conjunctiva (Krajnik 2001a; Yosipovitch 2003). These receptors may be acted upon directly by physical or chemical stimuli, or indirectly via histamine release. Itch impulses are transmitted through the C‐fibres of polymodal nociceptors to the dorsal root ganglia, where a synapse occurs with secondary neurons. Efferents traverse to the contralateral spinothalamic tract and pass to the posterolateral spinothalamic tract, the posterolateral ventral thalamic nucleus, and then to the somatosensory cortex of the postcentral gyrus (Mela 2003). One important neurotransmitter in these pathways is 5‐hydroxytryptamine (5‐HT; serotonin) (O'Donohue 2005). Ondansetron is one of a group of drugs that act as antagonists at 5‐HT₃ serotonin subtype receptors. Properties of drugs within this group differ with respect to the selectivity of receptor binding, potency, duration of action and dose‐response relationships.

• Leukotriene antagonists prevent the inflammatory response produced by leukotrienes (Watts 2012).

• Omega‐3 fatty acids/ fish oil tends to support the immune system and reduces inflammation, free radicals and leukotriene B‐4. Hence, omega‐3 fatty acids may be effective in UP (Ghanei 2012).

• Zinc sulphate: Pruritus patients with UP may benefit from zinc sulphate, as it is an antagonist of calcium (releases histamine) and prevents degranulation of mast cells (Mapar 2015; Najafabadi 2012).

• Topical capsaicin is the prototype of topical antipruritic agents that target the transient receptor potential (TRP) gene family of ion channels, which respond to physical activation (heat, cold), protons (pH changes) or biological mediators (for example prostanoids) and counteract itch via activating pain neurons (Derry 2012; Derry 2017; Steinhoff 2011). Capsaicin (trans‐8‐methyl‐N‐vanillyl‐6‐nonenamide) is an alkaloid naturally found in many botanical species of the nightshade plant family (Solanaceae).

• Opioid receptor antagonists and (partial) agonists were originally developed for the treatment of heroin addiction and for symptom reversal of postanaesthetic depression, narcotic overdose, and opioid intoxication (Gowing 2010; Rösner 2010). Clinical and experimental observations have demonstrated that endogenous or exogenous opioids can evoke or intensify pruritus (Metze 1999a; Metze 1999b). This phenomenon can be explained by the activation of spinal opioid receptors, mainly μ‐opioid receptors on pain‐transmitting neurons, which often induce analgesia in combination with pruritus. Thus, reversing this effect through μ‐opioid antagonists inhibits pruritus (Ständer 2008).

• Rifampicin, or rifampin in the USA, is an antibiotic that induces detoxicating hepatic enzymes and competitively inhibits the reuptake of bile acids by hepatocytic transporters (Trauner 2005). Some hypothesise that rifampicin might influence pruritus by changing the bacterial growth in the intestines, which can influence the reabsorption of pruritogens.

• Flumecinol: There are reports that flumecinol (3‐trifluoromethyl‐alpha‐ethylbenzhydrol), a benzhydryl derivative, induces microsomal drug metabolising enzymes (Turner 1990). Flumecinol also lowers serum bilirubin in Gilbert's syndrome, possibly by inducing bilirubin undine diphosphate (UDP)‐glucuronyl transferase. Therefore, it may induce a range of enzymes, similar to phenobarbitone and rifampicin.

• Histaminergic drugs: Of the mediators that trigger pruritus, histamine is the best known and most thoroughly researched. Preformed histamine is present in large amounts in mast cell granules. For this reason, after cell activation, it can be immediately released into the surrounding area, where it may induce pruritus via H₁ receptors on nerve fibres. Antihistamines act via prevention of the histamine fixation on the surface of the histamine receptors (Gaudy‐Marqueste 2010; Ständer 2008). Some antihistamines mentioned in this review are hydroxyzine and ketotifen.

• Serotonin reuptake inhibitors and antidepressants (SSRIs) like sertraline and paroxetine play an increasingly important role in the management of pruritus (Balaskas 1998; Larijani 1996; Raap 2012; Schworer 1995; Tandon 2007; Tennyson 2001; Wilde 1996; Ye 2001; Zylicz 1998). Experts believe that they raise the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell and increasing the level of serotonin in the synaptic cleft that is available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the noradrenaline and dopamine transporters.

• Immunosuppressants (e.g. tacrolimus, pimecrolimus) are used for the prevention of transplant rejection. They suppress the differentiation of Th1 lymphocytes and the ensuing IL‐2 production (Suthanthiran 1994; Webster 2005).

• Thalidomide is a drug that modifies or regulates the immune system and has anti‐inflammatory properties. It is used as an immunomodulator to treat graft versus host reactions. It suppresses tumour necrosis factor alpha (TNF‐α) production and leads to a predominant differentiation of Th2 lymphocytes with suppression of interleukin‐2 (IL‐2) producing Th1 cells (McHugh 1995; Mettang 2010). The antipruritic action of this drug may be secondary to inhibition of TNF‐α. Another possibility is that thalidomide can act as both a peripheral and a central nerve depressant (Moretti 2010).

• Erythropoietin is a hormone produced naturally by the kidneys that stimulates the production of red blood cells in the bone marrow. Studies have hypothesised that erythropoietin may have an antipruritic effect related to a lowering effect of the hormone on plasma histamine concentrations (Bohlius 2009).

• Ergocalciferol: Patients under haemodialysis often experience pruritus and may have an impaired metabolism of vitamin D. It is supposed that the administration of ergocalciferol (vitamin D₂) may have an antipruritic effect (Shirazian 2013).

• Nicotinamide (which is the amid of nicotinic acid, i.e. vitamin B₃/niacin) may have an antipruritic effect, mediated by its anti‐inflammatory and histamine‐release blocking characteristics (Omidian 2013).

• Activated charcoal is an agent that can bind many poisons in the stomach and therefore prevent them from being absorbed. Charcoal has also been shown to be effective in UP (Giovanetti 1995; Yatzidis 1972).

• Bile acid sequestrant cholestyramine is an intestinally active anion exchange resin. It interrupts the enterohepatic circulation of bile acids and has been used for many years to relieve pruritus in cholestatic disorders (Datta 1966; Sharp 1967). Another bile acid sequestrant also used for the treatment of pruritus is colesevelam.

• Cromolyn sodium is a drug that blocks mast cell degranulation in response to antigens, leading to decreased release of histamine, leukotrienes and other inflammatory mast cell products. It is hypothesised that mediators released from mast cells are most likely to be responsible for UP. Another hypothesis is that cromolyn sodium may decrease the severity of pruritus via reducing serum tryptase levels. Both oral and topical administration is possible.

• Local anaesthetics (lidocaine and pramoxine hydrochloride) are a local anaesthetic. They stabilise the neuronal membrane by an uncertain mechanism (Elmariah 2011; Hedayati 2005).

• Maralixibat chloride (formerly LUM001 or lopixibat) is a potent, apical, sodium‐dependent, bile acid transporter competitive inhibitor with minimal systemic absorption which may reduce CP (Mayo 2019).

• Nicergoline is an ergoline related to ergot alkaloids, being a dopamine‐receptor agonist and a partial α‐adrenergic blocker. The mechanism by which it may affect pruritus is unclear (Winblad 2008).

• Sodium thiosulfate is one of the cornerstones of calciphylaxis therapy and may reduce pruritus by acting as an antioxidant and inducing endothelial nitric oxide synthesis, which improves blood flow and tissue oxygenation (Kuypers 2009).

• Other treatments: Photodynamic therapy, transcutaneous electrical nerve stimulation (TENS), and other non‐pharmaceutical therapies for pruritus are assessed in a separate systematic review (Hercz 2020).

Summary of interventions

In conclusion, pruritus is a frequent and distressing symptom. The medical literature is full of recommendations for its management, but it contains only a few clinical trials and evidence‐based data. There are some reviews about pruritus in general (Winkelmann 1964; Winkelmann 1982; Yosipovitch 2013), dermatologic causes of pruritus (Fransway 1988), pruritus in systemic diseases (Kantor 1983; Summey 2005), and pruritus related to specific causes like cholestasis or uraemia (Khandelwal 1994; Szepietowski 2004). There is also some literature on the management of pruritus in palliative care patients (Krajnik 2001b). There have also been two systematic reviews that assessed the effectiveness of different medical interventions on pruritus in the field of palliative care (Siemens 2014; Xander 2013).

Why it is important to do this review

Pruritus or itch is one of the most puzzling symptoms in advanced incurable diseases and can cause considerable discomfort in patients. As already explained, pruritus is multifactorial in origin and can be a symptom of diverse pathophysiologies. Particularly over the last decade, clinical observation and controlled trials have done much to aid the understanding and treatment of pruritus, especially in liver disease, uraemia and other kinds of chronic pruritus. Therefore, this review aimed to systematically collect and evaluate the evidence for adequate treatment of pruritus in the field of palliative care, to put this symptom into perspective, and to make new therapeutic strategies accessible for clinicians and patients (Wee 2008).

Objectives

To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients.

Methods

Criteria for considering studies for this review

Types of studies

We considered full reports concerning pruritus in patients with advanced diseases with a focus on pharmacological treatment. The primary outcome of the studies had to be subjective measures of pruritus. We only included randomised controlled trials (RCTs) in adults which are the best design to minimise bias when evaluating the efficacy of an intervention. We defined 'randomised' as studies described as such by the authors anywhere in the manuscripts. Both published and unpublished studies were eligible for inclusion.

Contrary to our initial considerations in the protocol, we did not include controlled clinical trials (CCTs) (Differences between protocol and review).

Types of participants

Previous reviews have cited problems defining the population for systematic reviews in palliative care. Therefore, we drew upon the definition that other Cochrane reviews have used, “adult patients in any setting, receiving palliative care or suffering an incurable progressive medical condition“ (Storrar 2014; Murray‐Brown 2015). Studies eligible for this review included participants:

• suffering from pruritus combined with an incurable advanced malignant or non‐malignant disease such as advanced cancer, HIV/AIDS, renal failure, liver failure or others;

• aged 18 years or older; and

• of both sexes.

Since many of the studies we considered also included participants who were not necessarily in advanced stages of their disease and were not palliative care patients, we decided to define comprehensible criteria for the patients included in this systematic review. Concretely, we included all patients who were described as palliative care patients or as patients in advanced stages of malignant or non‐malignant diseases.

If no detailed information on the stages of the underlying disease was available, we considered the following patients to have palliative care needs.

• UP (also known as chronic kidney disease (CKD)‐associated pruritus, renal pruritus or end‐stage renal disease (ESRD) pruritus) in need of haemodialysis.

• CP or hepatogenic pruritus: all patients suffering from primary biliary cholestasis or primary sclerosing cholestasis and all patients who were described as being in an advanced stage of the disease. If patients with different kinds of CP were included in the studies, only studies that included more than 75% of patients with primary biliary cholestasis, primary sclerosing cholangitis or advanced‐stage disease were eligible for the systematic review.

• HIV‐associated pruritus: all patients with pruritus associated with HIV.

• Pruritus associated with malignancies: all patients in advanced stages of cancer (with metastases or described as in an advanced stage of the disease).

We excluded studies in people with pruritus related to acute or chronic cholestasis, acute or chronic dermatological diseases, or acute medical or surgical interventions. Furthermore, we did not include participants with primarily dermatological diseases or infections.

Types of interventions

We included studies using any pharmacological medication compared to placebo or another active control intervention to treat pruritus, regardless of dosage, route of administration or duration of follow‐up. Interventions with both internal and external application of the treatment were eligible for inclusion in the review. We did not focus on pharmacological interventions targeting the treatment of underlying diseases but rather on pharmacological interventions for treating pruritus as an accompanying symptom of advanced diseases.

We excluded complementary and alternative medical interventions (CAMs) and non‐pharmaceutical treatments such as photodynamic therapy or TENS, but a separate review evaluates these interventions (Hercz 2020). The definition of complementary medicine adopted by the Cochrane Collaboration is as follows: "CAM is a broad domain of healing resources that encompasses all health systems, modalities, and practices and their accompanying theories and beliefs, other than those intrinsic to the politically dominant health system of a particular society or culture in a given historical period. CAM includes all such practices and ideas self‐defined by their users as preventing or treating illness or promoting health and well‐being. Boundaries within CAM and between the CAM domain and that of the dominant system are not always sharp or fixed (Zollman 1999)".

Types of outcome measures

Given the heterogeneity of included trials, in Effects of interventions, we organised the reporting of primary and secondary outcomes according to types of participants and pharmacological interventions.

Primary outcomes

Primary outcomes were subjective measurements of pruritus.

• Scores on validated and reliable scales, such as unidimensional scales (e.g. visual analogue scales (VAS), numeric rating scales (NRS), categorical scales).

• Patient‐reported pruritus according to non‐validated pruritus scores (e.g. 1‐3 or 1‐4), which were substituted by estimations by nursing or medical staff if self‐assessment was not possible.

Studies commonly employ categorical research scales that consist of discrete divisions of the frequency or intensity of pruritus (e.g. none, mild, moderate, severe). Moreover, the Duo scale is used by some researchers (Duo 1987; Mettang 2002), which is a sum score covering areas like pruritus severity, distribution, frequency and sleep disturbance. The instrument is used in different ways resulting in ranges from 0‐36 to 0‐48.

Continuous scales like the VAS or NRS consist of a line with a specific length (e.g. 100 mm or 10 cm) with descriptive anchors at the extremes, for example, 'no pruritus' and 'pruritus as bad as it can be imagined'. Since the VAS is validated (Reich 2012), simple, accurate, and supposedly the most sensitive approach to measuring pruritus intensity, it is probably the most commonly used scale in pruritus research (Wallengren 2010; Weisshaar 2003).

Another approach to measure pruritus is scratching behaviour measurement. In contrast to patient‐reported measures of pruritus, it is possible to objectively quantify scratching activity by report of scratching behaviour, for example, with hand‐activated counters to record scratching (Melin 1986). This method is not suitable for recording nocturnal scratching, but other methods are, for example, nocturnal bed movement measured by a vibration transducer on one of the legs of the bed, and limb or forearm activity measured by movement‐sensitive meters. Researchers can also observe nocturnal scratching by infrared videotaping or by direct observation during the night.

One instrument for recording daily and nocturnal scratching is the “pruritometer”, which processes the signals of a piezoelectric vibration sensor fixed on the middle finger of the patient's dominant hand and sent to a counter worn by the patient like a wristwatch (Wallengren 2010).

Scores and measurement of scratching may also be determined through questionnaires asking for more information regarding the pruritus, for example, the 'Worcester Itch Index' or the 'Eppendorf Itch Questionnaire' (Weisshaar 2003).

In this systematic review, investigators evaluated treatment effect by estimations of nursing or medical staff if self‐assessment was not possible.

Since no gold standard concerning treatment or improvement of pruritus exists, we considered a reduction of pruritus symptoms by 30% as moderate and a reduction by 50% as substantial, assuming that there were no other specifications given in the studies. This is consistent with the IMMPACT recommendations introduced by Turk 2008.

The different measurement tools of the included studies are listed in additional tables (Table 13; Table 14; Table 15; Table 16).

1. Measurement of pruritus (1).

Study	Pruritus scale	Determination of score	Description of scale		Description of partial resolution
Amirkhanlou 2016	Clinical response	Number and percentage post treatment	1	Complete response (no itching or minimal itching after treatment)	See description of scale
			2	Partial response (mild or moderate severity of itching after treatment)
			3	No response (severe pruritus after treatment)
Aquino 2020	0‐10 cm VAS	Mean change in pruritus scores from baseline to week 2	0	No pruritus	Not available
			10	Worst possible itch
Ashmore 2000	0‐10 cm VAS	Median daily pruritus score and interquartile range for each period	0	No pruritus	Score reduction of 40% to 50% was chosen as desired improvement.
			10	Maximum pruritus
Ataei 2019	0‐10 VAS	Mean pruritus score at baseline and after 4 weeks	0	No pruritus	No significant difference in pruritus control between both drugs; but sertraline was safer than rifampin regarding hepatobiliary enzyme levels
			10	Maximum pruritus
Aubia 1980	Scored questionnaire made for this study	Custom itch: intensity, duration, localisation	0	not reported (n.r.)	n.r.
			8	n.r.
Bachs 1989	0‐3 score	Mean and standard deviation for pruritus 7 days before, and daily during treatment	0	No itching	Not available
			1	Mild intermittent pruritus which did not affect the patient's routine or disturb sleep pattern
			2	Moderate pruritus present most of the time but tolerable and not interfering with sleep pattern
			3	Continuous pruritus disturbing sleep pattern
Begum 2004	Duo score	n.r.	n.r.	n.r.	“The percent decrease in total pruritus score was greater for the FO group compared with the SO group.”
Bergasa 2006	0‐10 cm VAS	Mean difference of VAS: “Mean differences in measurements were determined by subtracting each on‐treatment value from each pretreatment value for each subject and calculating the mean of all the differences.”	—	Not stated	Not available
Bhaduri 2006	VAS	n.r.	n.r.	n.r.	Cumulated decrease in VAS
Borgeat 1993	0‐10 verbal rating score	Evaluation 10 minutes after administration and then every 10 minutes during the first hour	0	No pruritus	Decrease of at least 4 points
			10	Most severe pruritus imaginable
Breneman 1992a	4‐point scale	Follow‐up evaluations at weeks 1, 2, 3, 4 and 6	1	No itching	Not available
			2	Mild itching, occasionally noticeable
			3	Moderate itching, not interfering with daily life and/or sleep
			4	Severe itching, disturbing daily life and/or sleep
Cho 1997	4‐point scale	Mean values and standard error of the mean	1	None	Not available
			2	Mild
			3	Moderate
			4	Severe
Chourdakis 2019	5‐D Itch scale	Quantification of duration, degree, direction, disability and direction of itch at screening and after one month	5	No pruritus	“Bilastine prescription effectively decreased uraemic pruritus symptoms [...]”
			25	Most severe pruritus
De Marchi 1992	Scoring system proposed by Duo and modified by Mettang (Duo 1987; Mettang 1990)	Daily mean values and standard error	Scoring of severity:		Not available
			1	Pruritus without the need to scratch
			2	Pruritus with the need to scratch but without excoriations
			3	Pruritus that was unrelieved by scratching
			4	Pruritus accompanied by excoriations
			5	Total restlessness
			Scoring of distribution:
			1	Pruritus at a single location
			2	Scattered pruritus
			3	Generalised pruritus
			Scoring of frequency: each four short episodes (< 10 min) or one long episode (> 10 min) received 1 point, max. 5 points
			Scoring sleep disturbance: each episode of awaking due to pruritus received 2 points, max. 14 points
			The highest possible score for a 24‐hour period: 40 (with 35% of the points attributed to the night‐time period); total range: 0‐26
Duncan 1984	0‐3 score	Mean cumulative pruritus score (over 10 days)	0	No pruritus	Not available
			1	Mild
			2	Moderate
			3	Severe
Duque 2005	0‐10 cm VAS	Mean pruritus score; VAS was measured every visit for the intensity of itch in the last 24 hours	0	No itch	Not available
			10	Very strong itch
Feily 2012	0‐5 VAS	Mean weekly score	0	No pruritus	Not available
			5	The worst pruritus
Fishbane 2020a	Worst Itching Intensity NRS	Weekly mean score of daily 24‐hr WI‐NRS (over 7 days) More than 4 points on the scale = moderate‐to‐severe pruritus	0	n.r.	Decrease of at least 3 points in the WI‐NRS score in the difelikefalin group Significant reduction in itch intensity and improved itch‐related QoL
			10	Worst itch intensity
	5‐D‐Itch scale & Skindex‐10	Itch‐related QoL measures At baseline and at week 12	n.r.	n.r.
Fishbane 2020b	Worst Itching Intensity NRS (0‐10)	Weekly mean score of daily 24‐hr WI‐NRS (change from the week before randomisation (baseline) at week 8)	< 4	Mild	“[...] Difelikefalin effectively reduced itching intensity and improved sleep and itch‐related QoL.”
			≥ 4 ‐ 7	Moderate
			≤ 7	Severe
	Skindex‐10	Change from baseline at week 8 Itch‐related QoL	n.r.	n.r.
	Other	Change from baseline at week 8 Safety, sleep quality, and additional measures including the 5‐D Itch scale	n.r.	n.r.
Forouhari 2022	0‐100 mm VAS	Change from baseline to week 4	0	No pruritus	not available
			10	Maximum intensity of pruritus
Fouroutan  2017	0‐10 VAS	Measured the itch severity at baseline and after 1 week, 2 weeks, and 4 weeks of the treatment	0	No itch	“Pregabalin was more effective than doxepin in reducing the severity of UP and improving the QoL [...]”
			0.1‐3.9	Mild
			4‐6.9	Moderate
			7‐8.9	Severe
			9‐10	Very severe itch
	5‐D Itch scale	Evaluated duration, degree, direction, and distribution of itch and the impact of itch on the sleep and daily activities	5	No pruritus
			25	Most severe pruritus
	DLQI	Assessed the impact of the disease (pruritus) on the quality of life questionnaire with a total score	0	"No effect at all on the quality of life of patient"
			30	"Extremely large effect on the quality of life of patient"
Ghanei 2012	Detailed pruritus score introduced by Duo (Duo 1987)	Mean scores, 95% confidence interval	Scoring of severity:		Not available
			1	Itching sensation without necessity of scratching
			2	Itching that necessitates scratching, but without excoriations
			3	Itching that necessitates frequent scratching
			4	Itching that necessitates scratching accompanied by excoriation
			5	Pruritus causing total restlessness
			Scoring of distribution:
			1	Pruritus in 2 areas of the body or less
			2	Pruritus in more than 2 areas of the body
			3	Generalised pruritus
			Scoring sleep disturbance:
			Every waking up due to pruritus received 2 points (max. 10 points) and every scratching due to pruritus received 1 point (max. 5 points); total range: 0‐45
Ghent 1988	0‐100 VAS	Summed 7‐day pruritus score on mean VAS	0	None	Preference of rifampicin
			100	Severe
Gholyaf 2020	0‐10 VAS	Mean change in VAS score Responder rate (= percentage of patients with VAS score < 4 at the end of each treatment period)	0	Absence of pruritus	Mirtazapine can be an effective therapy for UP Further studies necessary
			10	Greatest severity of pruritus

DLQI: dermatology life quality index
FO: fish oil
n.r. not reported
NRS: numeric rating scale
QoL: quality of life
SO: safflower oil
VAS: visual analogue scale
WI: worst itch

2. Measurement of pruritus (2).

Study	Pruritus scale	Determination of Score	Description of scale		Description of partial resolution
Ghorbani 2012	0‐10 VAS	Average pruritus scores at baseline and at week 8 of treatment Measurement of VAS at each visit (9 x/8 weeks)	0	No pruritus	The average score of pruritus gradually decreased (significant) but no significant difference between treatment and placebo
			10	Worst pruritus
Ghorbani Birgani 2011	0‐10 VAS	Average pruritus scores at baseline and at week 8 of treatment Measurement of VAS at each visit (9 x/8 weeks)	0	No pruritus	Cromolyn sodium gel 4% is an effective drug compared to pimecrolimus cream 1% in reduction of pruritus
			10	Worst pruritus
Gobo‐Oliveira 2018	0‐10 VAS	Evaluation at baseline and at day 15 after treatment	0	No itch	37% reduction in median VAS 50% reduction in DLQI score
			10	Worst itch
	DLQI		n.r.
Gunal 2004	0‐10 cm VAS	Mean and standard deviation; measurement once a day for each period	0	No itch	Not available
			10	Worst possible imaginable itch
Kebar 2020	VAS	Measured pruritus intensity before and after the first and second period			Improvement and control of pruritus; no significant difference between both drugs
	Pruritus Scale checklist	Measured the severity and frequency of pruritus at baseline and after the intervention (at 6 weeks), and before and after the washout period
Kuiper 2010	0‐10 cm VAS	Morning and evening VAS; proportion of responders	0	No pruritus	40% reduction in pruritus visual analogue scale
			10	Severe pruritus
Kumada 2017	VAS	Both measured the severity of pruritus twice daily, during the pretreatment period, in weeks 1‐4, 8, and 12 of the study treatment, and in week 2 of the post‐observation period	n.r.		“[...] VAS and pruritus scores are significantly correlated with each other and are useful for assessing itch.”
	Pruritus Scale (5‐point scale)		0	Little or no itch
			4	Intolerable itch
Kumagai 2010	0‐100 mm VAS	Mean VAS values of previous 12 hours (morning and evening) were calculated for the last 7 days of the pre‐observation period, the first and latter 7 days of the treatment period and the 8‐day post‐observation period; 95% confidence interval	0	No itch	“[A]ssuming an expected difference of 10.0 mm [with a common standard deviation (SD) of 25 mm]”
			100	Strongest possible itch
Lahiji 2018	1‐10 VAS	Assessment of pruritus intensity at baseline, 2‐ and 4‐weeks post‐intervention in each study period	1	No pruritus	Omega‐3 supplementation is an effective treatment; further studies needed
			10	Unbearable pruritus
Legroux‐Crespel 2004	0‐10 cm VAS	Mean VAS scores; pruritus was evaluated on days 0, 7 and 14.	0	Not pruritus or sleep disorders	A marked improvement of pruritus was assessed by a decrease in the VAS score > 3.
			10	Maximum intense of these disorders
Mahmudpour 2017	VAS	Combined score of severity and distribution of pruritus and sleep disturbance Final score (scores were added up) at the start and the end of the study	n.r.		Mean reduction of VAS and DPS scores was greater in montelukast group Significant decrease in the DPS in the montelukast group Montelukast significantly more effective than placebo
	Detailed Pruritus Score (DPS) by Duo		Severity of pruritus:
			1	Mild need for scratching
			2	Need for scratching without excoriation
			4	Need for scratching with excoriation
			5	Frustrating pruritus
			Distribution of pruritus:
			1	Less tan 2 sites
			2	More than 2 sites
			3	Generalised
			Sleep disturbance as a result of pruritus:
			Every waking up due to pruritus received 1 point up to 10 points for each time per night, and every scratching during night with excoriation received 1 point up to 5 points for each time per night
Makhlough 2010	Detailed pruritus score introduced by Duo (Duo 1987)	Mean scores ± standard deviation; at the beginning of the study and at the end of weeks 1, 2, 3, and 4 of each study period	Scoring of severity:		Not available
			1	Itching sensation without necessity of scratching
			2	Itching that necessitates scratching, but without excoriations
			4	Itching that necessitates scratching accompanied by excoriation
			5	Pruritus causing total restlessness
			Scoring of distribution:
			1	Pruritus in 2 areas of the body or less
			2	Pruritus in more than 2 areas of the body
			3	Generalised pruritus
			Scoring sleep disturbance
			Every waking up due to pruritus received 2 points (max. 10 points) and every scratching due to pruritus received 1 point (max. 5 points); total range: 0‐30
Mapar 2015	Modified Duo Score (0‐45)	Mean scores ± standard deviation; baseline, week 1, 2, 3, and 4	0‐45	Higher scores indicating more severe symptoms; (calculation of the final score is based on severity, distribution and sleep disturbance of pruritus)	Discontinuation of pruritus: zinc sulphate: 4 (20%); placebo: 1 (5%)
Marin 2013	VAS	Assessed the severity of pruritus	n.r.	n.r.	Reduction of pruritus of 50%
	5‐D Itch Scale	Assessed other features of pruritus	n.r.	n.r.	Reduction of 2 points on the scale
					Gabapentin better than loratadine
Mathur 2017	0‐10 NRS	Measured change from baseline to treatment weeks 7 and 8 in itching intensity: worst daytime itching & worst night‐time itching	0	No itching	Nalbuphine 120 mg durably and significantly reduced the itching intensity.
			10	Worst possible itching
Mayo 2007	0‐10 cm VAS	Daily VAS scores were averaged	0	No pruritus	Clinically significant improvement defined as a 20% reduction in pruritus from baseline
			10	Worst pruritus imaginable
Mayo 2019	Adult Itch Reported Outcome (ItchRO)	Average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination Measurement 2 x/d (morning & evening)	0	No itching	Mean ItchRO weekly sum scores decreased from baseline to week 13 in both groups (maralixibat and placebo) Difference between groups was not significant.
			10	Very severe itching
Mirnezami 2013	10‐cm VAS	Change in VAS scores after treatment	n.r.	n.r.	n.r.
Mohamed 2012	DLQI	Measured QoL regarding pruritus at baseline, 2 weeks, 1 month, 2 months, 4 months and 6 months	The DLQI consists of 10 questions and is scored from 0 to 30. A person is considered to have severe pruritus if she/he has a DLQI from 11 to 30.		Sodium thiosulfate had significantly improved the QoL. Further studies needed
Mortazavi  2017	Pruritus Score	Recorded at the beginning and end of each treatment period	n.r.	n.r.	Significant reduction of pruritus score in omega‐3 fatty acid supplement group Mean reduction by 1.72
Murphy 2003	0‐10 cm VAS	Composite mean VAS score (morning and evening); mean score of the last 5 days of each week was calculated and referred to as the composite mean VAS score	0	No itch	Effect size of d = 0.8
			10	Maximum itch
Naghibi 2007	VAS	Mean difference of pruritus score before and after treatment	n.r.	n.r.	n.r.

DLQI: dermatology life quality index
DPS: detailed pruritus score
ItchRO: itch reported outcome
n.r.: not reported
NRS: numeric rating scale
QoL: quality of life
VAS: visual analogue scale

3. Measurement of pruritus (3).

Study	Pruritus scale	Determination of Score	Description of scale		Description of partial resolution
Naini 2007	0‐10 cm VAS	Mean pruritus score ± standard deviation; mean score of the last 5 days of each week was calculated and referred to as the composite mean VAS score.	0	No itch	Not available
			10	Worst possible itch
Najafabadi 2012	0‐10 VAS	Mean pruritus score ± standard deviation; every two weeks	0	No itching	Not available
			10	Worst pruritis
Najmeh 2019	VAS	Weekly assessment of efficacy of treatment and QoL	n.r.	n.r.	Significant decrease of pruritus severity during the time in both groups; no significant difference between both groups QoL significantly improved in pregabalin group compared to ketotifen group.
	Itchy QoL		n.r.	n.r.
Nakhaee 2015	0‐10 cm VAS	Mean pruritus score ± standard deviation at baseline and after 2 weeks	0	No pruritus	Not available
			10	Worst pruritus imaginable
Nasrollahi 2007	Detailed pruritus score introduced by Duo (Duo 1987)	Not stated	"Assessment of pruritus was done using Detailed Pruritus Score introduced by Duo. The scores for sleep disturbances and intensity, area of pruritus were added and the final score at the beginning and at the end of the study were calculated (maximum score: 45)".		Not available
Nofal 2016	10‐cm VAS	Measurement of pruritus severity at baseline, before every HD session (3 x/week) till the end of the study (1 month), and 1 week after stoppage of treatment	0	No itch	Highly statistical difference in favour of gabapentin group
			10	Worst possible itch
	5‐D pruritus scale		5	No pruritus
			25	Most severe pruritus
Noshad 2011	VAS	Determining the pruritus severity at baseline and after treatment	n.r.	n.r.	Significant decrease of pruritus severity & significant improvement in QoL in gabapentin group Gabapentin was more effective than antihistamine. Optimal dose of this drug: 100 mg/d
	HRQoL	Determining QoL	n.r.	n.r.
O'Donohue 2005	0‐10 cm VAS; additional measurement of scratching activity by piezoelectric vibration transducer	Mean pruritus score standard error of the mean; on day 0 and day 1: every 15 min during the first hour, and hourly thereafter during waking hours. On days 2–5, recordings were made at 3‐h intervals from 09:00 to 24:00 hours.	0	No pruritus	> 50% reduction in the severity of pruritus
			10	Worst imaginable pruritus
Omidian 2013	0‐5 VAS	Weekly mean score ± standard deviation	0	No itching	Not available
			5	Worst pruritus
Özaykan 2001	Scoring system proposed by Duo and modified by Mettang (Duo 1987; Mettang 1990)	Weekly mean scores	0‐48	Period: 0‐3	Not available
Pauli‐Magnus 2000	0‐10 cm VAS	Mean weekly pruritus score in percent of initial pruritus score; 95% confidence interval	0	No pruritus	Not available
			10	Unbearable pruritus
	Detailed pruritus score proposed by Duo (Duo 1987)	Mean detailed score and 95% confidence interval	Scoring of severity:
			1	Itching sensation without necessity of scratching
			2	Itching that necessitates scratching, but without excoriations
			3	Itching that necessitates frequent scratching
			4	Itching that necessitates scratching accompanied by excoriation
			5	Pruritus causing total restlessness
			Scoring of distribution:
			1	Pruritus in 2 areas of the body or less
			2	Pruritus in more than 2 areas of the body
			3	Generalised pruritus
			Scoring sleep disturbance:
			Every waking up due to pruritus received 2 points (max. 10 points) and every scratching due to pruritus received 1 point (max. 5 points); range: 0‐45
Pederson 1980	Questionnaire as suggested by Lowrie 1975	Pruritus scores in each individual were presented at week 0, 8 and 16; little information	1	I never itch	Not available
			2	I rarely itch but never complain
			3	I itch occasionally with mild annoyance
			4	I often itch; it may be severe but I can be active or rest easily.
			5	I often itch; it may be severe and interferes with rest but not activity.
			6	I always itch; it is severe and interferes both with rest and activity.
			Statements were arranged in nine paired response alternatives, allowing the ranking of the itching as a severity continuum on a scale of one (no itching) to 10 (severe constant itching)
Peer 1996	0‐10 cm VAS	Mean daily scores (recorded every 6 hours); medians and interquartile ranges were reported.	0	No pruritus	Not available
			10	Maximum intensity of pruritus
Podesta 1991a	0‐100 cm VAS	Mean pruritus score; pruritus was evaluated 15 days before and daily (between 8 and 12 AM, 12‐8 PM, and 8‐8 AM) during treatment.	100	Pruritus that interfered with sleep, altered daily activities, or resulted in self‐inflicted skin‐breakdown	Full response to treatment was defined as the complete lack of pruritus and a partial response as a 50% reduction in the pruritus score.
Pour‐Reza‐Gholi 2007	Not stated	Not stated	Response to treatment was recorded as: complete improvement (no more itching), relative improvement (reduction of the symptom), no effect (symptom remained unchanged or worsened).		Not available
Ravindran 2020	VAS	Analysing the intensity of itching before and after drug therapy Assessment of the efficacy and safety of the drugs after 6 weeks	n.r.	n.r.	Both gabapentin and pregabalin produced a significant difference in itching intensity No significant difference between the effectiveness of both drugs in reducing itch
	5‐D Ich scale		n.r.	n.r.
Rivory 1984	VAS	Not available	n.r.	n.r.	Not available
Rossi 2019	10‐cm/100‐mm VAS	Measurement of symptom severity Percent change in VAS & sleep disturbance outcome measures from baseline to day 14 After each DS during the 2 weeks of therapy and 1 week after therapy withdrawal	0	Absence of symptom/No itch	Significant itch reduction in the gabapentin 100 mg group No significance in the 300 mg group (presumably for the small number of patients) No significant decrease of nocturnal scratching episodes Significant decrease of waking up episodes due to itching in the 100 mg group
			10	Most intense expression/worst imaginable itch
	Sleep disturbance questionnaire		2 up to 10 points	Any episode of waking up due to itch
			1 up to 5 points	Each scratching episode with or without excoriation during the night
Shayanpour 2019	5‐D Itch scale		n.r.	n.r.	Not available
Shirazian 2013	Pruritus Severity Questionnaire	Biweekly mean scores ± standard deviation	Maximum pruritus score on the survey: 21 points		Not available
			5	Active itching (yes = 5)
			4	Itching affecting sleep or other activities in the past few days (yes = 4)
			In the past few days, how would you describe your itching?
			0	None
			1	Mild itching
			3	Moderate itching
			4	Severe itching
			In the past few days, what part of your body has felt itchy?
			1	Localised itching
			2	Itching in most of the body
			3	Itching in all the body
			5	Use of medications for itching (yes = 5)
Silva 1994	0‐3 score	Depicted as a percent of maximum score possible ± standard error; pruritus intensity was scored three times daily	0	Absent	Reduction of at least 50%
			1	Pruritus at rest or during usual tasks but not interfering with its accomplishment
			2	Pruritus perturbing but not interrupting performance of regular tasks
			3	Pruritus causing interruption of tasks or sleep
Silverberg 1977	0‐3 score	Mean of all daily scores; score for the 3 weeks before treatment was the mean of 21 days' values and the score during treatment was the mean of 28 days' values.	0	None	Not available
			1	Slight
			2	Moderate
			3	Great

DS: dialysis session
HD: hemodialysis
HRQoL: health related quality of life
QoL: quality of life
n.r. not reported
VAS: visual analogue scale

4. Measurement of pruritus (4).

Study	Pruritus scale	Determination of Score	Description of scale		Description of partial resolution
Sja'bani 1997	VAS of pruritus	At baseline and 5 weeks after treatment	n.r.		2000 units of erythropoietin 2 x/week increased the QoL and functional status but decreased severity of pruritus.
	QoL (DLQI?)
	Karnofsky Index
Smith 1997a	1‐4 score	Not stated	1	Periodic at night only	Not available
			2	Periodic during the day and night
			3	Periodic during the day, but interferes with sleep at night
			4	Interferes with daily activities as well as sleep at night
	0‐4 score	Categorical evaluation; median improvement; 25th and 75th percentile	Overall changes in pruritus after 4‐6 weeks of therapy were graded as follows:		Not available
			0	Increased pruritus
			1	No decrease
			2	Slight but definite decrease in pruritus
			3	Moderate decrease in pruritus
			4	Complete resolution of pruritus
Somkearti 2021	VAS	At baseline and every 4 weeks (12 weeks treatment, 4 weeks follow‐up)	n.r.		3 points and more from baseline (VAS) implies significant treatment
	Pruritus in Dialysis Patients (UP‐Dial)	At baseline and every 4 weeks (12 weeks treatment, 4 weeks follow‐up)	n.r.
Solak 2012	Short form McGill Pain Questionnaire (SF‐MPQ)	Evaluation of pain and pruritus at baseline and after each treatment phase	15 descriptors (11 sensory; 4 affective) which are rated on an intensity scale:		Gabapentin and pregabalin improved both neuropathic pain and pruritus significantly.
			0	None
			1	Mild
			2	Moderate
			3	Severe
	10‐cm VAS		0	No itch
			10	Worst possible itch
Spencer 2015	100‐mm VAS	Change in worst itch intensity from baseline to days 12‐15	0	No itch	Significant difference in itch intensity between placebo an CR845 groups CR845: 50% mean reduction in itch intensity & improvement of QoL
			100	Worst itch
	Skindex‐10	Measurement of pruritus‐related QoL	n.r.	n.r.
Subach 2001	VAS 10‐cm	At 30, 60, and 120 min after administration	n.r.	n.r.	Itch relief defined as 50% reduction in baseline
Suwanpidokkul 2007	VAS	n.r.	n.r.	n.r.	Reduction of man VAS: 39.0 (gabapentin) and 20.7 (loratadine)
Tapia 1977	n.r.	Itch relief or no relief at baseline vs. after treatment itch status	n.r.	n.r.	Not available
Tarng 1996	4‐point scale	Weekly mean values ± standard deviation	1	No itching	Not available
			2	Mild itching, occasionally noticeable
			3	Moderate itching, not interfering with daily life and/or sleep
			4	Severe itching, disturbing daily life and/or sleep
Terg 2002	0‐10 cm VAS	Mean values ± standard deviation of each period; assessment 1 week before starting treatment and during the 5 weeks of the study; daytime pruritus was assessed before retiring to sleep while night‐time pruritus was assessed at wake‐up.	0	Absence of pruritus	Complete response was defined as disappearance of pruritus and partial response as 50% reduction in the pruritus score.
			10	Pruritus that interfered with sleep, altered daily activities or resulted in self‐inflicted skin breakdown
Tol 2010	VAS	At baseline and end of treatment periods	n.r.	n.r.	Not available
	Post‐sleep Inventory
	Mental scale
	Depression scale
Turner 1994a Turner 1994b	0‐100 mm VAS	Mean VAS scores for the last 7 days (daily assessment reflecting the preceding 24 hours); 95% confidence interval	0	No itch	Subjective itch improvement (yes or no)
			100	Severe
Van Leusen 1978	n.r.	Daily pruritus score calculated before and during treatment Comparison of means of the scores 21 days before and 28 days during treatment	Pruritus graded:		Pruritus decreased considerably within 4 days in 4 of 5 patients taking cholestyramine.
			0	None
			1	Slight
			2	Moderate
			3	Great
Vessal 2010	0‐10 cm VAS	Weekly mean scores ± standard deviation for 12 weeks	0	Absence of pruritus	Not available
			10	Greatest severity of symptoms
Villamil 2005	0‐100 mm VAS	Daily mean VAS scores for the 7 days (measurement at baseline and every 12 hours before going to bed and after awakening); 95% confidence interval	0	Absence of pruritus	Difference of 30%
			100	Unbearable intensity
Wikström 2005a Wikström 2005b	0‐100 mm VAS	Mean worst itching VAS from run‐in to the end of week 4 (study 1) and week 2 (study 2) during the previous 12 hours; assessment every 12 hours during the run‐in period and throughout the studies; 95% confidence interval and standard deviation	0	No itching	Patient responders as defined by a reduction from run‐in of at least 50% in “worst itching” VAS
			100	Worst itching ever
Wolfhagen 1997	0‐100 mm VAS	Mean daytime/night‐time scores each day; ± standard error of the mean and 95% confidence interval	0	No itching	Not available
			100	Unbearable itching
Young 2009	0‐10 cm VAS	[1 − (mean VAS at the end of the study)/(mean VAS at baseline) * 100]	Itch intensity after a mosquito bite		Not available
			Individual itch on its best intensity
			Individual itch on its worst intensity
Yue 2015	0‐10 cm VAS	Biweekly mean scores ± standard deviation (12 weeks)	0	No pruritus	Not available
			10	Worst pruritus imaginable
	Modified Duo's VAG: 0 to 40	Mean scores ± standard deviation at baseline and week 12	0	Higher scores indicating more severe symptoms; (based on criteria such as scratching, severity, frequency, distribution of pruritus, number of sleeping hours, and frequency of waking‐up during the night for scratching)
			40
Zylicz 2003	0‐10 numerical analogue scale	Mean value of 7 days ± standard error and 95% confidence interval	0	No symptoms	Proportion of clinical responses defined as a pruritus reduction of at least 50% in the last 3 days of each period as compared to the last 3 days of the run‐in period
			10	Worst possible symptoms

DLQI: dermatology life quality index
n.r. not reported
QoL: quality of life
SF‐MPQ: short form McGill pain questionaire
UP: uraemic pruritus
VAS: visual analogue scale

Secondary outcomes

• Quality of life

• Patient satisfaction

• Depression

• Adverse events

For measuring quality of life, we considered the following scales or methods:

• Short Form 36 (8 dimensions that can be transformed on a 0‐100 scale, higher values = better status) and Liver Disease Symptom Index 2.0 (18 items, 0‐4, higher score = worse status) (Kuiper 2010).

• VAS (0 to 100 mm), 0 = able to cope with normal activities, 100 = completely incapacitated (Turner 1994a; Turner 1994b).

• Skindex‐10 Scale (Mathur 2010): Quality of life measure for patients with skin diseases; assesses three domains: disease (three items), mood/emotional distress (three items), and social functioning (four items); 0 = never bothered, 6 = always bothered per item; cumulative score 0 to 60 (Fishbane 2020a; Fishbane 2020b).

• Dermatology life quality index (DLQI, Finlay 1994): Ten questions with topics: symptoms, embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close relationships, sex, treatment. Each question is scored from 0 to 3; 0 = meaning no impact of skin disease on quality of life, 30 = meaning maximum impact on quality of life (Fouroutan  2017; Gobo‐Oliveira 2018).

• Primary biliary cirrhosis (PBC)‐40 (Jacoby 2005): six domains (fatigue, emotional, social, and cognitive function, general symptoms, and itch) with 40 questions; 1 = the least impact, 5 = the greatest impact (Mayo 2019).

• ItchyQoL (Desai 2008) for patients with chronic pruritus: 22 items (symptoms, functions, emotions and self‐perception), 1 = appearance “never”, 5 = appearance “always” (Najmeh 2019).

Other investigators assessed patient satisfaction using a seven‐point scale, where 0 meant indifferent, a value of −3 meant extremely poor, and a value +3 meant excellent (Zylicz 2003).

We considered depression using:

• Hospital Anxiety and Depression scale (HADS, Zigmond 1983), anxiety subscale (0‐21), depression subscale (0‐21) in Mathur 2017;

• Hamilton's depression rating scale (Hamilton 1960): includes items intrinsic to medical conditions (i.e. fatigue, sleep) and concern about health in Bergasa 2006;

• Structured Clinical Interview Questionnaire (SCID) for the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM‐IV), Axis I Disorders (a measure for the diagnosis of depression and anxiety syndromes) in Bergasa 2006; and

• 30‐item Inventory of Depressive Symptomatology‐Self‐Report (IDS‐SR_30, Rush 1996) in Mayo 2007.

For measuring adverse events, we considered the number of events.

Search methods for identification of studies

There were no language restrictions for either the searching strategies or study inclusion.

Electronic searches

For this second update, as for the first, we searched the following databases using following search strategies (see Appendix 1; Appendix 2; Appendix 3) after consultation with the Cochrane Pain, Palliative Care and Supportive Care Cochrane Review Group.

• Cochrane Central Register of Controlled Trials (CENTRAL) (searched from 9 June 2016 to 6 July 2022);

• MEDLINE Ovid (9 June 2016 to 6 July 2022);

• Embase Ovid (7 June 2016 to 6 July 2022).

We used the Cochrane highly sensitive search strategy (CHSSS) for identifying RCTs in MEDLINE, a sensitivity maximising version as referenced in Chapter 4: Searching for and selecting studies, 4.S1 Supplementary material, technical supplement detailed in Box 3.c of the Cochrane Handbook for Systematic Reviews of Interventions Version 6.2 (Higgins 2021). We used a similar study design filter for other databases, as appropriate.

We did not perform a separate search for adverse effects of the target intervention/s. We considered adverse effects described in the Included Studies only.

We decided not to search the other databases, (BIOSIS, CINAHL and PsycINFO), used for the original review as they did not yield any useful records.

In the original review, we searched the following databases (see Appendix 4, Appendix 5, Appendix 6, Appendix 7, Appendix 8 and Appendix 9).

• Cochrane Pain, Palliative and Supportive Care Trials Register (searched August 2012).

• The Cochrane Library via Wiley, including the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE) (searched August 2012);

• MEDLINE Ovid (including MEDLINE In‐process and other non‐indexed citations) (1950 to August 2012);

• Embase Ovid, including Embase Alert (1980 to August 2012);

• BIOSIS previews Ovid and Web of Knowledge (1969 to August 2012);

• CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1982 to August 2012);

• PsycINFO EBSCO (1806 to August 2012).

In addition, we performed Internet searches using Scirus (www.scirus.com) and Google Scholar (scholar.google.de) in the original review.

Searching other resources

Another Cochrane Review (Hercz 2020) included 19 of the 42 newly identified studies: Aubia 1980; Begum 2004; Bhaduri 2006; Ghorbani 2012; Ghorbani Birgani 2011; Marin 2013; Mirnezami 2013; Mohamed 2012; Mortazavi  2017; Naghibi 2007; Noshad 2011; Rivory 1984; Sja'bani 1997; Spencer 2015; Subach 2001; Suwanpidokkul 2007; Tapia 1977; Tol 2010; Van Leusen 1978. Authors agreed to share their data (risk of bias assessment, effects of interventions, and analyses) to be incorporated in this review.

Furthermore, we searched the following trial registers for ongoing studies.

• Current Controlled Trials (www.controlled-trials.com; searched 8 July 2022).

• WHO International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch; searched 8 July 2022).

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 8 July 2022).

Data collection and analysis

Selection of studies

For this update, two review authors (CB, LJ) screened all titles and abstracts of studies identified by the search strategies for relevance. We resolved disagreement by consensus and after discussion with a third review author (GB). If it was not possible to accept or reject a study with certainty, we obtained the full text of the study for further evaluation. Two review authors (CB, LJ) independently assessed the full text of all potentially relevant studies in accordance with the above inclusion criteria. We resolved any differences in opinion at this stage by consensus and discussion with a third review author (GB). We kept a record of all excluded studies and the reasons for exclusion. The most relevant excluded studies are mentioned in the Excluded studies section.

Data extraction and management

Two review authors (CB, LJ) independently extracted data from the selected studies using a standardised coding form. We discussed differences in data extraction and sought the input of a third review author (GB) as necessary. The data extraction form, specifically designed for the review, included the following.

• Study ID and publication details

  • Study aim

  • Study design (parallel‐group, cross‐over)

  • Type of control group

  • Number of participants in each group

• Quality of the study

  • Randomisation procedure

  • Concealment of treatment allocation

  • Details of blinding

  • Per‐protocol analysis or intention‐to‐treat analysis

  • Number of withdrawals described

  • Management of missing data

  • Follow‐up data

  • Details of analysis

• Patient characteristics

  • Demographics (sex, age)

  • Diagnosis

  • Status or course of disease

  • Type and stage of treatment

  • Type of pruritus

• Pharmacological interventions

  • Duration of therapy

  • Pharmacological regimen of drug treatment with the drug of interest (dose, frequency of application)

  • Description of placebo

  • Description of alternative treatment

  • Description of additional non‐pharmacological techniques if additionally used during similar regimens

• Outcome measures

  • Primary outcome, including the measurement of pruritus (mean, standard deviation (SD)) and the change in level of pruritus

  • Secondary outcomes, including the measurement of quality of life, patient satisfaction, depression and adverse events of treatments

• Additional information

  • Patient narrative comments, etc.

  • Conflicts of interest of study authors

  • Funding information

If further data were needed for the analysis, we contacted authors of the studies to obtain unpublished data, if possible.

Assessment of risk of bias in included studies

We performed the Risk of bias assessment for RCTs as recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors (CB, LJ) independently assessed the quality of included studies using the Cochrane Risk of bias 1 tool.

• Random sequence generation

  • Low risk: every participant had an equal chance to be selected for either treatment, and the investigator was unable to predict which treatment the participant would be assigned to.

  • Unclear risk: no information given.

  • High risk: for example, randomisation by date of birth or date of admission.

• Allocation concealment

  • Low risk: methods to conceal allocation included central randomisation, serially numbered, opaque, sealed envelopes, or other descriptions with convincing concealment.

  • Unclear risk: authors did not adequately report the method of concealment.

  • High risk: investigators enrolling participants could possibly foresee assignments because of the use of high‐risk methods to conceal allocation, such as an open random allocation schedule (e.g. a list of random numbers), assignment envelopes without appropriate safeguards (e.g. if envelopes were unsealed, non­‐opaque, or not sequentially numbered), alternation or rotation, date of birth.

• Blinding of participants and personnel

  • Low risk: blinding of participants and providers stated and unlikely that the blinding could have been broken.

  • Unclear risk: blinding not adequate, but the outcome measurement is unlikely to have been influenced by lack of blinding.

  • High risk: no blinding or incomplete blinding, and the outcome or outcome measurement is likely to have been influenced by lack of blinding.

• Blinding of outcome assessors

  • Low risk: blinding of providers and outcome assessor stated and unlikely that the blinding could have been broken.

  • Unclear risk: blinding of outcome assessment not adequate, but the outcome measurement is unlikely to have been influenced by lack of blinding.

  • High risk: no blinding or incomplete blinding of outcome assessment, and the outcome or outcome measurement is likely to have been influenced by lack of blinding.

• Incomplete outcome data

  • Low risk: no missing outcome data, or reasons for missing outcome data are unlikely to be related to true outcome.

  • Unclear risk: insufficient information to permit judgement.

  • High risk: reasons for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups, or 'as‐treated' analysis, where the intervention received differs substantially from that assigned at randomisation.

• Selective outcome reporting

  • Low risk: reports of the study free of selective outcome reporting.

  • Unclear risk: insufficient information to permit judgement.

  • High risk: reports of the study suggest selective outcome reporting.

• Size of study

  • Low risk: 200 participants or more per treatment arm.

  • Unclear risk: 50 to 199 participants per treatment arm.

  • High risk: fewer than 50 participants per treatment arm.

• Other sources of bias

  • Low risk of bias: the trial appears to be free of other components that could put it at risk of bias.

  • Unclear risk of bias: the trial may or may not be free of other components that could put it at risk of bias.

  • High risk of bias: there are other factors in the trial that could put it at risk of bias, e.g. for‐profit involvement, authors have conducted trials on the same topic, etc.

The review authors were blinded to each other's assessments. We resolved any disagreements by discussion. We did not automatically exclude any study as a result of a rating of 'unclear' or 'high' risk or based on a low‐quality score. We considered trials assessed as being at low risk of bias in all the specified key domains to be trials with overall low risk of bias. We considered studies at unclear risk of bias in one or more of the specified key domains to be trials with unclear risk of bias. Finally, we considered studies assessed at high risk of bias in one or more of the specified key domains to be trials with high risk of bias. Key domains for the subjective outcome pruritus were: random sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment.

Measures of treatment effect

We presented most outcomes in this review as continuous variables. We presented continuous outcomes, including the mean change in pruritus score between treatment and placebo, either as mean difference (MD) or standardised mean difference (SMD; 0.2 = small effect, 0.5 = moderate effect, 0.8 = large effect, Cohen 1988) with 95% confidence intervals (CI), depending on whether trials reported results on the same or different scales.

If data were not reported in a RCT in a format that could be entered directly into a meta‐analysis, we converted them to the required format using the information in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). We anticipated that some individual studies would have used final scores and others would use change scores and even analysis of covariance in their statistical analyses of the results. In this case, we combined these different types of analysis as MDs if trials reported results on the same scale. We used the random‐effects model in all meta‐analyses.

Unit of analysis issues

We evaluated the data of the RCTs. Identified studies had to evaluate and report the effect of a pharmacological treatment versus placebo, no treatment, or an alternative pharmacological treatment on pruritus in individuals. Our results did not contain studies with multiple observations or cluster‐RCTs. However, there were cross‐over studies, and we considered specific challenges, such as possible carry‐over effects.

Cross‐over trials may be combined with parallel‐group trials in principle (Higgins 2021, chapter 23). We included properly reported cross‐over trials (i.e. analysed with paired t‐test and without a carry‐over or period effect) in meta‐analyses using the generic inverse variance (GIV) method (Higgins 2021). When authors reported or analysed results inappropriately that did not allow calculation of the standard error (SE) of the mean difference in a paired analysis, we tried to approximate the SE by estimating the correlation amongst participants. In case there were insufficient data to calculate the correlation coefficient, we assumed a correlation of zero, which results in a conservative scenario, i.e. SE is slightly overestimated (Gunal 2004; Murphy 2003). Each comparison included a subgroup analysis by study design when both cross‐over and parallel‐group trials were included in a meta‐analysis.

In addition, the meta‐analyses and Summary of findings tables show the number of patients for parallel‐group trials and the number of cases for cross‐over trials, since there are two post‐treatment values for each patient in a cross‐over trial. However, the number of participants included in this review and also shown in the tables refers to participants and not to cases of the cross‐over RCTs.

Dealing with missing data

We did not impute missing outcome data. We analysed them on an endpoint basis, including only participants for whom final data were available. We did not assume that participants who dropped out after randomisation had a negative outcome.

Assessment of heterogeneity

We investigated heterogeneity using visual inspection of the forest plots as well as the I² statistic (Higgins 2002).

Assessment of reporting biases

There were insufficient studies in each of the meta‐analyses to assess reporting bias. We had planned funnel plots corresponding to meta‐analyses of the primary outcome to assess the potential for small study effects, such as publication bias, but there were insufficient studies to undertake this.

Data synthesis

We used Review Manager 5 (RevMan) for writing the protocol, R statistical software for data entry, statistical analysis, and creation of graphs for the original review and first update (R Foundation 2021; RevMan 2014; Schwarzer 2015). RevMan‐Web was used for this update (RevManWeb).

We decided not to pool the results in cases of substantial clinical heterogeneity (I² > 75%). We calculated the 95% CI for each effect size estimate.

We included studies with parallel‐group and cross‐over designs in the review, handling data from cross‐over trials according to the recommendations in section 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). If all necessary data were provided in the publications of cross‐over trials and if no carry‐over effect or periodic effect was apparent, we included the results of a paired analysis in the meta‐analyses. If the required data were available, we included only data from the first period of the cross‐over trial (if available) and thus treated this trial as a parallel‐group trial.

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses a priori and performed them when possible.

• UP versus CP.

• Parallel‐group versus cross‐over study design.

We conducted subgroup analyses as recommended in the Cochrane Handbook for Systematic Reviews of Interventions section 16 (Higgins 2021).

Sensitivity analysis

We planned sensitivity analyses to assess whether the quality of the chosen trials influenced the results of the meta‐analysis but, due to the small numbers of studies for a single comparison, we did not conduct sensitivity analyses based on quality criteria.

We performed sensitivity analyses using the fixed‐effect model.

Summary of findings and assessment of the certainty of the evidence

Two review authors (CB and LJ) independently rated the certainty of the body of evidence for the outcomes. We used the GRADE system to rank the certainty of the evidence (GRADEproGDT 2015), and the guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 14, Higgins 2021), GRADEpro Handbook (Schünemann 2013), and in accordance with recommendations of the GRADE working group (Guyatt 2013a; Guyatt 2013b).

The GRADE approach uses five considerations (study limitations (risk of bias), unexplained heterogeneity and inconsistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence for each outcome. The GRADE system uses the following criteria for assigning grades of evidence:

• High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different.

• Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.

• Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

The GRADE system considers study design as a marker of quality. Randomised controlled trials are considered to be high certainty of evidence and can be downgraded for important limitations.

Factors that may decrease the certainty level of a body of evidence are as follows.

• Serious or very serious study limitations (risk of bias)

• Important or serious inconsistency of results

• Some or major indirectness of evidence

• Serious or very serious imprecision

• Probability of publication bias

We planned to include 13 Summary of findings tables to present the main findings for the most important pharmacological treatments compared with active control or placebo in a transparent and simple tabular format. In particular, we included key information concerning the certainty of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the primary and secondary outcomes. We included the number of participants who experienced at least one adverse event as a binary outcome in our meta‐analyses and Summary of findings tables.

We made the following treatment comparisons which were summarised in summary of findings (SoF) tables (less relevant comparisons were not summarised in tables). Data from SoF tables 1‐12 originate from meta‐analyses 1‐12. SoF table 13 is shown in Figure 1.

1.

Summary of Findings Table 13

1. GABA‐analogues versus placebo.

2. Gabapentin versus pregabalin.

3. Kappa opioid agonists versus placebo.

4. Ondansetron versus placebo.

5. Montelukast versus placebo

6. Zinc sulphate versus placebo.

7. Cromolyn sodium versus placebo.

8. Topical capsaicin versus placebo.

9. Fish‐oil/omega‐3 fatty acids versus placebo.

10. Naltrexone versus placebo.

11. Rifampicin versus placebo or standard medication.

12. Flumecinol versus placebo.

13. Paroxetine versus placebo (Figure 1).

Results

Description of studies

Please see the Characteristics of included studies table for full information on the included studies.

Results of the search

In total, we identified 91 studies with 4652 participants. See Figure 2 for a flowchart of the study selection process.

2.

Study flow diagram

We included 42 new studies with 2839 additional participants: Aquino 2020 (N = 30); Ataei 2019 (N = 36); Aubia 1980 (N = 13); Begum 2004 (N = 22); Bhaduri 2006 (N = 78); Chourdakis 2019 (N = 20); Fishbane 2020a (N = 378); Fishbane 2020b (N = 174); Forouhari 2022 (N = 40); Fouroutan  2017 (N = 90); Gholyaf 2020 (N = 77); Ghorbani 2012 (N = 60); Ghorbani Birgani 2011 (N = 60); Gobo‐Oliveira 2018 (N = 60); Kebar 2020 (N = 32); Kumada 2017 (N = 317); Lahiji 2018 (N = 40); Mahmudpour 2017 (N = 80); Marin 2013 (N = 36); Mathur 2017 (N = 373); Mayo 2019 (N = 66); Mirnezami 2013 (N = 70); Mohamed 2012 (N = 45); Mortazavi  2017 (N = 20); Naghibi 2007 (N = 20); Najmeh 2019 (N = 30); Nofal 2016 (N = 54); Noshad 2011 (N = 40); Pakfetrat 2018 (N = 50); Ravindran 2020 (N = 50); Rivory 1984 (N = 13); Rossi 2019 (N = 21); Shayanpour 2019 (N = 64); Sja'bani 1997 (N = 29); Solak 2012 (N = 50); Somkearti 2021 (N = 55); Spencer 2015 (N = 65); Subach 2001 (N = 23); Suwanpidokkul 2007 (N = 19); Tapia 1977 (N = 20); Tol 2010 (N = 14); Van Leusen 1978 (N = 5).

We updated the study flow diagram (Figure 2) according to Stovold 2014. The 91 identified studies contained different assessment scales (Table 13) and a total of 51 different drugs/applications for the treatment of pruritus associated with different underlying diseases (Table 17). The drugs assessed were antiphlogistic substances, psychotropic drugs, antagonistic drugs, anaesthetics, adsorbent substances and topical treatments.

5. Study intervention and numbers attached to intervention (1).

Substance and participants		Dose	No. of participants randomised	Authors
Activated oral charcoal: 20 participants
UP	Activated oral charcoal vs. placebo	6 g/d	20	Pederson 1980
Capsaicin: 82 participants
UP	Capsaicin vs. vehicle	0.03% ointment 4  x/d	34	Makhlough 2010
UP	Capsaicin vs. vehicle	0.025% cream 4  x/d	19	Tarng 1996
UP	Capsaicin vs. placebo/vehicle	0.025% cream 4  x/d	22	Cho 1997
UP	Capsaicin vs. vehicle	0.025% cream 4  x/d	7	Breneman 1992a
Cholestyramine: 23 participants
UP	Cholestyramine vs. placebo	5 g 2 x/d	10	Silverberg 1977
CP	Cholestyramine vs. terfenadine vs. chlorpheniramine vs. placebo	4 g/d 60‐180 mg/d 4 mg–12 mg/d	8 for 2 weeks each	Duncan 1984
UP	Cholestyramine vs. placebo	5 mg 2 x/d	5	Van Leusen 1978
Cimetidine: 13 participants
UP	Cimetidine vs. placebo	600 mg/d	13	Aubia 1980
Colesevelam: 38 participants
CP	Colesevelam vs. placebo	1875 mg 2 x/d	38	Kuiper 2010
Cromolyn Sodium: 122 participants
UP	Topical cromolyn sodium (CS) vs. vehicle	Topical CS 4% 2 x/d	60	Feily 2012
UP	Oral CS vs. placebo	135 mg 3 x/d	62	Vessal 2010
Desloratadine: 20 participants
UP	Desloratadine vs. bilastine	5 mg/d, for 1 month 20 mg/d, for 1 month	20	Chourdakis 2019
Difelikefalin: 617 participants
UP	Difelikefalin vs. placebo	0.5 μg/kg IV	378	Fishbane 2020a
UP	Difelikefalin vs. difelikefalin vs. difelikefalin vs. placebo	0.5 μg/kg IV 1 μg/kg IV 1.5 μg/kg IV	174	Fishbane 2020b
UP	Difelikefalin (CR845) vs. placebo	1 μg/kg IV every dialysis session IV every dialysis session	65	Spencer 2015
Doxepin: 24 participants
UP	Doxepin vs. placebo	10 mg 2 x/d	24	Pour‐Reza‐Gholi 2007
Ergocalciferol: 50 participants
UP	Ergocalciferol vs. placebo	50,000 IU capsule, 1 pill/week	50	Shirazian 2013
Erythroprotein: 20 participants
UP	Erythropoietin vs. placebo	36 units/kg body weight 3 x/week IV	20	De Marchi 1992
Fish oil/omega‐3 fatty acids (oral): 208 participants
UP	Fish oil vs. safflower oil	6 g ethyl ester/d 6 g ethyl ester/d	22	Begum 2004
UP	Omega‐3 fatty acids vs. placebo	1 gram omega‐3 capsule (180 mg EPA & 120 mg DHA) 3 x/d for 1 month	40	Forouhari 2022
UP	Omega‐3 fatty acids vs. placebo	1 g omega‐3 capsule 3 x/d	22	Ghanei 2012
UP	Omega‐3 fatty acids vs. placebo	1 g omega‐3 3 x/d, for 1 month	40	Lahiji 2018
UP	Fish oil vs. placebo	1 g 3 x/d 3 x/d	20	Mortazavi  2017
UP	Omega‐3 fatty acids vs. placebo	2 g omega‐3 capsule daily before lunch	64	Shayanpour 2019
Flumecinol: 69 participants
CP	Flumecinol low‐dose vs. placebo	600 mg 1 x/week	50	Turner 1994a
CP	Flumecinol high‐dose vs. placebo	300 mg/d	19	Turner 1994b
Gabapentin (oral): 473 participants
UP	Gabapentin vs. placebo	300 mg 3 x/week	25	Gunal 2004
UP	Gabapentin vs. placebo	400 mg 2 x/week	34	Naini 2007
CP	Gabapentin vs. placebo	300 mg‐2400 mg/d	16	Bergasa 2006
UP	Gabapentin vs. ketotifen	100 mg/d 1 mg 2 x/d	52	Amirkhanlou 2016
UP	Gabapentin vs. dexchlorpheniramine	300 mg 3 x/week 6 mg 2 x/d	60	Gobo‐Oliveira 2018
UP	Gabapentin vs. hydroxyzine	100 mg/d 25 mg/d	32	Kebar 2020
UP	Gabapentin vs. loratadine	300 mg/d 10 mg/d	36	Marin 2013
UP	Gabapentin vs. hydroxyzine	100 to 200 mg/d 10 mg/d	40	Noshad 2011
UP	Gabapentin vs. pregabalin	300 mg 3 x/week (after each haemodialysis session) 75 mg/d	50	Solak 2012
UP	Gabapentin vs. placebo	300 mg every HD session	14	Tol 2010
UP	Gabapentin vs. placebo	Gabapentin 100 mg (up to max. 300 mg)	54	Nofal 2016
UP	Gabapentin vs. gabapentin vs. placebo	100 mg after dialysis (3 x/week) 300 mg after dialysis (3 x/week)	21	Rossi 2019
UP	Gabapentin vs. placebo	Dose and frequency n.r.	20	Naghibi 2007
UP	Gabapentin first; washout; loratadine second vs. loratadine first; washout; gabapentin second	100 mg/d over 4 weeks; washout 2 weeks; 10 mg/d over 4 weeks   10 mg/d over 4 weeks; washout 2 weeks; 100 mg/d over 4 weeks	19	Suwanpidokkul 2007
Gabapentin (topical): 30 participants
UP	Topical gabapentin vs. vehicle/placebo	Topical 6% gabapentin permetaion cream daily application	30	Aquino 2020
Hydroxyzine/pentoxifylline/indomethacin/triamcinolone: 65 participants per intervention
HIV‐1 disease patients	Hydroxyzine‐HCl with or without doxepin‐HCl at night vs. pentoxifylline vs. indomethacin vs. triamcinolone	25 mg 3 x/d or 25 mg at bedtime   400 mg 3 x/d 25 mg 3 x/d 0.025% lotion 120 mL/week	40	Smith 1997a
UP	Hydroxyzine   vs. avena sativa vs. vinegar	Hydroxyzine tablet, 10 mg tablets every night Avena sativa lotion 2 x/d Vinegar solution (30 mL synthetic white vinegar 5% in 500 mL of water) 2 x/d	25	Nakhaee 2015
Lidocaine: 38 participants
CP	Lidocaine vs. placebo	100 mg/d IV	18	Villamil 2005
UP	Lidocaine   vs. placebo	200 mg infused over 15 min during HD & additional 3 x if no effect Infused over 15 min during HD & additional 3 x if no effect	20	Tapia 1977
Maralixibat: 66 participants
CP	Maralixibat vs. maralixibat vs. placebo	10 mg/d 20 mg/d	66	Mayo 2019
Mirtazapine: 77 participants
UP	Mirtazapine vs. gabapentin	15 mg/d 100 mg/d	77	Gholyaf 2020
Montelukast: 96 participants
UP	Montelukast vs. placebo	10 mg/d	16	Nasrollahi 2007
UP	Montelukast vs. placebo	10 mg	80	Mahmudpour 2017
Nalbuphine: 373 participants
UP	Nalbuphine vs. nalbuphine vs. placebo	120 mg (BID) 2 x/d 60 mg (BID) 2 x/d	373	Mathur 2017
Nalfurafine: 846 participants
UP	Nalfurafine	5 µg 3 x/week IV	51	Wikström 2005a
UP	Nalfurafine	5 µg 3 x/week IV	34	Wikström 2005b
UP	Nalfurafine hydrochloride vs. nalfurafine hydrochloride vs. placebo	5 µg/d 2.5 µg/d	337	Kumagai 2010
UP	Nalfurafine vs. nalfurafine vs. placebo	5 µg IV post dialysis 2.5 µg IV post dialysis	78	Bhaduri 2006
CP	Nalfurafine hydrochloride vs. nalfurafine hydrochloride vs. placebo	5 µg/d (oral) 2.5 µg/d (oral)	317	Kumada 2017
Naltrexone: 126 participants
UP	Naltrexone vs. placebo	50 mg/d	15	Peer 1996
UP	Naltrexone vs. placebo	50 mg/d	23	Pauli‐Magnus 2000
UP	Naltrexone vs. loratadine	50 mg/d 10 mg/d	52	Legroux‐Crespel 2004
CP	Naltrexone vs. placebo	50 mg/d	16	Wolfhagen 1997
CP	Naltrexone vs. placebo	25 mg 2 x/d	20	Terg 2002
Nicergoline: 13 participants
UP	Nicergoline (oral) vs. nicergoline (IV) vs. placebo	30 mg/d (oral) 5 mg (as continuous IV infusion) oral & IV	13	Rivory 1984
Nicotinamide: 50 participants
UP	Nicotinamide vs. placebo	500 mg 2 x/d	50	Omidian 2013
Ondansetron: 175 participants
UP	Ondansetron vs. placebo	8 mg 3 x/d	24	Murphy 2003
UP	Ondansetron vs. placebo	8 mg 3 x/d	19	Ashmore 2000
CP	Ondansetron vs. placebo	8 mg 2 x/d, 5 days	19	O'Donohue 2005
UP	Ondansetron vs. cyproheptadine	4 mg 2 x/d, 30 days 2 mg/5 mL 2 x/d, 30 days	20	Özaykan 2001
UP	Ondansetron vs. loratadine	8 mg 3 x/d 10 mg 2 x/d	70	Mirnezami 2013
UP	Ondansetron vs. diphenhydramine vs. placebo	8 mg 3 x/d 25 mg 3 x/d	23	Subach 2001

BID: twice daily
CP: cholestatic pruritus
CR845: difelikefalin
CS: romolyn sodium
DHA: docosahexaenoic acid
EPA: eicosapentaenoic acid
HCI: hydrochloride
HD: hemodialysis
HIV: human immunodefeciency virus
IU: international units
IV: intravenous
n.r.: not reported
UP: uraemic pruritus
vs.: versus

The participants suffered from UP (3894 participants), CP caused by hepatobiliary diseases (692 participants), pruritus associated with malignancies (26 participants) (Zylicz 2003), and pruritus as a symptom associated with HIV (40 participants) (Smith 1997a).

Amongst the included studies, 37 were cross‐over studies, while the remaining 54 studies had a parallel‐group design. Two studies were already pooled in a meta‐analysis (Wikström 2005a; Wikström 2005b). The studies took place in different countries in Europe, North America and Asia. Twenty‐six (29%) studies were multicentre trials.

A few studies assessed quality of life (Fishbane 2020a; Fishbane 2020b; Fouroutan  2017; Gobo‐Oliveira 2018; Kuiper 2010; Mathur 2017; Mayo 2019; Najmeh 2019; Sja'bani 1997; Somkearti 2021; Turner 1994a; Turner 1994b; Yue 2015), patient satisfaction (Zylicz 2003), and depression (Bergasa 2006; Mathur 2017; Mayo 2007), and most of them reported adverse events. Study interventions and numbers attached to the interventions (participants, dosing) are listed in additional tables (Table 17; Table 18).

6. Study interventions and numbers attached to intervention (2).

Substance and participants		Dose	No. of participants randomised	Authors
Paroxetine: 26 participants
Palliative care patients	Paroxetine vs. placebo	20 mg/d	26	Zylicz 2003
Pimecrolimus: 120 participants
UP	Pimecrolimus 1% vs. placebo	2 x/d	60	Ghorbani 2012
UP	Cromolyn cream 4% vs. pimecrolimus cream 2%	2 x/d 2 x/d	60	Ghorbani Birgani 2011
Pramoxine‐HCl: 28 participants
UP	Pramoxine‐HCl lotion vs. cetaphil moisturising lotion	1% lotion 2 x/d	28	Young 2009
Pregabalin: 358 participants
UP	Pregabalin vs. doxepin	50 mg every second day 10 mg/d	90	Fouroutan  2017
UP	Pregabalin vs. gabapentin	25 mg 100 mg	50	Ravindran 2020
UP	Pregabalin vs. ketotifen	50 mg 3 x/day 2 x/d	30	Najmeh 2019
UP	Ondansetron vs. pregabalin vs. placebo	8 mg/d 75 mg 2 x/week	188	Yue 2015
Propofol:12 participants
CP	Propofol vs. placebo	15 mg (1.5 mL)/d IV	12	Borgeat 1993
Recombinant Human Erythropoietin (rHuEPO): 29 participants
UP	rHuEPO (SC) vs. placebo	SC: 2000 IU 2 x/week	29	Sja'bani 1997
Rifampicin: 45 participants
CP	Rifampicin vs. placebo	300 mg 2 x/d	14	Podesta 1991a
CP	Rifampicin vs. placebo	150 mg 2‐3 x/d	9	Ghent 1988
CP	Rifampicin vs. phenobarbitone	10 mg/kg 3 mg/kg	22	Bachs 1989
Sertraline: 98 participants
CP	Sertraline vs. placebo	25–100 mg/d	12	Mayo 2007
CP	Sertraline vs. rifampin	100 mg/d 300 mg/d	36	Ataei 2019
UP	Sertraline vs. placebo	50 mg 2 x/d	50	Pakfetrat 2018
Sodium thiosulfate: 45 participants
UP	Sodium thiosulfate vs. placebo	12.5 mg IV 1 x/dialysis IV 1 x/dialysis	45	Mohamed 2012
Tacrolimus: 22 participants
UP	Tacrolimus vs. vehicle	0.1% ointment 2 x/d	22	Duque 2005
Thalidomide: 29 participants
UP	Thalidomide vs. placebo	100 mg/d	29	Silva 1994
Zinc sulphate: 136 participants
UP	Zinc sulphate vs. placebo	220 mg 2 x/d	40	Najafabadi 2012
UP	Zinc sulphate vs. placebo	220 mg/d	40	Mapar 2015
UP	Zinc sulphate vs. placebo	220 mg 2 x/d	56	Somkearti 2021

CP: cholestatic pruritus
HCI: hydrochloride
IV: intravenous
rHuEPO: recombinant human erythropoetin
SC: subcutanous
UP: uraemic pruritus
vs.: versus

Search results for the previous versions of the review

The original review (Xander 2013) identified 40 RCTs. Two review authors (Edith Motschall (EM), SB) searched the databases in June 2010, and one review author (CX) updated the search in November 2011 and January 2012. Overall, the literature search yielded a total of 771 citations. Furthermore, we identified one additional study by handsearching the reference lists of the original studies, textbooks and websites. Personal contact with several investigators did not yield any additional studies or unpublished data. We excluded 144 duplicates. Review authors evaluated the titles and abstracts of 628 studies, selecting relevant studies if they met the inclusion criteria. At this stage, we excluded 546 studies. We obtained a full copy of 82 studies that were potentially eligible for more detailed evaluation. After assessing the reports and in some cases contacting the study authors, we found 38 papers (reporting on 40 studies) that met the eligibility criteria.

The first update of the review identified 50 RCTs (Siemens 2016). One review author (WS) searched the databases in June 2016. Overall, the literature search yielded a total of 528 citations. Furthermore, we identified three additional studies by handsearching the reference lists of the original studies and websites. We excluded 11 duplicates. Review authors (WS, CX) evaluated the titles and abstracts of 520 studies, selecting relevant studies if they met the inclusion criteria. At this stage, we excluded 510 studies. We obtained a full copy of 10 studies that were potentially eligible for more detailed evaluation. After assessing the reports (WS, CX), we found all 10 studies met the eligibility criteria.

Included studies

In this update, we report the study results first organised by type of pruritus and then by type of intervention (see Effects of interventions). Most included studies researched the effect of different interventions on pruritus in participants suffering from advanced diseases and which was associated with UP (71 studies) or CP/hepatogenic pruritus (18 studies). Two studies explored pharmacological interventions in participants with HIV infection and in participants treated in palliative care wards, respectively (Smith 1997a; Zylicz 2003). The trials explored a total of 51 different interventions/applications. For the drugs researched and the total numbers of participants assigned to the drugs, see Table 17 and Table 18. For an overview of the secondary outcomes, see Table 19, and adverse events according to the different studies, see Table 20 and Table 21.

7. Secondary outcomes.

Quality of life	Method/scale	Results
Fishbane 2020a	Skindex‐10 Scale (quality of life measure for patients with skin disease): assesses three domains (disease (three items), mood/emotional distress (three items), and social functioning (four items); 0 = never bothered 6 = always bothered per item; cumulative score 0 to 60	Least‐squares mean change from baseline at week 12 in Skindex‐10 scale total score: Quality of life (Skindex‐10 Scale): Difelikefalin: ‐17.1 (SEM 1.3) Placebo: ‐12.0 (SEM 1.2); P < 0.001
Fishbane 2020b	Skindex‐10 Scale (quality of life measure for patients with skin disease)	Least‐squares mean change from baseline at wk 12 in Skindex‐10 scale total score: Quality of life (Skindex‐10 Scale): Difelikefalin 0.5 µg/kg: ‐18.7 (SE 2.0) Difelikefalin 1.0 µg/kg: ‐15.5 (SEM 2.2) Difelikefalin 1.5 µg/kg: ‐15.1 (SEM 2.3) All difelikefalin: ‐16.4 (SEM 1.3) Placebo: ‐8.2 (SEM 2.0); versus all difelikefalin P < 0.001
Fouroutan  2017	Dermatology life quality index (DLQI): 10 questions with topics: symptoms, embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close relationships, sex, treatment. Each question is scored from 0 to 3. 0 = meaning no impact of skin disease on quality of life 30 = meaning maximum impact on quality of life	Scores on the rating scales at baseline and after one week, two weeks, and four weeks of the treatment: Baseline: pregabalin: 3.8 (SD 1.8), doxepin: 3.6 (SD 1.4); P = 0.551 Week 1: pregabalin: 2.1 (SD 1.6), doxepin: 2.8 (SD 1.4); P = 0.060 Week 2: pregabalin: 1.6 (SD 1.7), doxepin: 2.2 (SD 1.3); P = 0.055 Week 4: pregabalin: 1.2 (SD 1.5), doxepin: 2.2 (SD 1.4); P = 0.007
Gobo‐Oliveira 2018	Dermatology life quality index (DLQI)	Pre‐randomisation after 15 days treatment with cold cream: Median scores decreased by 50% from 4 (IQR 2‐8) to 2 (IQR 1‐3); P < 0.01) Post‐randomisation after treatment for 15 days: Gabapentin: reduction by 50%, from 2 (IQR 1‐3) to 1 (IQR 0‐1) Dexchlorpheniramine: 2 (IQR 1‐4) to 0 (IQR 0‐1)
Kuiper 2010	Quality‐of‐life scores: Short Form 36 and Liver Disease Symptom Index 2.0	No statistically significant changes were found. Both treatment groups were comparable before and after treatment: Short Form 36 questionnaire in the colesevelam group before and after treatment physical functioning (P = 0.67), role physical functioning (P = 0.50), bodily pain (P = 1.00), general health (P = 0.48), vitality (P = 0.90), social functioning (P = 0.37), emotional functioning (P = 0.17) and mental health (P = 0.26)
Mathur 2017	Skindex‐10 Scale (quality of life measure for patients with skin disease)	Changes from baseline to the evaluation period: Nalbuphine (60 mg): ‐13.8 (SD 14.6) Nalbuphine (120 mg): ‐17.0 (SD 14.5) Placebo (60 mg): ‐15.0 (SD 14.1)
Mayo 2019	Primary biliary cirrhosis (PBC)‐40: six domains (fatigue, emotional, social, and cognitive function, general symptoms, and itch) with 40 questions 1 = the least impact 5 = the greatest impact	Insignificant changes in the different domains between maralixibat and placebo: Fatigue (11 items): 2.3 (95% CI ‐1.4 to 6.1) Emotional (3 items): ‐0.8 (95% CI ‐1.7 to 0.1) Social (10 items): ‐0.2 (95% CI ‐3.1 to 2.6) Cognitive (6 items): 0.6 (95% CI ‐1.1 to 2.3) Symptoms (7 items): 1.2 (95% CI ‐0.6 to 2.9) Itch (3 items): ‐0.3 (95% CI ‐1.8 to 1.2)
Najmeh 2019	ItchyQoL for patients with chronic pruritus: 22 items (symptoms, functions, emotions and self‐perception) 1 = appearance “never” 5 = “always”	Quality of life in improved significantly in the pregabalin group compared to the ketotifen group (P < 0.05): Pregabalin: 7.42 (SEM 1.21) to 3 (SEM 1.19) Ketotifen: 5.85 (SEM 1.20) to 3.71 (SEM 1.19)
Sja'bani 1997	Not specified	“Quality of life” post‐treatment scores: EPO: 8.9 (SD 1.3) Placebo: 7.6 (SD 1.1); P = 0.003
Somkearti 2021	QoL	No difference in both groups in improving QoL
Spencer 2015	Skindex‐10	“...significant improvement [...] (P = 0.031)”. No scores reported
Turner 1994a	VAS: 0 = able to cope with normal activities 100 = completely incapacitated	Median improvement in quality of life assessment between flumecinol and placebo was 5.0 mm (95% CI 0.4 to 13.0, P = 0.02), in favour of flumecinol At entry: active = 26, placebo = 11 At completion: active = 21, placebo = 7 Median fall: active = 3.5, placebo = 0.1
Turner 1994b	VAS: 0 = able to cope with normal activities 100 = completely incapacitated	Quality of life was not significantly improved by the higher dose of flumecinol with the difference in median improvement between the 2 groups being 3.5 mm (95% CI 5.9 to 24.9 mm): At entry: active = 32, placebo = 42 At completion: active = 19, placebo = 44 Median fall: active = 4.4, placebo = 3.0
Yue 2015	Health‐related quality of life: Mental Component Summary scale (MCS) from the 12‐item short‐form (SF‐12; version 2); SF‐12 was scored from 0 to 100, with higher scores indicating better HRQoL	Results: Post‐treatment scores: Quality of life (SF‐12 MCS) (mean ± SD): pregabalin: 47.3 ± 11.6, ondansetron: 42.8 ± 13.1, placebo: 42.5 ± 8.7 Mean change from baseline versus placebo (95% CI): statistically significant for pregabalin and not statistically significant for ondansetron or placebo Quality of life (SF‐12 MCS): pregabalin: 4.1 (2.9 to 5.3), ondansetron: 1.2 (−0.1 to 2.5), placebo: —
Patient Satisfaction	Method/scale	Results
Zylicz 2003	7‐point scale, where “0” means indifferent, a negative value of “−3” extremely poor, and a positive value “+3” excellent	On average, patients treated with paroxetine had higher satisfaction scores (mean = 0.41 (SE 0.36)) as compared to patients who received placebo (mean = 0.66 (SE 0.36)). Treatment effect: Placebo: mean ± SE = −0.66 ± 0.36 Paroxetine: mean ± SE = 0.41 ± 0.36 Mean difference (95% CI): −1.08 (−0.19 to 1.96); P = 0.027 Period effect: Placebo: mean ± SE = −0.09 ± 0.36 Paroxetine: mean ± SE = −0.16 ± 0.36 Mean difference (95% CI): 0.08 (−0.81 to 0.96); P = 0.967
Depression	Method/scale	Results
Bergasa 2006	Hamilton depression rating scale: includes items intrinsic to medical conditions (i.e. fatigue, sleep) and concern about health Structured Clinical Interview Questionnaire (SCID) for DSM IV, Axis I Disorders: interview measure for the diagnosis of depression and anxiety syndromes.	Only measured at baseline: Data on the full psychiatric evaluation were available for 13 participants. Hamilton's scale: 8 participants with mild depression, 3 moderate depression, 2 none to minimal depression When items relating to medical conditions were omitted: 7 participants mild depression, no moderate depression, and 6 none to minimal depression SCID: 1 major depressive disorder with atypical features. The remainder of the participants were diagnosed with a mood disorder because of a general medical condition: 8 with depressive features and 4 with major depression‐like episodes. The results of the psychiatric evaluations suggested that liver disease and pruritus might have contributed to the depressive symptomatology of the participants.
Mathur 2017	Hospital Anxiety and Depression scale (HADS) Anxiety subscale (0 to 21), Depression subscale (0 to 21)	Changes from baseline to the evaluation period, Anxiety subscale: Nalbuphine (60 mg): ‐1.72 (SD 3.0) Nalbuphine (120 mg): ‐1.64 (SD 3.1) Placebo (60 mg): 1.89 (SD 3.1) Depression subscale: Nalbuphine (60 mg): ‐0.68 (SD 3.1) Nalbuphine (120 mg): ‐1.03 (SD 3.5) Placebo (60 mg): ‐1.31 (SD 3.2)
Mayo 2007	30‐item Inventory of Depressive Symptomatology‐Self‐report (IDS‐SR30)	All 4 participants with moderate or severe depression improved with sertraline. One of these subjects also improved with placebo. Subjects with mild depressive symptoms did not reliably improve their IDS‐SR30 score with sertraline. 2 of 9 participants improved on open‐label sertraline, but no subject in the cross‐over study with mild depressive symptoms improved.

CI: confidence interval
DLQI: dermatology life quality index
DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition
EPO: erythropoetin
HADS: hospital anxiety and depression scale
HRQoL: health‐related quality of life
IDS‐SR₃₀: 30‐item Inventory of Depressive Symptomatology‐Self‐report
IQR: interquartile range
MCS: mental component summary scale
PBC: primary billary cirrhosis
QoL: quality of life
SCID: structured clinical interview questionnaire
SD: standard deviation
SE: standard error
SEM: standard error of the mean
SF‐12: 12‐item short‐form
VAS: visual analogue scale

8. Adverse events according to different studies (1).

Study	Design	Pruritus/disease	Intervention	Dose	Participants (dropouts included)	Adverse events
Activated oral charcoal
Pederson 1980	Randomised, placebo‐controlled cross‐over study	UP	Activated oral charcoal	6 g/d	20	None reported
Cimetidine
Aubia 1980	Randomised, placebo‐controlled study	UP	Cimetidine	600 mg/d	13	None reported
Cholestyramine
Duncan 1984	Randomised, controlled, comparative cross‐over study	CP	Cholestyramine	4 g/d	8	Diarrhoea and vomiting (n = 4)
			Terfenadine	60‐180 mg/d		Emotional lability (n = 1)
			Chlorpheniramine	4 mg‐12 mg/d		Drowsiness (n = 2), headache (n = 1)
			Placebo	lactose, 200 mg 1‐3/d		Nausea and cutaneous burning (n = 1)
Silverberg 1977	Randomised, placebo‐controlled study	UP	Cholestyramine	10 g/d	10	Cholestyramine: constipation (n = 1), nausea 10‐15 min after every dose (n = 1) Placebo: none given
Van Leusen 1978	Randomised, placebo‐controlled cross‐over study	UP	Cholestyramine	Cholestyramine (oral) 5 mg 2 x/d	5	None reported
Colesevelam
Kuiper 2010	Randomised, placebo‐controlled study	CP	Colesevelam	3750 mg/d	35	Colesevelam: minor: 1 (no more than mild stool changes) Placebo: minor: 4 (no more than mild stool changes)
Cromolyn sodium
Feily 2012	Randomised, vehicle‐controlled study	UP	Topical cromolyn sodium 4%	topical CS 4% 2 x/d	60	Topical cromolyn sodium: Burning sensation (n = 6); gradually subsided during treatment Placebo: none
Vessal 2010	Randomised, vehicle‐controlled study	UP	Oral cromolyn sodium	405 mg/d	62	Oral cromolyn sodium: Minor: flatulence (n = 1) Placebo: Minor: nausea (n = 2), diarrhoea (n = 1), nausea and diarrhoea (n = 3)
Desloratadine
Chourdakis 2019	Randomised, controlled comparative study	UP	Desloratadine	Desloratadine: 5 mg/d	20	No major adverse events reported
			Bilastine	20 mg/d
Difelikefalin
Fishbane 2020a	Randomised, placebo‐controlled study	UP	Difelikefalin	0.5 µg/kg IV, 3  x/week	378	Difelikefalin:mild‐to‐moderate: diarrhoea (n = 18), dizziness (n = 13), vomiting (n = 10), nasopharyngitis (n = 6) serious: hyperkalemia(n = 4), pneumonia (n = 3), sepsis (n = 3), hypotension (n = 3), chronic obstructive pulmonary disease (n = 3), death due to sepsis (n = 2) Placebo: diarrhoea (n = 7), dizziness (n = 2), vomiting (n = 6), nasopharyngitis (n = 10) serious: hyperkalemia(n = 4), pneumonia (n = 5), sepsis (n = 4), hypotension (n = 2), chronic obstructive pulmonary disease (n = 1), death due to septic shock (n = 2)
Fishbane 2020b	Randomised, placebo‐controlled, dose‐ranging study	UP	Difelikefalin	Difelikefalin 0.5 μg/kg	175	μg/kg: diarrhoea (n = 7), dizziness (n = 6), nausea (n = 5) somnolence (n = 2), fall (n = 3), abdominal pain (n = 4), hyperglycaemia (n = 3), paraesthesia (n = 1), fatigue (n = 1), hyperkalemia (n = 3), pruritus (n = 3), pulmonary oedema (n = 1), death (n = 1)
				Difelikefalin 1 μg/kg		Diarrhoea (n = 4), dizziness (n = 4), nausea (n = 2) somnolence (n = 2), fall (n = 2), abdominal pain (n = 1), hyperglycaemia (n = 1), mental status changes (n = 1), paraesthesia (n = 2), fatigue (n = 1), headache (n = 5), hyperkalemia (n = 1), pruritus (n = 1), hypertension (n = 1), anaemia (n = 1)
				Difelikefalin 1.5 μg/kg		Diarrhoea (n = 5), dizziness (n = 2), nausea (n = 3) somnolence (n = 5), fall (n = 2), abdominal pain (n = 1), hyperglycaemia (n = 2), mental status changes (n = 5), paraesthesia (n = 3), fatigue (n = 3), hyperkalemia (n = 1), pruritus (n = 1), hypertension (n = 3), pulmonary oedema (n = 3), death (n = 2)
				Placebo		Dizziness (n = 2), somnolence (n = 1), headache (n = 1), anaemia (n = 3), death (n = 1)
Spencer 2015	Randomised, placebo‐ controlled study	UP	Difelikefalin (CR845)	1 µg/kg every dialysis session	65	None reported
Doxepin
Pour‐Reza‐Gholi 2007	Randomised, placebo‐controlled cross‐over study	UP	Doxepin	20 mg/d	24	Minor: drowsiness (n = 11); Major (leading to withdrawal): drowsiness (n = 1)
Ergocalciferol (Vitamin D2)
Shirazian 2013	Randomised, placebo‐controlled study	UP	Ergocalciferol	50,000 IU capsule, 1 x/week	50	None observed
Erythropoietin
De Marchi 1992	Randomised, placebo‐controlled cross‐over study	UP	Erythropoietin	36 units/kg body weight 3 x/wk IV	20	None given
Fish oil/omega‐3 fatty acids
Begum 2004	Randomised comparative study	UP	Fish oil	6 g/d	22	None reported
			Safflower oil	6 g/d
Forouhari 2022	Randomised, placebo‐controlled cross‐over study	UP	Omega‐3 fatty acids	1 g, 3 x/d	40	None reported
Mortazavi  2017	Randomised, placebo‐controlled cross‐over study	UP	Fish oil	1 g, 3 x/d	20	None reported
Shayanpour 2019	Randomised, placebo‐controlled cross‐over study	UP	Omega‐3 fatty acids	2g, 1x/d before lunch	64	None reported
Flumecinol
Turner 1994a	Randomised, placebo‐controlled study	CP	Flumecinol low‐dose	600 mg 1 x/wk	50	None observed
Turner 1994b	Randomised, placebo‐controlled study	CP	Flumecinol high‐dose	300 mg/d	19	None observed
Gabapentin (oral)
Amirkhanlou 2016	Randomised, controlled, comparative study	UP	Gabapentin	100 mg/d	52	Drowsiness: n = 4 (7.7%), dizziness: n = 1 (1.9%)
			Ketotifen	1 mg 2 x/d		Drowsiness: n = 4 (7.7%), dizziness: n = 1 (1.9%); same between groups
Bergasa 2006	Randomised, placebo‐controlled study	CP	Gabapentin	300‐2400 mg/d	16	Gabapentin: Minor: fatigue (n = 1), dizziness (n = 1), worsening symptoms of carpal tunnel syndrome (n = 1), dizziness on increasing dose and fluctuating rise in serum creatinine (n = 1); Major: vomiting (n = 1) Placebo: Minor: fatigue and leukopenia (n = 1), symptoms of carpal tunnel syndrome (n = 1)
Gobo‐Oliveira 2018	Randomised controlled comparative study	UP	Gabapentin	300 mg 3 x/wk	60	Total patients with adverse events n = 11; drowsiness with interference in daily activities most common (17%), others not reported
			Dexchlorpheniramine	6 mg 2 x/d		Total patients with adverse events n = 8; no further information given
Gunal 2004	Randomised, placebo‐controlled cross‐over study	UP	Gabapentin	300 mg 3 x/wk	25	Gabapentin: Minor to moderate: somnolence, fatigue, dizziness (usually occurring after first dose) Placebo: none given
Kebar 2020	Randomised, controlled, comparative cross‐over study	UP	Gabapentin	100 mg/d	32	None reported
			Hydroxyzine	25 mg/d
Marin 2013	Randomised controlled, comparative study	UP	Gabapentin	300 mg/d	36	Somnolence (n = 8)
			Loratadine	10 mg/d		None reported
Naghibi 2007	Randomised, placebo‐controlled, cross‐over study	UP	Gabapentin	Dose and frequency not reported	20	Gabapentin: somnolence (number of participants not reported) Placebo: none reported
Naini 2007	Randomised, placebo‐controlled study	UP	Gabapentin	400 mg 2 x/wk	34	Gabapentin: Minor: somnolence, dizziness, nausea (subsided) Major: attacks of dizziness in 1 participant (subsided gradually) Placebo: none given
Nofal 2016	Randomised, placebo‐controlled trial	UP	Gabapentin	100 mg 3 x/wk	54	Dizziness (n = 5), somnolence (n = 3), fatigue (n = 1)
Noshad 2011	Randomised controlled, comparative trial	UP	Gabapentin	100‐200 mg/d	40	Complications (7/20)
			Hydroxyzine	10 mg/d		Complications (10/20)
Ravindran 2020	Randomised, placebo‐controlled trial	UP	Gabapentin	100 mg	50	Sedation (no further information given)
			Pregabalin	25 mg		No information given
Rossi 2019	Randomised, placebo‐controlled, dose‐ranging study	UP	Gabapentin	100 mg 3 x/wk	21	None reported
				300 mg 3 x/wk		Excessive sedation (n = 2), no further adverse events reported
Solak 2012	Randomised, comparative cross‐over study	UP	Gabapentin	300 mg 3 x/wk	50	Dizziness (n = 6), somnolence (n = 5), dry mouth (n = 3), balance disorder (n = 2), myoclonus (n = 1), diarrhoea (n = 3), nausea (n = 2), constipation (n = 2), tremor (n = 3)
			Pregabalin	75 mg/d		Dizziness (n = 7), somnolence (n = 5), dry mouth (n = 1), balance disorder (n = 1), myoclonus (n = 1), insomnia (n = 1), euphoria (n = 1)
Suwanpidokkul 2007	Randomised, controlled, comparative cross‐over study	UP	Gabapentin	100 mg/d	19	9/18 participants; no further information given
			Loratadine	10 mg/d		4/16 participants; no further information given
Tol 2010	Randomised, placebo‐controlled cross‐over study	UP	Gabapentin	300 mg/HD session	14	None reported
Gabapentin (topical)
Aquino 2020	Randomised, placebo‐controlled trial	UP	6% gabapentin	1 x/d	30	Acute adverse events, not significant
Hydroxyzine hydrochloride
Nakhaee 2015	Randomised, controlled, comparative three‐armed study	UP	Avena sativa	2 x/d (lotion)	25	None observed
			Vinegar solution	2 x/d
			Hydroxyzine	10 mg tablets 1 x/d
Smith 1997a	Randomised controlled, comparative study	Pruritus in patients with HIV‐1 disease	Hydroxyzine‐HCl with/without doxepin‐HCl	25 mg 3 x/d or 25 mg q.h.s.	40	Major: tiredness, drowsiness, sleepiness (n = 2) Minor: tiredness, drowsiness, sleepiness (n = 6); dry mouth or eyes (n = 5), headache (n = 1)
			Pentoxifylline	400 mg 3 x/d		Minor: headache (n = 2)
			Indomethacin	25 mg 3 x/d		Minor: abdominal pain (n = 2), headache (n = 1), indigestion (n = 4); major: abdominal pain (n = 1)
			Triamcinolone	0.025% lotion		Minor: nausea (n = 1)
Lidocaine
Tapia 1977	Randomised placebo‐controlled study	UP	Lidocaine	single dose of 200 mg IV	20	None reported
Villamil 2005	Randomised placebo‐controlled study	CP	Lidocaine	100 mg/d IV	18	Lidocaine: Minor: mild tinnitus associated with lingual paraesthesia during infusion (n = 2) (symptoms subsided 2‐5 min post infusion) Placebo: none given
Maralixibat
Mayo 2019	Randomised, placebo‐controlled, dose‐ranging study	CP	Maralixibat	10 mg/d	66	Diarrhoea (n = 14), abdominal pain (n = 4), abdominal pain upper (n = 4), nausea (n = 5), abdominal distension (n = 3), chills (n = 2), back pain (n = 2), muscle spasms (n = 2), headache (n = 3), cough (n = 4)
				20 mg/d		Diarrhoea (n = 11), abdominal pain (n = 5), abdominal pain upper (n = 6), nausea (n = 4), pain in extremity (n = 3), headache (n = 2), cough (n = 1), pruritus (n = 1)
			Placebo	matching		Diarrhoea (n = 6), abdominal pain (n = 1), abdominal pain upper (n = 2), nausea (n = 4), abdominal distension (n = 3), headache (n = 8), pruritus (n = 3)
Mirtazapine
Gholyaf 2020	Randomised, controlled, comparative cross‐over study	UP	Mirtazapine	Mirtazapine: 15 mg/d	77	Drowsiness (n = 20), dizziness (n = 4), dry mouth (n = 13), constipation (n = 8), nausea (n = 3), dyspepsia (n = 3)
			Gabapentin	100 mg/d		Drowsiness (n = 10), dizziness (n = 11), dry mouth (n = 5), constipation (n = 3), nausea (n = 9), dyspepsia (n = 5)
Montelukast
Mahmudpour 2017	Randomised, placebo‐controlled study	UP	Montelukast	10 mg/d	80	None reported
Nasrollahi 2007	Randomised, placebo‐controlled cross‐over study	UP	Montelukast	10 mg/d	16	Major (leading to withdrawal): 1 man faced anaemia that was diagnosed as myelodysplastic syndrome during placebo period after receiving montelukast for 20 days; 1 diabetic woman with ischaemic heart disease died during placebo period of myocardial infarction.

CP: cholestatic pruritus
CR845: difelikefalin
CS: cromolyn sodium
HCl: hydrochloride
HD: hemodialysis
HIV: human immunodefeciency virus
IU: international units
IV: intravenous
q.h.s.: every night at bedtime
SAE: serious adverse event
TSH: thyroid stimulating hormone
UP: uraemic pruritus

9. Adverse events according to different studies (2).

Study	Design	Pruritus/disease	Intervention	Dose	Participants (dropouts included)	Adverse events
Nalbuphine
Mathur 2017	Randomised, placebo‐controlled, dose‐ranging study	UP	Nalbuphine	120 mg	373	nausea (10%), vomiting (5%), somnolence (1.7%)
				60 mg		nausea (9.5%), vomiting (9.5%), somnolence (4%)
				Placebo		nausea (9.5%), vomiting (2.4%), death (n = 1)
Nalfurafine
Bhaduri 2006	Randomised, placebo‐controlled, dose‐ranging trial	UP	Nalfurafine	IV: 2.5, 5 µg with dialysis	78	None reported
Kumada 2017	Randomised, placebo‐controlled, dose‐ranging study	CP	Nalfurafine	2.5 μg /d	317	insomnia (n = 6), somnolence (n = 6), dizziness (n = 2), constipation (n = 4), pollakiuria (n = 6), blood prolactin increased (n = 14), blood antidiuretic hormone increased (n = 8), blood thyroid stimulating hormone increased (n = 7), total bile acids increased (n = 8)
				5 μg/d		insomnia (n = 5), somnolence (n = 8), dizziness (n = 6), constipation (n = 8), pollakiuria (n = 8), blood prolactin increased (n = 8), blood antidiuretic hormone increased (n = 8), blood thyroid stimulating hormone increased (n = 4), total bile acids increased (n = 2)
				Placebo		insomnia (n = 3), somnolence (n = 1), dizziness (n = 4), constipation (n = 2), pollakiuria (n = 1), blood prolactin increased (n = 9), blood antidiuretic hormone increased (n = 9), blood thyroid stimulating hormone increased (n = 7), total bile acids increased (n = 2)
Kumagai 2010	Randomised, placebo‐controlled study	UP	Nalfurafine	2.5 µg/d	337	nasopharyngitis (12.3%), insomnia (14.9%), somnolence (3.5%), constipation (7.9%) Adverse drug reactions: incidence 35.1%: insomnia (n = 16), anorexia (n = 1), headache (n = 1), pruritus (n = 1), decreased blood TSH (n = 2), mood altered (n = 1), elevated mood (n = 1), feeling abnormal (n = 1), increases in prolactin (n = 3), decrease in free testosterone (n = 1)
				5 µg/d		nasopharyngitis (8.0%), insomnia (7.1%), somnolence (4.5%), diarrhoea (4.5%) Adverse drug reactions: incidence 25.0%, insomnia (n = 8), sudden hearing loss (n = 1), hypertension (n = 1), vomiting (n = 1), nausea (n = 1), increased eosinophiles (n = 1), increases in prolactin (n = 3), decrease in free testosterone (n = 1)
				Placebo		nasopharyngitis (17.1%), headache (3.6%), vomiting (3.6%) Adverse drug reactions: incidence 16.2%, headache (n = 1), increases in prolactin (n = 1), decrease in free testosterone (n = 1)
Wikström 2005a	Meta‐analysis of 2 randomised, double‐blind, placebo‐controlled studies	UP	Nalfurafine	5 µg 3 x/wk IV	79	Nalfurafine: 17 of 26 participants: headache (n = 3), nausea (n = 3), insomnia (n = 2), vertigo (n = 2), vomiting (n = 2), severe headache (n = 1), severe insomnia (n = 1); Leading to withdrawal: moderate nausea and vomiting (n = 1) Placebo: 13 of 25 participants had adverse drug reactions: no description Serious adverse event (SAE): n = 2 (8%) participants in the nalfurafine 5 µg group and n = 6 (24%) participants in the placebo group reported at least one SAE, but none were considered to be drug‐related
Wikström 2005b	Meta‐analysis of 2 RCTs	UP	Nalfurafine	5 µg 3 x/wk IV	65 (not clearly stated)	Nalfurafine: 2 of 16 participants: vertigo (n = 1), elevations of aspartate aminotransferase and alanine transaminase (n = 1) Placebo: 2 of 18 participants had adverse drug reactions: no description Serious adverse event (SAE): 3 participants in the nalfurafine 5 µg group and 3 participants in the placebo group reported a SAE, but none were considered to be drug‐related
Naltrexone
Legroux‐Crespel 2004	Randomised, controlled, comparative trial	UP	Naltrexone	50 mg/d	52	30 events in 15 participants: Major: vertigo (n = 4), nausea (n = 9), malaise (n = 1), cramps (n = 2), sleeping disturbances (n = 1), anorexia (n = 1) Minor: vomiting (n = 2), abdominal distention (n = 1), sleep disturbances (n = 4), vertigo (n = 1), headaches (n = 2), somnolence (n = 1), paraesthesia (n = 1) Withdrawals: 12 participants (n = 4 due to vertigo, n = 3 due to nausea, n = 1 due to malaise, n = 2 for cramps, n = 1 due to sleeping disturbances and n = 1 due to anorexia
			Loratadine	50 mg/d		3 events in 2 participants: Major: vomiting (n = 1), malaise (n = 1) Minor: vomiting (n = 1) Withdrawals: 3 participants (n = 1 due to vomiting, n = 1 due to malaise, n = 1 without relation with loratadine
Pauli‐Magnus 2000	Randomised, placebo‐controlled cross‐over study	UP	Naltrexone	50 mg/d	23	Naltrexone: Major: gastrointestinal side effects (leading to withdrawal: n = 3) Minor: gastrointestinal side effects (n = 6) Placebo: Major: gastrointestinal side effects (leading to withdrawal; n = 1)
Peer 1996	Randomised, placebo‐controlled cross‐over study	UP	Naltrexone vs. placebo	50 mg/d	15	Naltrexone: Minor: minor heart burn (n = 2), upper abdominal discomfort (n = 3) Placebo: adverse events not given
Terg 2002	Randomised, placebo‐controlled cross‐over study	CP	Naltrexone	50 mg/d	20	Naltrexone: dizziness (n = 10), nausea (n = 8), vomiting (n = 6), headache (n = 5), abdominal cramps (n = 5), asthenia (n = 3), drowsiness (n = 3), irritability (n = 3), dry mouth (n = 3), insomnia (n = 2), tremor (n = 1), tachycardia (n = 1), anorexia (n = 1), flushing (n = 1), arterial hypertension (n = 1) Placebo: nausea (n = 1), vomiting (n = 2), headache (n = 3), abdominal cramps (n = 1), drowsiness (n = 2), irritability (n = 2)
Wolfhagen 1997	Randomised, placebo‐controlled study	CP	Naltrexone	50 mg/d	16	Naltrexone: nausea (n = 4), dizziness (n = 3), flushing (n = 2), drowsiness (n = 2), headache (n = 1), nightmares (n = 1), tremor (n = 1), abdominal cramps (n = 5), dry mouth (n = 2), peripheral oedema (n = 1), night‐sweating (n = 1) Placebo: abdominal cramps (n = 1), dry mouth (n = 1), irritability (n = 1), epistaxis (n = 1), swelling of the hands (n = 1)
Nicergoline
Rivory 1984	Randomised, placebo‐controlled, dose‐ranging cross‐over study	UP	Nicergoline	Nicergoline (oral): 30 mg/d	13	No information given
				Nicergoline 5 mg as a continuous IV infusion
Nicotinamide (vitamin B3)
Omidian 2013	Randomised, placebo‐controlled study	UP	Nicotinamide	500 mg 2 x/d	50	None observed
Omega‐3 with active ingredients: Eicosapentaenoic Acid (EPA), Docosahexaenoic Acid (DHA)
Ghanei 2012	Randomised, placebo‐controlled cross‐over study	UP	Omega‐3	1 g omega‐3 capsule contained 180 mg of eicosapentaenoic acid (EPA) and 120 mg of docosahexaenoic acid (DHA), 1 x/8h	22	None observed
Lahiji 2018	Randomised, placebo‐controlled cross‐over study	UP	Omega‐3	3 omega‐3 capsules; each 1 g capsule of omega‐3 contained 180 mg EPA and 120 mg DHA	40	None reported
Ondansetron
Ashmore 2000	Randomised, placebo‐controlled cross‐over study	UP	Ondansetron	8 mg 3 x/d	16	Not given
Mirnezami 2013	Randomised, controlled, comparative trial	UP	Ondansetron	8 mg 3 x/d	70	None reported
			Loratadine	10 mg, 2 x/d
Murphy 2003	Randomised, placebo‐controlled, cross‐over study	UP	Ondansetron	8 mg 3 x/d	24	Ondansetron: Major (leading to withdrawal): constipation (n = 1) Placebo: none given
O'Donohue 2005	Randomised, placebo‐controlled study	CP	Ondansetron	8 mg 2 x/d	19	Ondansetron: Minor: moderate increases from baseline in serum alkaline phosphatase and bilirubin levels (n = 1), constipation (n = 4) Placebo: Minor: nausea (n = 3), headache (n = 2)
Özaykan 2001	Randomised, controlled, comparative trial	UP	Ondansetron	8 mg/d	20	nausea (n = 3) but disappeared at the end of therapy
			Cyproheptadine	8 mg/d		None observed
Subach 2001	Randomised, comparative, placebo‐controlled three‐way cross‐over study	UP	Ondansetron	3 doses of 8 mg	23	None reported
			Diphenhydramine	3 doses of 25 mg
			Placebo	3 doses of matching placebo
Yue 2015	Randomised, placebo‐controlled 3‐armed comparative trial	UP	Pregabalin	75 mg 2 x/wk	188	Major (leading to withdrawal): somnolence: n = 3; dizziness: n = 1; loss of balance: n = 1
			Ondansetron	8 mg/d		Major (leading to withdrawal): nausea and vomiting: n = 2
Paroxetine
Zylicz 2003	Randomised, placebo‐controlled cross‐over study	Pruritus in palliative care patients (var.)	Paroxetine	20 mg/d	26	Paroxetine: Major: severe nausea and vomiting (leading to withdrawal: n = 2) Minor: sleepiness
Pimecrolimus
Ghorbani 2012	Randomised, placebo‐controlled trial	UP	Pimecrolimus ointment (topical): 1%	2 x/d	60	Pimecrolimus: burning sensation which disappeared by the end of 8 weeks Placebo: none given
Ghorbani Birgani 2011	Randomised, controlled, comparative trial	UP	Pimecrolimus: 2%	2 x/d	60	None reported
			Cromolyn: 4%
Pramoxine‐Hydrochloride
Young 2009	Randomised, vehicle‐controlled study	UP	Pramoxine‐HCl	1% lotion 2 x/d	28	None observed
Pregabalin
Fouroutan  2017	Randomised, controlled, comparative study	UP	Pregabalin	50 mg every second day	90	somnolence (n = 6), oedema (n = 3), drowsiness (n = 3), imbalance during walking (n = 1) and numbness (n = 1)
			Doxepin	10 mg/d		somnolence (n = 5), nervousness (n = 1)
Najmeh 2019	Randomised, controlled, comparative study	UP	Pregabalin	50 mg/d	30	None reported
			Ketotifen	2 x/d amount not reported
Propofol
Borgeat 1993	Randomised, placebo‐controlled cross‐over study	CP	Propofol	15 mg/d IV	10	Propofol: Minor: presence of pain on injection (n = 3), dizziness of 10‐20 seconds' duration (n = 2) Placebo: none observed
Rifampicin
Bachs 1989	Randomised, placebo‐controlled cross‐over study	CP	Rifampicin	10 mg/kg/d	22	Haemolytic anaemia and renal failure (n = 1)
			Phenobarbitone	3 mg/kg/d		Skin rash after a few days of treatment (n = 3), sedative effect
Ghent 1988	Randomised, placebo‐controlled cross‐over study	CP	Rifampicin	300 mg/d‐450 mg/d	9	None reported
Podesta 1991a	Randomised double‐blind placebo‐controlled cross‐over study	CP	Rifampicin	600 mg/d	14	None reported
Sertraline
Ataei 2019	Randomised, controlled comparative trial	CP	Sertraline	100 mg/d	36	mild nausea (n = 3)
			Rifampin	300 mg/d		mild nausea (n = 1); change of urine colour; adverse effects on hepatobiliary enzyme levels
Mayo 2007	Randomised, placebo‐controlled cross‐over study	CP	Sertraline	25‐100 mg/d	12	Sertraline: Minor (during dose‐escalation trial): increase in bowel frequency (n = 2), visual hallucinations (n = 2), increase in fatigue (n = 2), insomnia (n = 3), nausea (n = 1); Major: (during dose‐escalation trial): dizziness (n = 1), beneficial effect of increased mood stability Placebo: Minor: increase in fatigue (n = 1), insomnia (n = 6), nausea (n = 1), taking no drug (baseline, washout): increase in fatigue (n = 1), insomnia (n = 14), nausea (n = 1)
Pakfetrat 2018	Randomised, placebo‐controlled trial	UP	Sertraline	50 mg 2 x/d	50	None reported
Sodium thiosulfate
Mohamed 2012	Randomised, placebo‐controlled trial	UP	Sodium thiosulfate	12.5 mg/dialysis session	45	None reported
Tacrolimus
Duque 2005	Randomised, vehicle‐controlled study	UP	Tacrolimus	0.1% ointment 2 x/d	22	Tacrolimus: At baseline: warm sensations (n = 8) In week 4: warm sensations (n = 6), significant burning sensation (n = 1) Vehicle: At baseline: warm sensations (n = 2) In week 4: warm sensations (n = 3)
Thalidomide
Silva 1994	Randomised, placebo‐controlled cross‐over study	UP	Thalidomide	100 mg/d	29	None observed
Topical capsaicin
Breneman 1992a	Randomised, vehicle‐controlled study	UP	Capsaicin	0.025% cream 4 x/d	7	Capsaicin: Minor: mild burning sensation in both arms (n = 1) Major: mild burning sensation in the capsaicin‐treated arm (n = 1) Placebo: none observed
Cho 1997	Randomised vehicle‐controlled cross‐over study	UP	Capsaicin	0.025% cream 4 x/d	22	Capsaicin: Minor: skin burning or stinging sensations (or both) (n = 11), cutaneous erythema (n = 5); adverse events were mild and tolerable Vehicle:None reported
Makhlough 2010	Randomised vehicle‐controlled cross‐over study	UP	Capsaicin	0.03% ointment 4 x/d	34	Capsaicin: Minor: skin burning mild (n = 23), moderate (n = 10), severe (n = 1) Placebo: none observed
Tarng 1996	Randomised, vehicle‐controlled cross‐over study	UP	Capsaicin	0.025% cream 4 x/d	19	Capsaicin: 75% (12 of 16) adverse events occurred during treatment Placebo: 25% (4 of 16) adverse events occurred on placebo Adverse events: 93.7% were related to local burning and/or stinging sensations and 6.3% to cutaneous erythema; adverse events were mild, transient and tolerable by the participants.
Zinc sulphate
Mapar 2015	Randomised, triple, placebo‐controlled study	UP	Zinc sulphate	220 mg daily	40	None observed
Najafabadi 2012	Randomised, placebo‐controlled study	UP	Zinc sulphate	220 mg 2 x/d	40	None observed
Somkearti 2021	Randomised, placebo‐controlled study	UP	Zinc sulphate	220 mg 2 x/d	56	No difference between groups

CP: cholestatic pruritus
DHA: docosahexaenoic acid
EPA: eicosapentaenoic acid
HCl: hydrochloride
IV: intravenous
SAE: serious adverse event
TSH: thyroid stimulating hormone
UP: uraemic pruritus
vs.: versus

See the Characteristics of included studies table for detailed information on each trial.

Participants with advanced diseases suffering from UP or CP

GABA‐analogues (gabapentin, pregabalin)

Oral and topical GABA‐analogues versus placebo

Eight placebo‐controlled RCTs examined the effect of gabapentin (Aquino 2020; Gunal 2004; Naghibi 2007; Naini 2007; Nofal 2016; Rossi 2019; Tol 2010) and pregabalin (Yue 2015) in participants suffering from UP.

Aquino 2020: in a double‐blind, vehicle (placebo)‐controlled trial, 30 participants on haemodialysis were randomly assigned to receive either topical 6% gabapentin for two weeks or vehicle (placebo). Topical gabapentin (6 g gabapentin in 100 g permeation cream) or placebo was administered once per day.

Gunal 2004: in a double‐blind, placebo‐controlled, cross‐over study, 25 participants on haemodialysis were randomly assigned to receive gabapentin for four weeks followed by placebo for four weeks, or vice versa. Oral gabapentin (300 mg) or placebo was administered three times weekly at the end of the haemodialysis sessions.

Naghibi 2007: in a double‐blind, placebo‐controlled cross‐over study 20 participants on maintenance haemodialysis were enrolled and assigned to receive four weeks of treatment with either oral gabapentin (dose and frequency not reported) or placebo.

Naini 2007: in a double‐blind, placebo‐controlled trial, 34 participants on maintenance haemodialysis were enrolled and assigned to receive four weeks of treatment with either oral gabapentin (400 mg) or placebo administered twice‐weekly after haemodialysis sessions.

Nofal 2016: in a single‐blind, placebo‐controlled trial, 54 participants on maintenance haemodialysis were enrolled and assigned to receive four weeks of treatment with either oral gabapentin (starting with 100 mg; in cases with no improvement, the dose was gradually titrated up to a maximum of 300 mg after each HD session) or placebo administered after haemodialysis sessions.

Rossi 2019: in a double‐blind, placebo‐controlled trial with three arms, 25 participants on maintenance haemodialysis were enrolled and assigned to receive two weeks of treatment with either oral gabapentin (100 mg or 300 mg each HD session) or placebo administered three times/week after haemodialysis sessions.

Tol 2010: in a placebo controlled cross‐over trial, 14 UP participants were assigned to either take oral gabapentin 300 mg/HD session or placebo. The authors did not report placebo results.

Yue 2015: in a double‐blind, placebo‐controlled trial with three arms, 188 participants on maintenance haemodialysis were enrolled and assigned to receive two weeks of treatment with either 75 mg oral pregabalin twice‐weekly, 8 mg oral ondansetron per day, or placebo.

GABA‐analogues versus active control

Twelve RCTs examined the effect of gabapentin compared to an active control in participants with UP (Amirkhanlou 2016; Begum 2004; Fouroutan  2017; Gholyaf 2020; Gobo‐Oliveira 2018; Kebar 2020; Marin 2013; Najmeh 2019; Noshad 2011; Ravindran 2020; Solak 2012; Suwanpidokkul 2007). Begum 2004 is described elsewhere (Fish‐oil/omega‐3 fatty acids).

Amirkhanlou 2016: in a double‐blind comparative trial, 52 participants received either oral 100 mg gabapentin daily or 1 mg ketotifen twice daily for two weeks.

Fouroutan  2017: in a comparative trial with unclear blinding, 90 participants received either 100 mg oral pregabalin every second day or 10 mg doxepin daily for four weeks.

Gholyaf 2020: in a double‐blind controlled cross‐over trial, 77 participants were treated with either 15 mg oral mirtazapine or 100 mg oral gabapentin for two weeks.

Gobo‐Oliveira 2018: in a double‐blind trial, 60 participants received either 300 mg oral gabapentin per day or 25 mg hydroxyzine per day for two weeks.

Kebar 2020: in a double‐blind cross‐over trial, 32 participants received either 100 mg oral gabapentin or 25 mg hydroxyzine for six weeks (six weeks sequence 1, two weeks washout, six weeks sequence 2).

Marin 2013: in an open‐label comparative trial, 36 participants received either 300 mg oral gabapentin per day or 10 mg loratadine per day for nine weeks.

Najmeh 2019: in a double‐blind trial, 30 participants received either 50 mg oral pregabalin per day or ketotifen (amount not reported) per day for four weeks.

Noshad 2011: in a double‐blind trial, 40 participants received either 100‐200 mg oral gabapentin per day or 10 mg hydroxyzine per day for four weeks.

Ravindran 2020: in a single‐blind trial, 50 participants received either 100 mg gabapentin per day or 25 mg pregabalin (route not reported, probably per os) per day for six weeks.

Solak 2012: in a double‐blind cross‐over trial, 50 participants received either 300 mg oral gabapentin after HD (thrice weekly) or 75 mg oral pregabalin per day for six weeks (six weeks sequence 1, two weeks washout, six weeks sequence 2).

Suwanpidokkul 2007: in a double‐blind cross‐over trial, 19 participants received either 100 mg oral gabapentin per day or 10 mg loratadine per day for four weeks (four weeks sequence 1, two weeks washout, four weeks sequence 2).

One study researched gabapentin in participants with CP. Bergasa 2006: in a double‐blind, randomised, placebo‐controlled trial, 16 CP participants (women) with chronic liver disease and chronic pruritus were randomised to gabapentin or placebo, starting with a divided dose of 300 mg oral gabapentin per day and increasing to a maximum of 2400 mg per day until relief of pruritus.

κ‐opioid agonists (difelikefalin, nalbuphine, nalfurafine) versus placebo

Eight placebo‐controlled RCTs (Bhaduri 2006; Fishbane 2020a; Fishbane 2020b; Kumagai 2010; Mathur 2017; Spencer 2015; Wikström 2005a; Wikström 2005b) examined the effect of opioid kappa agonists (difelikefalin, nalbuphine, nalfurafine) in 1550 participants with UP and one study (Kumada 2017) investigated the effects of nalfurafine on participants suffering from CP.

Bhaduri 2006: in a placebo‐controlled trial with unclear blinding and three arms, 78 participants were enrolled and assigned to receive five weeks of treatment with either intravenous nalfurafine (2.5 or 5 μg) or placebo. No decrease in itch on VAS was reported.

Fishbane 2020a: in a double‐blind, placebo‐controlled trial, 378 participants were enrolled and assigned to receive 12 weeks of treatment with either intravenous difelikefalin (CR845) every dialysis session (thrice a week) or placebo.

Fishbane 2020b: in a double‐blind, placebo‐controlled trial with four arms, 174 participants were enrolled and assigned to receive eight weeks of treatment with either an intravenous bolus of difelikefalin (0.5, 1.0, or 1.5 μg/kg) at the end of each haemodialysis session or placebo.

Kumada 2017: in a double‐blind, placebo‐controlled trial with three arms, 317 adult participants were enrolled and assigned to receive 12 weeks of treatment with either oral nalfurafine (2.5 or 5 μg) once daily after the evening meal or placebo.

Kumagai 2010: in a phase III, double‐blind placebo‐controlled study, 337 participants were enrolled to receive 5 μg (N = 114) or 2.5 μg (N = 112) of nalfurafine or a placebo (N = 111) orally for two weeks.

Mathur 2017: in a double‐blind, placebo‐controlled trial with three arms, 373 participants were enrolled and assigned to receive eight weeks of treatment with either oral nalbuphine (60 or 120 mg) twice daily or placebo.

Wikström 2005a and Wikström 2005b: two multicentre, double‐blind, placebo‐controlled studies enrolled 144 participants to postdialysis intravenous treatment with either nalfurafine or placebo for two to four weeks. The first study (study 1) used a parallel‐group design with treatment lasting for four weeks. Seventy‐nine participants were randomly assigned in this study, and 74 completed the four weeks of treatment. After the run‐in period, participants were randomly assigned to receive nalfurafine 5 g (N = 26) or placebo (N = 25) three times weekly by intravenous infusion, immediately after completion of each haemodialysis session during the four weeks. A follow‐up visit was performed two weeks after administration of the final dose of study medication. The second study (study 2) used a cross‐over design in which participants were randomly chosen to receive an intravenous infusion of either nalfurafine 5 g or placebo three times weekly for two weeks. At the completion of the first treatment period, participants underwent a three‐week washout period followed by another one‐week run‐in period. Participants were then crossed over to the other study medication for an additional two weeks of therapy. Thirty‐four participants were randomly assigned to this study, and 31 completed the four weeks of treatment.

Spencer 2015: in a double‐blind, placebo‐controlled trial, 65 participants were enrolled and assigned to receive 15 days of treatment with either 1 µg/kg intravenous difelikefalin (CR845) every dialysis session or placebo.

Serotonin 5‐HT₃ antagonist ondansetron versus active control or placebo

Six RCTs researched the effect of the emetic agent ondansetron comparing to placebo or active control in 341 participants suffering from UP (Ashmore 2000; Mirnezami 2013; Murphy 2003; Özaykan 2001; Subach 2001; Yue 2015). One RCT examined the effect of ondansetron in 19 participants suffering from CP (O'Donohue 2005).

Ashmore 2000: in a double‐blind, placebo‐controlled cross‐over study, 16 participants were assigned to treatment with 8 mg oral ondansetron or placebo three times daily for two weeks, washout 1 (day 1‐7), ondansetron/placebo (day 8‐21), washout 2 (day 22‐28), cross‐over (day 29‐42).

Mirnezami 2013: in a double‐blind comparative study, 70 participants were treated with either oral ondansetron (8 mg) thrice per day or oral loratadine (10 mg) twice per day for two weeks.

Murphy 2003: in a double‐blind, placebo‐controlled trial, 24 UP participants on haemodialysis were enrolled and blindly allocated on a random basis to the ondansetron–placebo sequence (14 participants) or to the placebo–ondansetron sequence (10 participants). During the treatment, participants received either 8 mg of ondansetron three times a day or a placebo tablet three times a day for two weeks. The washout period between the cross‐over treatment periods was seven days.

O'Donohue 2005: in a double‐blind, placebo‐controlled study, a total of 19 UP participants with resistant pruritus were randomised to receive either ondansetron 8 mg or placebo as a single intravenous bolus, followed by oral ondansetron 8 mg or placebo twice daily for two days.

Özaykan 2001: an open‐label, comparative trial investigated the antipruritic effects of ondansetron and cyproheptadine in 20 UP participants. Ten participants were given 8 mg/d ondansetron, and the other 10 participants were given 8 mg/d cyproheptadine orally, for 30 days. The study was published in Turkish.

Subach 2001: in a double‐blind, placebo‐controlled cross‐over study, 23 UP participants treated with either ondansetron (8 mg), diphenhydramine 25 mg, or matching placebo during 9 separate occasions of HD. VAS was measured at 30, 60, and 120 min after administration.

Yue 2015: see Description of studies, GABA‐analogues.

Leukotriene receptor antagonist montelukast versus placebo

Mahmudpour 2017: in a placebo‐controlled RCT, 80 UP participants received either 10 mg oral montelukast or placebo for 30 days.

Nasrollahi 2007: in a single‐blind, placebo‐controlled cross‐over multicentre trial with refractory UP, 16 participants were divided into two groups to first receive montelukast 10 mg daily for 20 days and then placebo, or vice versa. The washout period was 14 days.

Fish‐oil/omega‐3 fatty acids versus active control or placebo

Begum 2004: in a comparative trial with unclear blinding, 22 participants with UP received either oral fish oil (6 g ethyl ester) once per day every second day or oral safflower oil (6 g ethyl ester) daily for 14 weeks.

Forouhari 2022: in a double‐blind, placebo‐controlled cross‐over trial, 40 participants with UP were randomised and treated with omega‐3 fatty acids (capsules containing 180 mg EPA and 120 mg DHA) or placebo. The 1 g capsules of the study drug and placebo had to be taken every eight hours for four weeks (four weeks sequence 1, six weeks washout, four weeks sequence 2).

Ghanei 2012: in a double‐blind, placebo‐controlled cross‐over trial, 22 participants with UP were randomised and treated with omega‐3 fatty acids or placebo. The 1 g capsules of the study drug and placebo had to be taken every eight hours for 20 days (20 days sequence 1, two weeks washout, 20 days sequence 2).

Lahiji 2018: in a double‐blind, placebo‐controlled cross‐over trial, 40 participants with UP received either 3 omega‐3 capsules (each 1‐g capsule of omega‐3 contained 180 mg EPA and 120 mg DHA) once per day for four weeks or placebo (four weeks sequence 1, six weeks washout, four weeks sequence 2).

Mortazavi  2017: in a double‐blind cross‐over trial, 20 participants with UP received either oral fish oil (1 g) thrice per day for four weeks or placebo (four weeks sequence 1, washout, four weeks sequence 2).

Shayanpour 2019: in a double‐blind, placebo‐controlled trial, 64 participants with UP received either a single‐dose of 2 g omega‐3 daily before lunch for three weeks or placebo.

Zinc sulphate versus placebo

Mapar 2015: in a double‐blind, placebo‐controlled study, 40 participants with UP were treated with either 220 mg oral zinc sulphate daily or the placebo for four weeks.

Najafabadi 2012: in a double‐blind, placebo‐controlled study, 40 participants with UP were treated with either 220 mg oral zinc sulphate twice daily or placebo for eight weeks.

Somkearti 2021: in a double‐blind, placebo‐controlled study, 55 participants with UP were treated with either 220 mg oral zinc sulphate twice daily or placebo for 12 weeks.

Oral and topical mast cell stabiliser cromolyn sodium versus placebo

Feily 2012: in a double‐blind, vehicle‐controlled trial, 60 participants with UP received topical cromolyn sodium (4%) twice a day or a vehicle for four weeks.

Vessal 2010: in a double‐blind, placebo‐controlled study, 62 participants with UP received 135 mg oral cromolyn sodium thrice daily or placebo for eight weeks.

Topical capsaicin versus placebo

Breneman 1992a: in a double‐blind, vehicle‐controlled trial conducted to evaluate the efficacy and safety of capsaicin 0.025% cream in the treatment of localised areas of pruritus in participants with UP, seven participants were treated with either capsaicin 0.025% cream or the vehicle for six weeks. Each participant was provided with two sets of tubes: one contained capsaicin 0.025% cream and the other contained the vehicle. Participants were assigned on a random basis to either arm in a double‐blinded fashion. The tubes were identical except for the designations of right and left. Participants were instructed to apply the cream four times daily and to apply medication from one set of tubes only, and specifically to one arm of the body, and medication from the other set of tubes likewise to the other arm for six weeks.

Cho 1997: a double‐blind, vehicle‐controlled, cross‐over single‐centre study of capsaicin 0.025% cream with two four‐week treatment periods and a 14‐day washout period was conducted with 22 participants with UP to evaluate the role of parathyroid hormone (PTH) and substance P in UP and to elucidate the underlying mechanisms. For this purpose, in the first phase of the study the correlation between the intensity of itching and serum levels of intact PTH was tested. For the second phase, participants were further stratified into two subgroups with low intact PTH (≤ 35 pg/mL) and high intact PTH (> 35 pg/mL). Subsequently, the double‐blind cross‐over trial with topical capsaicin was conducted in the two subgroups. Participants applied capsaicin or vehicle creams four times daily to a pre‐selected area of skin throughout each treatment period.

Makhlough 2010: a double‐blind, vehicle‐controlled cross‐over clinical trial was performed on 34 participants with UP to research the effect of topical capsaicin versus vehicle in a single‐centre clinical setting. The participants were divided into two groups: one group received capsaicin 0.03% and the other vehicle for four weeks. Treatment was stopped for two weeks during the washout period and was then continued following a cross‐over.

Tarng 1996: to assess the efficacy and safety of capsaicin 0.025% cream in the treatment of UP and to further explore the underlying pathomechanism in a double‐blind, vehicle‐controlled, cross‐over, single‐centre study, 19 haemodialysis participants with UP were treated with capsaicin 0.025% cream or vehicle during two four‐week treatment periods, with a two‐week washout phase between treatments and a follow‐up of eight weeks without treatment. Treatment was applied to a selected area four times daily.

Opioid antagonist naltrexone versus active control or placebo

Three studies researched the antipruritic effect of the opioid antagonist naltrexone in participants suffering from UP or CP (Legroux‐Crespel 2004; Pauli‐Magnus 2000; Peer 1996); two studies evaluated naltrexone in patients with CP (Terg 2002; Wolfhagen 1997).

Legroux‐Crespel 2004: in a comparative trial with unclear blinding researching naltrexone versus loratadine, 52 participants with UP received 50 mg oral naltrexone daily or 10 mg oral loratadine daily for two weeks, after a washout of 48 hours.

Pauli‐Magnus 2000: in a double‐blind, placebo‐controlled cross‐over trial, 23 participants with UP received either a four‐week naltrexone sequence (50 mg/d) or matched placebo (four weeks sequence 1, one week washout, four weeks sequence 2).

Peer 1996: in a double‐blind, placebo‐controlled cross‐over trial, 15 participants received either 50 mg oral naltrexone daily or placebo (one week sequence 1, one week washout, one week sequence 2).

Terg 2002: in a double‐blind, placebo‐controlled cross‐over study, 20 participants with CP were included and randomised to receive oral 50 mg/d of naltrexone or placebo for two weeks (two weeks sequence 1, one week washout, two weeks sequence 2).

Wolfhagen 1997: in a double‐blind, placebo‐controlled study, 16 participants with CP were randomised to receive 50 mg/d of oral naltrexone or placebo daily for four weeks.

Antihistamines (bilastine, cimetidine, desloratadine, hydroxyzine) versus active control or placebo

Aubia 1980: in a double‐blind, placebo‐controlled trial, 13 UP participants received either 600 mg oral cimetidine per day or placebo for four weeks.

Chourdakis 2019: in an open‐label, comparative trial, 20 UP participants received either 5 mg oral desloratadine per day or 20 mg oral bilastine per day for one month.

Nakhaee 2015: in a non‐blinded, cross‐over trial, 25 UP participants treated for two weeks with avena sativa (twice daily), vinegar solution (twice daily) or 10 mg oral hydroxyzine per day (every night). Although we did not consider avena sativa and vinegar solution as pharmacological interventions, we included the study because the treatments were compared to hydroxyzine.

Antidepressants (sertraline, mirtazapine, doxepin, paroxetine) versus active control or placebo

Ataei 2019: in a single‐blind, comparative trial, 36 participants with CP received either 100 mg oral sertraline per day or 300 mg rifampin per day for four weeks.

Gholyaf 2020: in a double‐blind, cross‐over trial, 77 participants with UP received either 15 mg oral mirtazapine daily or 100 mg oral gabapentin for eight weeks (two weeks washout, two weeks sequence 1, two weeks washout, two weeks sequence 2).

Mayo 2007: 21 participants with CP underwent an open‐label, dose escalation to determine the dose with optimal efficacy and tolerability. After a washout period, 12 of the participants entered a randomised, double‐blind, placebo‐controlled cross‐over trial. Participants were treated for six weeks, then had a washout period of four weeks, and crossed over to the other therapy for six weeks.

Pakfetrat 2018: in a placebo controlled, cross‐over trial, 77 participants with UP received either 50 mg oral sertraline twice daily or placebo (two weeks washout, two weeks sequence 1, two weeks washout, two weeks sequence 2).

Pour‐Reza‐Gholi 2007: a double‐blind trial with a cross‐over design assigned 24 participants with UP to two groups, who received either 10 mg oral doxepin twice daily or placebo for one week. After a one‐week washout period, the two groups switched treatments.

Bile acid sequestrants (cholestyramine, colesevelam) versus active control or placebo

Four RCTs (Duncan 1984; Kuiper 2010; Silverberg 1977; Van Leusen 1978) investigated the effect of cholestyramine in participants with CP or UP.

Duncan 1984: a single‐blind, cross‐over comparative trial compared the antipruritic activity of oral cholestyramine (4 g twice daily), oral chlorpheniramine (4 mg up to three times daily), and placebo (lactose 200 mg up to three times daily) versus oral terfenadine (60 mg up to three times daily) in eight participants with CP over a treatment period of two weeks for each drug.

Silverberg 1977: in a double‐blind, placebo‐controlled trial, ten participants with UP received either 5 g oral cholestyramine twice daily or placebo over four weeks.

Kuiper 2010: in double‐blind, placebo‐controlled trial, 38 participants with CP, both treatment‐naive and previously treated, received 1875 mg of colesevelam or an identical placebo twice daily for three weeks.

Van Leusen 1978: in a double‐blind, placebo‐controlled, cross‐over trial, five participants with UP received either oral cholestyramine (5 mg) twice per day or placebo for four weeks (four weeks sequence 1, washout, four weeks sequence 2).

Immunosuppressants versus active control or placebo

Thalidomide

Silva 1994: in a double‐blind, placebo‐controlled cross‐over trial, 29 participants with UP were treated with 100 mg/d of oral thalidomide or placebo for seven days. After a washout period of one week, drugs were crossed over for another treatment period of one week.

Tacrolimus

Duque 2005: in a double‐blind, vehicle‐controlled trial, in 22 participants with UP investigators assessed the efficacy of tacrolimus ointment 0.1% for a treatment period of four weeks. Participants used one to eight 30 g tubes, with an average of four per participant. Medication was applied only on pruritic areas three times weekly by one of the investigators and by the participants at home twice a day for four weeks.

Pimecrolimus

Ghorbani 2012: in a double‐blind, placebo‐controlled trial, 60 UP participants received either topical pimecrolimus ointment 1% (amount not stated) or placebo twice per day for eight weeks.

Ghorbani Birgani 2011: in a blinded (unclear if double or single‐blind) comparative trial, 60 UP participants received either topical cromolyn cream 4% (amount not stated) or pimecrolimus cream 2% (amount not stated) twice per day for eight weeks.

Erythropoietin versus placebo

De Marchi 1992: in a double‐blind, placebo‐controlled cross‐over study, 20 participants with UP were enrolled to investigate the effects of recombinant human erythropoietin on pruritus and plasma histamine levels; participants with uraemia (10 with severe pruritus and 10 without) were randomised to receive either erythropoietin intravenously (36 U/kg of body weight three times weekly) or placebo for five weeks and then crossed over.

Sja'bani 1997: in a double‐blind, placebo‐controlled cross‐over study, 29 participants with UP were enrolled receiving either erythropoietin intravenously (2000 IU twice per week) or placebo.

Vitamin D2 ergocalciferol versus placebo

Shirazian 2013: in this double‐blind RCT, 50 participants with UP were randomised to the ergocalciferol group (vitamin D₂; 50,000 IU, one pill per week) or the placebo group for 12 weeks.

Vitamin B3 Nicotinamide versus placebo

Omidian 2013: in a double‐blind, placebo‐controlled trial, 50 participants with UP were randomised to the nicotinamide group or placebo group. The duration of the treatment was four weeks and nicotinamide was administered orally (500 mg twice daily).

Activated oral charcoal versus placebo

Pederson 1980: in a double‐blind, placebo‐controlled, cross‐over trial, 11 participants with UP were treated with oral charcoal 6 g daily or placebo and then vice versa in two consecutive eight‐week treatment periods. Authors did not mention a washout period between the treatments (eight weeks sequence 1, unspecified washout, eight weeks sequence 2).

Local anaesthetic lidocaine versus placebo

Villamil 2005: in a double‐blind, placebo‐controlled trial, 18 participants with CP were randomised (2:1) to receive 100 mg intravenous lidocaine (5 mL saline) over five minutes or placebo (5 mL saline). Investigators performed electrocardiographic monitoring during infusion and recorded vital signs every 15 minutes for the first hour after infusion.

Tapia 1977: in a double‐blind, placebo‐controlled trial, 20 participants with UP received 200 mg intravenous lidocaine (during HD and additional three times if no effect) over 15 minutes or placebo.

Pramoxine hydrochloride versus active control

Young 2009: a double‐blind, placebo‐controlled comparative trial assessed the efficacy of a commercially available anti‐itch lotion containing pramoxine hydrochloride versus control lotion in the treatment of UP in 28 participants for a one‐week treatment period.

Nicergoline versus placebo

Rivory 1984: in a double‐blind cross‐over trial with three treatment groups, 13 participants received either 30 mg oral nicergoline, 5 mg intravenous nicergoline (continues IV) or placebo for 12 weeks.

Sodium thiosulfate versus placebo

Mohamed 2012: in a placebo‐controlled trial with unclear blinding, 45 participants with UP received either intravenous sodium thiosulfate (12.5 mg) once per HD session or placebo for six months.

Semi‐antibiotic rifampicin versus active control or placebo

Three included studies with 55 participants investigated the treatment of CP with semi‐antibiotic rifampicin (Bachs 1989; Ghent 1988; Podesta 1991a).

Bachs 1989: in a comparative cross‐over trial with probably no blinding, 22 participants received either oral rifampicin (10 mg/kg) or oral phenobarbitone (3 mg/kg) for two weeks (two weeks sequence 1, 30 days washout, two weeks sequence 2).

Ghent 1988: a double‐blind, placebo‐controlled, cross‐over trial nine participants received either 300 mg to 450 mg/d oral rifampicin or placebo (two weeks sequence 1, two weeks washout, two weeks sequence 2).

Podesta 1991a: in a double‐blind, placebo‐controlled cross‐over study, researchers studied 14 participants with CP for three weeks after a 15‐day washout period. During the first and third week, participants received 600 mg of rifampicin or placebo. No treatment was administered during the second week (washout period and cross‐over). Subsequently, an open study evaluated the persistence of antipruritic effect and safety of rifampicin over an eight‐month period.

Flumecinol versus placebo

Turner 1994a: the initial trial was a double‐blind, placebo‐controlled study investigating the effect of low‐dose oral flumecinol (600 mg once weekly) in 50 participants with CP for three weeks. After a seven‐day baseline period, participants were randomised to flumecinol 600 mg or the identical placebo once weekly for three weeks. Participants took the medication on days 0, 7, and 14.

Turner 1994b: at least one month after completing the initial low dose trial, another double‐blind, placebo‐controlled study investigated the effect of high dose flumecinol in 19 participants with CP, two of whom had not participated in the low dose trial. The participants completed a seven‐day baseline VAS assessment of pruritus and quality of life and then were randomised to take either the treatment with 300 mg of flumecinol or identical placebo daily for 21 days.

Anaesthetic propofol versus placebo

Borgeat 1993: in a double‐blind, placebo‐controlled, cross‐over trial, 10 participants with CP received two doses of intravenous propofol (1.5 mL) and two doses of placebo (1.5 mL of intralipid) during a four‐day study period (two days sequence 1, unspecified washout, two days sequence 2).

Maralixibat versus placebo

Mayo 2019: in a double‐blind, placebo‐controlled trial with three arms, 66 participants with UP were randomised to receive either oral maralixibat (10 or 20 mg) once per day or placebo for 13 weeks.

Palliative care patients with pruritus of different origin

Selective serotonin reuptake inhibitor (SSRI) paroxetine versus placebo

Zylicz 2003: a double‐blind, placebo‐controlled cross‐over trial of the SSRI paroxetine versus placebo took place in two hospices. The 26 total participants, who had solid tumours (17/26), haematological malignancies (4/26), and various non‐malignant or idiopathic conditions (5/26), were heterogeneous and representative of people receiving palliative care. After a run‐in period, participants were randomly assigned to treatment with 20 mg paroxetine or placebo. Due to the advanced nature of their disease, the trial had to be short, and the cross‐over took place after seven days.

Participants with HIV‐associated pruritus

Hydroxyzine hydrochloride, pentoxifylline, triamcinolone, and indomethacin versus active control

Smith 1997a: a comparative trial with unclear blinding and four arms investigated the antipruritic effect of hydroxyzine hydrochloride with or without doxepin hydrochloride, pentoxifylline, triamcinolone, and indomethacin in patients with advancing HIV disease. Altogether, 40 participants (10 participants in each treatment group) took part in the study. Duration of the treatment was four to six weeks.

Funding sources

Pharmaceutical companies sponsored 17 of the 91 studies (19%): Ashmore 2000; Duque 2005; Fishbane 2020a; Fishbane 2020b; Ghanei 2012; Gobo‐Oliveira 2018; Kuiper 2010; Kumada 2017; Mathur 2017; Mayo 2019; O'Donohue 2005; Peer 1996; Smith 1997a; Spencer 2015; Suwanpidokkul 2007; Wolfhagen 1997; Young 2009 In Breneman 1992a, industry provided only capsaicin and vehicle creams. Another 19 studies (21%) were funded by the related university hospital (Ataei 2019; Fouroutan  2017; Ghent 1988; Gholyaf 2020; Kebar 2020; Pakfetrat 2018; Shayanpour 2019), the Robert Bosch Foundation (Pauli‐Magnus 2000) or other independent (e.g. government) sources (Bergasa 2006; Ghent 1988; Marin 2013; Mayo 2007; Murphy 2003; Pauli‐Magnus 2000; Shirazian 2013; Solak 2012; Tapia 1977; Terg 2002; Vessal 2010). In three studies (3%), the authors declared that they did not receive any funding. However, most studies (n = 51; 56%) provided no information on financial resources.

Ongoing studies

The last update (Siemens 2016) included 16 ongoing studies. One study has since been completed, and we include the results in this update (Mathur 2017). We removed eight studies from status “ongoing” because no changes of the registry data had been documented for >10 years and two studies because they were using complementary treatments. One study was terminated.

We found 69 ongoing studies (search 6th July 2022) for this update using the following search terms: (itch OR pruritus) AND (palliative OR progressive OR advanced OR terminal OR dialysis OR hemodialysis OR “end stage”) AND (randomised OR randomized OR random) NOT animal | Adult. After the screening, we identified and included 14 additional ongoing studies resulting in a total of 18 studies classified as ongoing (see Ongoing studies).

Excluded studies

In the original review (Xander 2013), we excluded 44 of 82 records in the full‐text screening because they did not meet the inclusion criteria: 32 were not RCTs; 7 did not meet the inclusion criteria concerning palliative care patients; one study intervention targeted the treatment of underlying disease; and one did not focus on a pharmacological intervention. Two records could not be included because only the abstract was available and the data were reported inadequately. For both of these records, we did not receive a response from the authors despite multiple requests. Details regarding reasons for exclusions are provided in the Characteristics of excluded studies table.

In the last update (Siemens 2016), we did not exclude any records after the initial screening.

In this update, we excluded 15 of 53 records in the full‐text screening because they did not meet the inclusion criteria: five used complementary therapies, in five pruritus was not the primary endpoint, four were not RCTs and one record was the abstract of an already included study.

Risk of bias in included studies

We present the risk of bias of the included studies graphically (Figure 3; Figure 4) and report details justifying our decisions in the Characteristics of included studies table. The main reason for giving a high risk of bias rating was a small sample size. Seventy‐nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains (Aquino 2020; Cho 1997; Gobo‐Oliveira 2018; Kuiper 2010; Mathur 2017; O'Donohue 2005; Shirazian 2013; Vessal 2010). One study (Tapia 1977) had low risk of bias in the specified key domains, but had high risk of bias in three other domains, therefore overall judgement was high risk of bias. The remaining studies would have an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%).

3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

4.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

Allocation

Random sequence generation (selection bias)

We included 30 studies (33%) that used appropriate methods of randomisation (e.g. drawing lots, flipping coins, computer‐generated table of random numbers) (low risk of bias) and 60 trials (66%) that reported using randomisation but failed to state the method of randomisation (unclear risk of bias). We rated the risk of bias of the random sequence generation in one study (1%) as high because investigators used an alternation method (Ghanei 2012).

Allocation concealment (selection bias)

Twenty‐two trials (24%) described allocation concealment (low risk), whereas the remainder of the trials did not mention the method of allocation concealment (unclear risk; 69 studies, 76%) or did not conceal allocation (high risk; two studies; Chourdakis 2019; Marin 2013).

Blinding

Seventy studies (77%) were at low risk of performance bias concerning blinding of participants and personnel, but 15 studies (16%) were at high risk of bias. The remaining six studies (7%) were at unclear risk.

The risk for detection bias was high in 12 studies (13%), unclear in 52 studies (57%) and low in 27 studies (30%). Six of the included studies (7%) were single‐blind (Ataei 2019; Duncan 1984; Marin 2013; Nasrollahi 2007; Nofal 2016; Ravindran 2020), five studies (5%) were open trials (Bachs 1989; Chourdakis 2019; Nakhaee 2015; Özaykan 2001; Solak 2012), and in another two studies (2%) the use of blinding was unclear (Legroux‐Crespel 2004; Smith 1997a). To our knowledge, the included studies did not carry out any analyses of the efficacy of blinding.

Incomplete outcome data

With regard to incomplete outcome data, bias of the included studies was quite heterogeneous. The dropout rate was low in most trials. We judged 57 studies (63%) to be at low risk of bias and 30 studies (33%) to be at an unclear risk of bias for this domain. We judged four studies (4%) with high dropout rates to be at high risk of bias (Borgeat 1993; Chourdakis 2019; Rossi 2019; Tapia 1977). This high dropout rate may be due to the advanced stage of disease of the participants included in the studies. Most trials reported reasons for dropout. Detailed information on dropouts and reasons for dropout are included in the Characteristics of included studies and in Table 17; Table 18.

Selective reporting

Risk of bias concerning selective reporting was unclear in 38 of 91 studies (42%), and we judged the risk of bias to be low in 41 studies (45%). Since we did not have access to all protocols of the included studies, there was not enough information to assess selective reporting bias in detail. Nevertheless, 12 studies (13%) showed a high risk of selective reporting bias. Please see the Characteristics of included studies table for more details.

Size of study (biases confounded by small size)

The risk of bias concerning the sample size was high in 79 of 91 studies (87%). We rated 12 studies (13%) that had between 50 and 199 participants per treatment arm as being at unclear risk of bias.

Other potential sources of bias

Other potential sources of bias may have related to missing washout periods leading to carryover effects in cross‐over studies (Cho 1997; Solak 2012; Tarng 1996), inadequate study designs (Smith 1997a; Tarng 1996), differences in baseline values (Lahiji 2018; Ravindran 2020; Rossi 2019), and conflicting data (Feily 2012; Omidian 2013). We rated the bias of 11 studies (12%) as high, of 35 studies (38%) as unclear and of 45 studies (49%) as low.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12

We researched pruritus as the primary outcome. An overall meta‐analysis was not possible because of the diversity of the different kinds of aetiologies of pruritus (uraemic and cholestatic) and interventions included in this review. Therefore, we considered several analysed treatment comparisons (see 'Summary of findings' tables and Data and analyses). Some meta‐analyses cover the outcomes 'pruritus' and 'risk for at least one adverse event'. We performed subgroup and sensitivity analyses as stated in the paragraphs Subgroup analysis and investigation of heterogeneity and Sensitivity analysis.

If we were unable to summarise data in meta‐analyses, we reported results descriptively according to the different pharmacological interventions and the underlying kind of pruritus. The description of results focused on pruritus scores. We present additional outcomes of the studies in the Characteristics of included studies table and Table 19 for secondary outcomes.

Primary outcome: subjective measures of pruritus

Participants with advanced diseases suffering from UP

GABA‐analogues (gabapentin, pregabalin)

GABA analogues versus placebo

GABA analogues (gabapentin and pregabalin) compared to placebo reduced UP (Table 1; Analysis 1.1; 5 studies: Gunal 2004; Naghibi 2007; Naini 2007; Nofal 2016; Yue 2015; 297 participants): VAS 0‐10 (cm) MD −5.10, 95% CI −5.65 to −4.55; certainty of evidence: moderate. The certainty of evidence was downgraded because of serious imprecision. The pooled estimate remained robust in the sensitivity analysis (Analysis 1.3) under the fixed‐effects model (−5.05, 95% CI −5.52 to −4.58). We could not include Tol 2010 in the analyses because placebo results were not reported. The administered doses ranged from 400 mg gabapentin twice‐weekly to 300 mg thrice weekly. One RCT (Rossi 2019) with three arms and 25 participants treated with either oral gabapentin (100 mg or 300 mg) or placebo. We did not include this study in the meta‐analysis because results were not normally distributed. The authors reported medians (of change values) showing a reduction of itch on the VAS 0‐100 (mm) in the 100 mg gabapentin group (P = 0.0078) based on the Wilcoxon matched‐pairs signed‐rank test. It should be noted that the 300 mg gabapentin arm stopped enrolment prematurely because of adverse events; this led to smaller number of participants in this group. A difference was observed in median percent VAS reduction (day 14 vs. baseline) between the 100 mg and placebo (‐37.19%; P = 0.0379), the 300 mg (‐70.5%; P = 0.00121) and placebo, and the 300 mg and 100 mg arms (‐33.31%; P = 0.00121).

1.1. Analysis.

Comparison 1: GABA‐analogues versus placebo, Outcome 1: A) Pruritus on VAS scale (0‐10 cm) in UP participants

1.3. Analysis.

Comparison 1: GABA‐analogues versus placebo, Outcome 3: A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐10 cm); UP participants

One study (Bergasa 2006) researched gabapentin in 16 participants with CP. We could not include data from the study because we could not calculate MD or SMD. The study did not find any therapeutic advantage over the placebo. On the contrary, these data in 15 participants suggested a placebo effect. The data given in the study did not allow us to calculate an estimate of the effect.

Topical gabapentin versus placebo

Aquino 2020 investigated the effect of topical 6% gabapentin in a double‐blind, vehicle (placebo)‐controlled trial in 30 participants. Topical gabapentin (6g gabapentin in 100g permeation cream) or placebo was administered once per day for two weeks and reduced pruritus more (10 cm VAS) in the gabapentin group (MD ‐4.6 (SD 2.0)) than in the placebo group (MD ‐2.6 (SD 1.9)); P = 0.01.

GABA analogues versus active control

Seven studies (Amirkhanlou 2016; Gobo‐Oliveira 2018; Kebar 2020; Marin 2013; Najmeh 2019; Noshad 2011; Suwanpidokkul 2007, 269 participants) comparing gabapentin to different antihistamines (ketotifen, dexchlorpheniramine, hydroxyzine, loratadine) could not be included in a meta‐analysis because of heterogeneity of the antihistamines. Amirkhanlou 2016 assessed the clinical response (complete, partial and no response) of gabapentin versus ketotifen in 52 participants after a two‐week intervention period. Both drugs tended to be effective (complete response > 50%), and investigators observed only slight differences between the groups (gabapentin: no response: three (11.5%), partial response: nine (34.6%); ketotifen: no response: six (23.1%), partial response: seven (26.9%)). Gobo‐Oliveira 2018 assessed the decrease in pruritus score (VAS 0‐10 cm) in 58 participants (two dropouts) after a three‐week intervention period with gabapentin or dexchlorpheniramine. Overall, the VAS 0‐10 (cm) median decreased by 80% in both groups, from 5 (IQR 2 to 7) to 1 (IQR 0 to 2); from 5 (IQR 4 to 8) to 2 (IQR 0 to 3) in the gabapentin group and from 5 (IQR 3 to 7) to 1 (IQR 0 to 2) in the dexchlorpheniramine group with no difference between groups (P > 0.7). Kebar 2020 assessed the decrease in pruritus score (VAS 0‐10cm) in 32 participants in a cross‐over design after six‐week intervention periods with gabapentin or hydroxyzine. Again, the VAS median decreased in both groups from 7.1 (SD 1.46) at baseline to 2.17 (SD 1.82) at six weeks in the gabapentin group (P < 0.01) and from 6.83 (SD 2.11) to 2.86 (SD 1.67) in the hydroxyzine group (P = 0.001). In period 2, pruritus severity decreased from 5.1 (SD 1.61) at baseline to 1.56 (SD 1.87) in the hydroxyzine group (P = 0.001). Differences of reduction of VAS scores in between the two groups were not statistically significant. Marin 2013 assessed the decrease in pruritus score (VAS 0‐10cm) in 60 participants after a 12‐week intervention period with gabapentin or loratadine. A reduction of pruritus of 50% was considered effective: effectiveness was reported in 20 patients in the gabapentin group versus 10 patients in loratadine group (P = 0.025). Najmeh 2019 assessed the decrease in pruritus score (VAS 0‐10cm) in 30 participants after a 12‐week intervention period with pregabalin or ketotifen. Severity of pruritus decreased in both groups, but the difference was not statistically different in between the groups (the abstract did not report specific scores). Noshad 2011 assessed the decrease in pruritus score (10cm VAS) in 40 participants after a four‐week intervention period with gabapentin or hydroxyzine. Pruritus remained present in two patients (10%) in the gabapentin group and in 16 patients (80%) in the hydroxyzine (P < 0.001); the abstract did not report specific scores. Suwanpidokkul 2007 assessed the decrease in pruritus score (VAS 0‐10cm) in a cross‐over design in 14 participants after a four‐week intervention period with gabapentin or loratadine. Differences in mean change in treatment groups were ‐3.9 (SD 1.8) in the gabapentin group and ‐2.07 (SD 3.4) in the loratadine group.

One study Fouroutan  2017 in a RCT in 90 participants (18 dropouts) suffering from UP compared either 50 mg oral pregabalin every second day with 10 mg doxepin daily for four weeks. In the cases of insufficient response defined as less than two units decrease in score of visual analog scale (VAS 0‐10 cm) after one week of the therapy the dose of pregabalin and doxepin was increased up to 50 mg per day and 10 mg two times per day, respectively. The mean VAS decreased in both groups from 7.5 (SD 1.4) at baseline to 2.1 (SD 2.6) at four weeks in the pregabalin group (P < 0.001) and from 7.1 (SD 1.3) to 4.2 (SD 2.6) in the doxepine group (P < 0.001). The change was higher in the pregabalin group (P = 0.001).

Two studies (Ravindran 2020; Solak 2012, 50 participants) comparing gabapentin to pregabalin were included in a meta‐analysis (Table 2; Analysis 2.1), which did not show an effect favouring one of the two substances: MD −0.23 cm, 95% CI −1.29 to 0.83; certainty of evidence: low. The certainty of evidence was downgraded due to serious risk of bias and serious imprecision. The pooled estimate remained robust in the sensitivity analysis under the fixed‐effects model. The administered doses ranged from gabapentin 100 mg daily‐300 mg thrice per week or pregabalin 25‐75 mg daily.

2.1. Analysis.

Comparison 2: Gabapentin versus pregabalin, Outcome 1: A) Pruritus on VAS scale (0‐10 cm) in UP participants; parallel group and cross‐over design

κ‐opioid agonists (difelikefalin, nalbuphine, nalfurafine) versus placebo

Kappa‐opioid agonists compared to placebo reduced UP (Table 3; Analysis 3.1; six studies: Fishbane 2020a; Fishbane 2020b; Kumagai 2010; Mathur 2017; Spencer 2015; Wikström 2005b; 1292 participants): VAS 0‐10 (cm) MD −0.96 cm, 95% CI −1.22 to −0.71; certainty of evidence: high. The pooled estimate remained robust in the sensitivity analysis (Analysis 3.2) under the fixed‐effects model. Mathur 2017, a three‐armed study, compared daily oral nalbuphine 60 mg, nalbuphine 120 mg and placebo. Since dosing of nalbuphine had different effects (60 mg: MD −0.30 cm, 95% CI −1.12 to 0.52; 120 mg: MD −0.70 cm, 95% CI −1.51 to 0.11) we included the two groups separately in the meta‐analysis. The meta‐analysis combined data from a study with parallel‐group design and a cross‐over design (Wikström 2005a; Wikström 2005b). We considered it appropriate to use only the data from the first two weeks of treatment in both studies because of concerns about carryover effects of the drug and regression to the mean. We divided the results of Kumagai 2010 and Wikström by 10 in order to show meta‐analysis on a 10 point scale (better comparability with other analyses). We pooled the 5 μg and the 2.5 μg groups for the meta‐analysis because they showed similar results. The administered doses ranged from 0.5 to 1.5 μg/kg intravenous difelikefalin thrice a week, from 60 to 120 mg oral nalbuphine twice daily, and from 5 µg intravenous nalfurafine to 2.5‐5 µg oral nalfurafine daily.

3.1. Analysis.

Comparison 3: Kappa‐opioid agonist versus placebo, Outcome 1: A) Pruritus on VAS scale (0‐10 cm) in UP participants; parallel‐group design; Wikström b: Wikström a (week 2) + period 1 Wikström b

3.2. Analysis.

Comparison 3: Kappa‐opioid agonist versus placebo, Outcome 2: A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐10 cm); UP participants

Bhaduri 2006 reported no decrease in itch on the VAS.

One RCT (Kumada 2017) investigated the effects of oral nalfurafine (2.5 or 5 μg) given once daily versus placebo in 318 participants suffering from CP. Changes on the VAS 0‐100 (mm) at week four (using last observation carried forward as imputation method) were greater in the nalfurafine group at 28.56 and 27.46 in the 2.5 μg and 5 μg groups, respectively, compared to 19.25 in the placebo group (P = 0.0022 and 0.0056, respectively).

Serotonin 5‐HT₃ antagonist ondansetron versus active control or placebo

Serotonin 5‐HT₃ antagonist ondansetron compared to placebo did not reduce UP/CP (Analysis 4.1; four studies: Ashmore 2000; Murphy 2003; O'Donohue 2005; Yue 2015; 202 participants): VAS 0‐10 (cm) MD −0.06 cm, 95% CI −0.71 to 0.58; certainty of evidence: low. The certainty of evidence was downgraded because of serious inconsistency and serious imprecision. O'Donohue 2005 involved 19 participants with CP, while four other studies in 241 participants researched participants with UP (Ashmore 2000; Murphy 2003; Özaykan 2001; Yue 2015; Table 4, Analysis 4.2 for subgroup analysis by nature of pruritus). The pooled estimate remained robust in the sensitivity analysis (Analysis 4.3) under the fixed‐effects model. We did not include Özaykan 2001 because it used a different measurement (Duo scale) to assess the intensity of pruritus. Pruritus was measured by the 0 to 48 unit pruritus scale introduced by Duo 1987. We found no difference amongst the groups in itching scores at the end of the first and second weeks of the therapy. At the end of the third and fourth weeks, participants receiving ondansetron had statistically significant lower itching scores (week three: 4 units versus 12.6 units; week four: 3.2 units versus 11 units). Interestingly, participants on ondansetron had a lower pruritus score (MD 7.80 units, 95% CI −14.27 to −1.33) than participants treated with cyproheptadine. Furthermore, it was not possible to include Ashmore 2000 in the pooled analysis because it used IQRs but did not supply information on the SEM. In the placebo‐controlled cross‐over study in 19 participants (three dropouts), the median daily pruritus score measured via a VAS 0‐10 (cm) did not change (P = 0.9) during active or placebo treatment (pre‐ondansetron 5.3; IQR 3.4 to 6.3; during ondansetron 3.9; IQR 2.7 to 5.0; P = 0.02; pre‐placebo 3.7; IQR 3.0 to 4.6; during placebo 3.6 cm; IQR 2.4 to 4.8; P = 0.03). The administered doses ranged from 8 mg per day to 8 mg three times per day.

4.1. Analysis.

Comparison 4: Ondansetron versus placebo or standard medication, Outcome 1: A) Pruritus on VAS scale (0‐10 cm) in UP and CP participants

4.2. Analysis.

Comparison 4: Ondansetron versus placebo or standard medication, Outcome 2: A) Subgroup analysis by nature of pruritus and study design; pruritus on VAS scale (0‐10 cm)

4.3. Analysis.

Comparison 4: Ondansetron versus placebo or standard medication, Outcome 3: A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐10 cm) in UP and CP participants

Subach 2001 enrolled 23 participants suffering from UP in a cross‐over RCT treating with either 8 mg oral ondansetron, 25 mg oral diphenhydramine, or placebo. Mirnezami 2013 enrolled 70 participants with UP and treated with either 8 mg oral ondansetron or 10 mg oral loratadine. Neither study found any difference in measured itch.

Leukotriene receptor antagonist montelukast versus placebo

Montelukast compared to placebo did reduce UP (Table 5; Analysis 5.1; two studies: Mahmudpour 2017; Nasrollahi 2007; 87 participants): SMD −1.40, 95% CI −1.87 to ‐0.92; certainty of evidence: very low. The certainty of evidence was downgraded because of serious risk of bias, serious inconsistency, and serious imprecision. The pooled estimate remained robust in the sensitivity analysis (Analysis 5.2) Nasrollahi 2007 researched the effect of montelukast in a multicentre, randomised, single‐blind, placebo‐controlled cross‐over study in 16 participants with UP. Results at the end of the treatment with montelukast showed a reduction of pruritus by 35% (95% CI 9.5 to 62.5) compared to a reduction of 7% (95% CI 0.5 to 15.9) with placebo (P = 0.002). The mean change in pruritus score was 16.1 units (95% CI 9.5 to 22.5) with montelukast and 7.1 units (95% CI 0.5 to 13.7) with placebo, using the 0 to 45 Detailed Pruritus Score (Duo 1987). Mahmudpour 2017 enrolled 80 participants suffering from UP in a placebo‐controlled RCT. The participants received either 10 mg oral montelukast daily or placebo for 30 days. The mean reduction on the VAS 0‐10 (cm) was greater in the montelukast group (‐3.7 (SD 2.2)) compared to the placebo group (‐0.53 (SD 2.17), P < 0.001).

5.1. Analysis.

Comparison 5: Montelukast versus placebo, Outcome 1: A) Pruritus on different scales; SMD in UP participants; parallel‐group design

5.2. Analysis.

Comparison 5: Montelukast versus placebo, Outcome 2: A) Sensitivity analysis: fixed‐effects model; Pruritus on different scales; SMD in UP participants; parallel‐group design

Fish‐oil/Omega‐3 fatty acids versus active control or placebo

Fish oil/omega‐3 fatty acids compared to placebo did reduce UP (Table 6; Analysis 6.1; four studies: Forouhari 2022; Ghanei 2012; Lahiji 2018; Shayanpour 2019; 160 observations): SMD −1.60, 95% CI −1.97 to ‐1.22; certainty of evidence: low. The certainty of evidence was downgraded because of serious risk of bias and serious imprecision. The pooled estimate remained robust in the sensitivity analysis (Analysis 6.2). We included three cross‐over RCTs (Forouhari 2022; Ghanei 2012; Lahiji 2018) and one parallel‐group RCT (Shayanpour 2019) in the meta‐analysis. Because of carry‐over effects we only used period 1 from Forouhari 2022: 40 participants were treated with either omega‐3 fatty acids (each capsule contained 180 mg of EPA and 120 mg of DHA) every eight hours for four weeks or placebo. The omega‐3 group showed reduced pruritus on the VAS 0‐10 (cm) (MD ‐3.41 (SD 2.62)) while the placebo group remained without change (MD 0.06 (SD 2.54)). In Ghanei 2012 (22 participants) investigators assessed pruritus on the Duo pruritus scale (0 to 45, higher scores indicate a more severe pruritus). The duration of the treatment was 20 days, and participants had to take a 1 g capsule (verum or placebo) every eight hours. After 20 days, the pruritus in the omega‐3 group decreased from a score of 20.3 units (95% CI 16.7 to 23.8) to 6.4 units (95% CI 2.9 to 9.8), a 65% decrease. The placebo group reported a mean score of 14.4 units (95% CI 10.5 to 18.2), from a baseline level of 17.0 units (95% CI 12.4 to 21.6), a 15% decrease. Lahiji 2018 enrolled 40 participants receiving either 3 omega‐3 capsules (each 1‐g capsule of omega‐3 contained 180 mg EPA and 120 mg DHA) once per day for four weeks or placebo. VAS scores were more reduced in the omega‐3 group in both periods respectively (MD ‐3.02 (SD 1.8) and ‐4.09 (SD 1.09)) than in the placebo group (MD ‐0.48 (SD 1.44) and ‐0.43 (SD 1.77)); P <  0.01. Shayanpour 2019 enrolled 64 participants receiving either a single‐dose of 2g omega‐3 daily before lunch or placebo for three weeks. Using the standard 5‐D itch scale questionnaire the domain "degree" of pruritus was reduced more in the omega‐3 group than in the placebo group (MD between treatment groups ‐1.31 95% CI ‐1.72 to ‐0.9).

6.1. Analysis.

Comparison 6: Fish‐oil/Omega‐3 fatty acids versus placebo, Outcome 1: A) Pruritus on different scales; SMD in UP participants; parallel‐group design and cross‐over design

6.2. Analysis.

Comparison 6: Fish‐oil/Omega‐3 fatty acids versus placebo, Outcome 2: A) Sensitivity analysis: fixed‐effects model; pruritus on different scales; SMD in UP participants; parallel‐group design and cross‐over design

We did not include Mortazavi  2017 into the meta‐analysis because neither CIs nor SDs were reported and authors did not respond to our query. In a double‐blind cross‐over RCT Mortazavi  2017 enrolled 20 participants suffering from UP. Participants received either oral fish oil (1 g) thrice per day for four weeks or placebo and reported a small but statistically significant benefit versus placebo: the mean pruritus score on the VAS 0‐10 (cm) was reduced by 1.72 in patients who took fish oil, compared to a decrease of 0.45 in the placebo group (P = 0.03). Furthermore, we did not include the comparative trial (Begum 2004) into the meta‐analysis, because it was not placebo‐controlled. It enrolled 22 participants suffering from UP in a RCT comparing intake of oral fish oil (6 g ethyl ester) once per day with oral safflower oil (6 g ethyl ester, both polyunsaturated fatty acids) daily for 14 weeks and found no reduced itch.

Zinc sulphate versus placebo

Zinc sulphate compared to placebo did not reduce UP (Table 7; Analysis 7.1; two studies: Mapar 2015; Najafabadi 2012; 76 participants): SMD −0.13, 95% CI −0.58 to 0.32; certainty of evidence: low. The certainty of evidence was downgraded because of very serious imprecision. The pooled estimate remained robust in the sensitivity analysis (Analysis 7.2) under the fixed‐effects model. We did not include Somkearti 2021 in the meta‐analysis because post‐intervention values and change scores should not in principle be combined using standard meta‐analysis approaches when the effect measure is an SMD (Higgins 2021). Although the mean difference of the VAS score from the baseline was more in the zinc group (1.41: 95% CI, 0.095 to 2.732; P = 0.036) at week four of the trial, there was no difference in degree of changed VAS score at week 12 (1.131 (95% CI −0.423 to 2.684; P = 0.150) (Somkearti 2021). The administered doses ranged from 220 mg per day to 220 mg twice per day.

7.1. Analysis.

Comparison 7: Zinc sulphate versus placebo, Outcome 1: A) Pruritus on different scales; SMD in UP participants; parallel‐group design

7.2. Analysis.

Comparison 7: Zinc sulphate versus placebo, Outcome 2: A) Sensitivity analysis: fixed‐effects model; Pruritus on different scales; SMD in UP participants; parallel‐group design

Oral and topical mast cell stabiliser cromolyn sodium versus placebo

Cromolyn sodium compared to placebo could reduce UP (Table 8; Analysis 8.1; two studies: Feily 2012; Vessal 2010; 100 participants): MD −3.27, 95% CI −5.91 to ‐0.63; certainty of evidence: very low. We downgraded the certainty of evidence because of serious inconsistency and very serious imprecision. However, the subgroup analysis emphasises that the effect could depend on the route of administration (oral versus topical) (Analysis 8.2). The oral administration (MD −4.70, 95% CI −6.57 to −2.83; one RCT, N = 40) seemed to be more effective than the topical (MD −2.00, 95% CI −3.37 to −0.63; one RCT, N = 60). The 95% CI decreased (MD −2.94, 95% CI −4.04 to −1.83) under the fixed‐effects model (Analysis 8.3). We multiplied the values from Feily 2012 (VAS (0 to 5)) by a factor of 2 in order to enable a pooled analysis with Vessal 2010.

8.1. Analysis.

Comparison 8: Cromolyn sodium versus placebo, Outcome 1: A) Pruritus on VAS scale (0‐10 cm; values from Feily (2012) multiplied by factor 2); UP participants; parallel‐group design

8.2. Analysis.

Comparison 8: Cromolyn sodium versus placebo, Outcome 2: A) Subgroup analysis by route of administration; values from Feily (2012) multiplied by factor 2); UP participants; parallel‐group design

8.3. Analysis.

Comparison 8: Cromolyn sodium versus placebo, Outcome 3: A) Sensitivity analysis: fixed‐effects model; values from Feily (2012) multiplied by factor 2; UP participants; parallel‐group design

Topical capsaicin versus placebo

Topical capsaicin compared to placebo may reduce UP (Table 9; Analysis 9.1; Analysis 9.2; two studies: Cho 1997; Makhlough 2010; 112 participants): SMD −1.06, 95% CI −1.55 to ‐0.57; certainty of evidence: low. We downgraded the certainty of evidence because of very serious imprecision. The result remained stable in the sensitivity analysis under the fixed‐effects model (Analysis 9.3). Investigators of Cho 1997 presented the findings for the individual participants graphically, which indicated a carry‐over effect of the capsaicin treatment that could impede the interpretability from the second treatment phase. Groups were divided and analysed in the meta‐analysis according to the intact parathyroid hormone (iPTH) ≤ 35 pg/mL and > 35 pg/mL. Both groups showed an improvement in pruritus on the 4‐point scale (1 = none, 4 = severe): pooled effect: MD −0.88 points, 95% CI −1.31 to −0.44. The iPTH ≤ 35 pg/mL group had a greater (and statistically significant) effect (MD −1.50 points, 95% CI −2.21 to −0.79; one RCT, N = 20) than the iPTH > 35 pg/mL group (MD −0.50 points, 95% CI −1.05 to 0.05). Topical capsaicin versus vehicle applied four times daily.

9.1. Analysis.

Comparison 9: Topical capsaicin versus vehicle, Outcome 1: A) Pruritus on different scales; SMD in UP participants; cross‐over design (Cho: 1. iPTH =< 35 pg/mL and 2. iPTH > 35 pg/mL)

9.2. Analysis.

Comparison 9: Topical capsaicin versus vehicle, Outcome 2: A) Subgroup analysis by pruritus scales; SMD; UP participants; cross‐over design (Cho: 1. iPTH =< 35 pg/mL and 2. iPTH > 35 pg/mL)

9.3. Analysis.

Comparison 9: Topical capsaicin versus vehicle, Outcome 3: A) Sensitivity analysis: fixed‐effects model; pruritus on different scales; UP participants; cross‐over design (Cho: 1. iPTH =< 35 pg/mL and 2. iPTH > 35 pg/mL)

Two other studies did not provide sufficient data or appropriate statistical analyses for their findings to be evaluated in a meta‐analysis for efficacy (Breneman 1992a; Tarng 1996). Breneman 1992a compared topical capsaicin and vehicle applied four times daily to either the right or left arm over six weeks. The sample was very small (N = 7), and only five participants were evaluable. Authors presented findings descriptively for these five participants (two capsaicin‐treated participants reported complete resolution of itching), and no statistical analysis was available, but the report stated that there was an improvement in the participants treated with capsaicin. Tarng 1996 carried out a similar cross‐over study with two four‐week treatment periods of capsaicin versus vehicle. The study involved 19 participants and also reported a statistically significant effect of capsaicin. Despite a 14‐day washout period between the treatments, we must assume a carry‐over effect according to the graphical data presented. Data did not allow intergroup statistical comparisons to be made for the first phase of the cross‐over.

Opioid antagonist naltrexone versus active control or placebo

Three studies included 90 participants with UP (Legroux‐Crespel 2004; Pauli‐Magnus 2000; Peer 1996). We could not perform meta‐analysis, because in one study the results concerning pruritus were not interval‐scaled (Peer 1996) and another study had poor methodological quality and lack of data (Legroux‐Crespel 2004) (see Assessment of risk of bias in included studies).

Results of the RCTs regarding the effects of naltrexone in UP were contradictory (Pauli‐Magnus 2000; Peer 1996). Peer 1996 involved 15 participants and showed that administration of the oral mu‐receptor antagonist naltrexone was associated with a decrease in pruritus perception. At the end of the naltrexone treatment, the median pruritus scores on the VAS 0‐10 (cm) were 2.1 (IQR 1.5 to 2.15) for the naltrexone‐placebo sequence and 1.0 (0.4 to 1.15) for the placebo‐naltrexone sequence. The respective baseline values were 9.9 (IQR 9.85 to 9.95) and 9.9 (IQR 9.3 to 10.0). The results of this study suggested short‐term efficacy with few side effects for the amelioration of UP with naltrexone (Mettang 2010; Peer 1996). Pauli‐Magnus 2000 (involving 23 participants) showed no statistically significant difference between the naltrexone and the placebo treatment periods. During the naltrexone period, pruritus decreased by 29.2% (95% CI 18.7 to 39.6) on the VAS and by 17.6% (95% CI 4.2 to 31.1) on the detailed score (pruritus score proposed by Duo 1987). The percent difference between the naltrexone and the placebo treatment periods was not statistically significant (−12.30%, 95% CI −25.82 to 1.22; P = 0.07; one RCT, N = 32). The third study, researching the effect of naltrexone in participants suffering from UP, was a comparative study comparing naltrexone versus loratadine. In this study, seven of the 52 participants showed a dramatic improvement when using naltrexone (> 3 cm, marked improvement), whereas the mean VAS score was identical to the alternative medication, the H₁ receptor antagonist loratadine (Legroux‐Crespel 2004). The results of the studies are conflicting. Both Pauli‐Magnus 2000 and Peer 1996 were randomised, placebo‐controlled, double‐blind cross‐over trials, so we cannot explain the difference between these two studies by differences in participant compliance, naltrexone dose or study design.

Antihistamines (bilastine, cimetidine, desloratadine, hydroxyzine) versus active control or placebo

Antihistamines were compared with four other interventions in participants suffering from UP: ondansetron (Özaykan 2001), topically applied dilute vinegar (Nakhaee 2015), GABA agonists (gabapentin; see above section on GABA analogues), and Mu opioid antagonists (naltrexone, see above section on Mu opioid antagonists).

Aubia 1980 compared cimetidine, another 'classical antihistamine' and placebo in a RCT in 13 participants. The study found no difference between the three groups. No measures of variability (e.g. standard error) were reported.

Chourdakis 2019 compared desloratadine and bilastine in a comparative RCT with 20 participants (10 of them either refused to receive or discontinued treatment before the end of follow‐up). On the 5 to 25 5‐D itch score, the desloratadine group did not have reduced scores: 13.4 (SD 4.8) versus 11.8 (SD 5.6) while scores were reduced in the bilastine group 14 (SD 2.6) versus 9.2 (SD 2.9), P = 0.016.

Vinegar solution and avena sativa were compared with hydroxyzine in a non‐blinded cross‐over trial (Nakhaee 2015). All three treatments reduced pruritus statistically significant by more than 1.1 on the VAS 0‐10 (cm). However, the post‐treatment scores differed only slightly (vinegar: 3.73 (SD 2.41), avena sativa: 4.10 (SD 2.34), hydroxyzine: 3.5 (SD 2.52)).

Antidepressants (sertraline, mirtazapine, doxepin, paroxetine) versus active control or placebo

In a cross‐over RCT by Pour‐Reza‐Gholi 2007, performed on 24 participants with UP, investigators described complete improvement in 58.3% of participants treated with doxepin. This was higher than improvements with placebo (P < 0.001). Overall, doxepin was effective (complete improvement or relative improvement according to the participant) in 21 (87.5%) of the participants (P < 0.001). Since no raw data were available, further statistical analysis was not possible (Pour‐Reza‐Gholi 2007).

In a cross‐over RCT by Gholyaf 2020, performed on 77 participants with UP compared to baseline, both mirtazapine (− 5.31 (SD 1.60)) and gabapentin (− 3.96 (SD 1.22)) treatment resulted in improvement in VAS 0‐10 (cm) scores, but decreasing in pruritus severity was greater in the mirtazapine‐treatment period compared with the gabapentin‐treatment period (P < 0.001).

Pakfetrat 2018 enrolled 50 participants (four dropouts) suffering from UP in a placebo‐controlled RCT. Before treatment, the mean was 6.7 cm (SD 2.3) on the VAS 0‐10 (cm) in the sertraline group and 6.7 (SD 2.2) in the placebo group. Participants taking sertraline and placebo improved significantly in both groups. No mean post‐treatment VAS‐scores for all participants were reported, only VAS scores of eight participants with VAS scores of 10 (5 sertraline group, 3 placebo group). After eight weeks of treatment, three of them reported no itching, one of them mentioned VAS score was 2 and one reported a score of 3 (mean: 1.0 (SD 1.41)). In the control group, two participants reported VAS of 3 and 2 (mean: 2.67 (SD 0.58)).

Bile acid sequestrants (cholestyramine, colesevelam) versus active control or placebo

Two RCTs researched the effect of cholestyramine in participants with UP: Silverberg 1977 was a parallel‐group trial including 10 participants with UP and Van Leusen 1978 was a cross‐over trial with five participants without a washout period. Very small samples limited the informative value of these results, and we therefore decided against performing meta‐analyses.

Immunosuppressants versus active control or placebo

Thalidomide

There was evaluable data from 18 of 29 participants in a double‐blind, randomised cross‐over trial on thalidomide against UP. Silva 1994 found a similar proportion of participants in phase 1 and 2 responding to thalidomide (responders in phase 1: 55% and responders in phase 2: 57%). The reduction on the three‐item pruritus score was 78% (SE 6%) in phase 1 and 81% (SE 10%) in phase 2 and this differed from placebo (54%, SE 1, P < 0.05). The authors found a positive effect of thalidomide in 67% of the study population, with a mean reduction of pruritus scoring of approximately 80% (Silva 1994).

Topical Tacrolimus

A randomised, double‐blind, vehicle‐controlled study assessed the efficacy of tacrolimus ointment 0.1% for the treatment of pruritus in participants undergoing haemodialysis. The study found a similar effect for both tacrolimus ointment and vehicle in regard to the reduction of itch (range for both groups: tacrolimus: 72% to 77%, vehicle: 79% to 81%) (Duque 2005).

Topical Pimecrolimus

Two RCTs compared in 60 participants (each suffering from UP) topical pimecrolimus to either placebo (Ghorbani 2012) or cromolyn cream (Ghorbani Birgani 2011) for eight weeks. It was unclear if pimecrolimus cream can reduce pruritus compared to vehicle on the VAS 0‐10 (cm): MD 1.2, 95% CI ‐0.36 to 2.76 (Ghorbani 2012). Ghorbani Birgani 2011 reported both interventions reduced pruritus on a VAS with a statistically non‐significant difference between the two.

Erythropoietin versus placebo

A 10‐week, randomised, controlled cross‐over trial in 10 participants with UP and 10 participants without pruritus treated both groups with erythropoietin and placebo, respectively. Eight of the 10 participants suffering from pruritus showed reductions in their mean pruritus score (Duo 1987; Mettang 2002; Duo scale, range: 0 to 40), which decreased from 25 units (SE 3) to 11 units (SE 6) in group one and from 27 units (SE 4) to 9 units (SE 4) in group two during treatment with erythropoietin (De Marchi 1992). The authors concluded a positive effect of erythropoietin. However, the small sample size prohibits the generalisation of the results.

Sja'bani 1997 reported that the erythropoietin group experienced a greater mean reduction in itch than the placebo group. However, baseline itch scores are not fully reported as allowing for inclusion in a quantitative review.

Vitamin D2 ergocalciferol versus placebo

Fifty participants with UP were randomised to ergocalciferol (vitamin D₂; 50,000 IU, one pill per week) or placebo for 12 weeks in one double‐blind RCT (Shirazian 2013). The groups did not differ at baseline regarding the pruritus score (assessed with the 0 to 21 point Pruritus Severity Questionnaire). None of the biweekly measured pruritus values showed a statistically significant difference between groups. The authors concluded that ergocalciferol was not effective for participants with UP.

Vitamin B3 Nicotinamide versus placebo

Omidian 2013 investigated 50 participants with UP in a double‐blind RCT. Participants received oral nicotinamide (500 mg twice a day) for four weeks, and pruritus was measured on a VAS (0 to 5: 0 = no pruritus and 5 = the worst pruritus). The pruritus decreased to a score of 1.52 (SD 1.61) in the nicotinamide group and to 1.29 (SD 1.08) in the placebo group. However, the group differences were not statistically significant (P = 0.167).

Activated oral charcoal versus placebo

Pederson 1980 contained two consecutive eight‐week treatment periods involving 11 participants with UP. This randomised, placebo‐controlled, cross‐over study showed a statistically significant difference favouring charcoal over placebo during the first study period (P = 0.01) and a tendency during the second study period (P = 0.05). Missing data did not enable further statistical analysis. The small sample size affects the generalisation of the results.

Local anaesthetic lidocaine versus placebo

A RCT from Tapia 1977 investigated in 20 participants suffering from UP the effects of 600 mg intravenous lidocaine during HD or placebo. Only acute (15 to 30 minutes) relief of pruritus was included in the analysis. It is unclear whether lidocaine relieved itch (within 30 minutes) compared to placebo: MD ‐0.63 cm, 95% CI ‐1.46 to 0.19. Longer‐term assessment was not reported.

Pramoxine hydrochloride versus active control

In a randomised, double‐blind, controlled, comparative trial, Young 2009 found a 61% decrease in the average reported VAS in UP participants treated with pramoxine hydrochloride as compared to participants treated with placebo. Since authors presented results graphically with no raw data, statistical analysis was not possible.

Nicergoline versus placebo

Rivory 1984 enrolled 13 participants with UP in a three‐armed RCT receiving 30 mg oral nicergoline, 5 mg intravenous nicergoline (continuous IV) or placebo for 12 weeks and reported a small improvement in itch with nicergoline compared to placebo.

Sodium thiosulfate versus placebo

Mohamed 2012 enrolled 45 UP participants receiving intravenous sodium thiosulfate (12.5 mg) once per HD session or placebo for six months. Overall, there was no reported statistically significant difference comparing sodium thiosulfate and placebo.

Summary of treatments for UP

As we could not meta‐analyse the data across the comparisons due to heterogeneity of data, we have summarised and ranked MDs and SMDs of effect estimates, as follows:

Treatments compared to placebo

MDs of meta‐analyses:

• GABA‐analogues (gabapentin, pregabalin) versus placebo: VAS 0‐10 (cm) MD −5.10, 95% CI −5.65 to −4.55; certainty of evidence: moderate (Analysis 1.1; Table 1).

• Oral and topical mast cell stabiliser (cromolyn sodium): VAS 0‐10 (cm) MD −3.27, 95% CI −5.91 to ‐0.63; certainty of evidence: very low (Analysis 8.1; Table 8).

• κ‐opioid agonists (difelikefalin, nalbuphine, nalfurafine) versus placebo: VAS 0‐10 (cm) MD −0.96, 95% CI −1.22 to −0.71; certainty of evidence: high (Analysis 2.1; Table 3).

• Serotonin 5‐HT₃ antagonist (ondansetron) versus placebo: VAS 0‐10 (cm) MD −0.06, 95% CI −0.71 to 0.58; certainty of evidence: low (Analysis 4.1; Table 4; also including patients with CP).

SMDs of meta‐analyses:

• Fish‐oil/omega‐3 fatty acids: SMD −1.60, 95% CI −1.97 to ‐1.22; certainty of evidence: low (Analysis 6.1; Table 6).

• Leukotriene receptor antagonist (montelukast): SMD −1.40, 95% CI −1.87 to ‐0.92; certainty of evidence: very low (Analysis 5.1; Table 5).

• Topical capsaicin: SMD −1.06, 95% CI −1.55 to ‐0.57; certainty of evidence: low (Analysis 9.1; Table 9).

• Zinc sulphate: SMD −0.13, 95% CI −0.58 to 0.32; certainty of evidence: low (Analysis 7.1; Table 7).

Topical gabapentin (Aquino 2020) reduced pruritus more (10‐cm VAS) in the gabapentin group (MD ‐4.6 (SD 2.0)) than in the placebo group (MD ‐2.6 (SD 1.9)), but more studies are needed to reproduce these results.

Other treatments compared to placebo with contradictory results, methodological concerns or insufficient benefit included naltrexone, antihistamines, bile acid sequestrants, immunosuppressants, erythropoietin, vitamins D2/B3, activated oral charcoal, local anaesthetic lidocaine, pramoxine hydrochloride, nicergoline, and sodium thiosulfate.

Treatments compared to other treatments

• One study compared mirtazapine and pregabalin finding better improvement of pruritus in participants treated with mirtazapine (Gholyaf 2020).

• Studies comparing GABA‐analogues with antihistamines showed contradicting results. While some studies reported no difference (Amirkhanlou 2016; Gobo‐Oliveira 2018; Kebar 2020; Najmeh 2019), other studies reported more reduction of pruritus for GABA‐analogues than for antihistamines (Marin 2013; Noshad 2011; Suwanpidokkul 2007).

Participants with advanced diseases suffering from CP

Opioid antagonist naltrexone versus placebo

Two trials involving 36 participants examined the antipruritic effect of naltrexone in participants suffering from CP (Terg 2002; Wolfhagen 1997). We conducted separate meta‐analyses, measuring absolute change in pruritus severity and relative change in Terg 2002 and Wolfhagen 1997.

Naltrexone compared to placebo may reduce CP (Table 10; Analysis 10.1; two studies: Terg 2002; Wolfhagen 1997, 52 participants): MD of −2.42 cm (95% CI −3.90 to −0.94), certainty of evidence: low. We downgraded the certainty of evidence because of serious inconsistency and serious imprecision. The result remained stable in the sensitivity analysis under the fixed‐effects model (Analysis 10.3).

10.1. Analysis.

Comparison 10: Naltrexone versus placebo, Outcome 1: A) Pruritus on VAS scale (0‐10 cm) in CP participants

10.3. Analysis.

Comparison 10: Naltrexone versus placebo, Outcome 3: A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐10 cm) in CP participants

Subgroup analysis by study design (Analysis 10.2) resulted in an MD of −3.32 cm (95% CI −5.01 to −1.63; N = 16) for Wolfhagen 1997, which had a parallel‐group design, and an MD of −1.79 cm (95% CI −2.91 to −0.67; N = 36) for Terg 2002, a cross‐over study. The difference between the two subgroups was not statistically significant (P = 0.14).

10.2. Analysis.

Comparison 10: Naltrexone versus placebo, Outcome 2: A) Subgroup analysis by study design: pruritus on VAS scale (0‐10 cm) in CP participants

The subgroup analysis by nature of pruritus was only possible for group differences in percent change of the two studies (Pauli‐Magnus 2000; N = 16; Wolfhagen 1997; N = 16). However, the sample sizes were small, the studies had different study designs, and CP patients were compared with UP patients, which may have contributed to the different effects (Pauli‐Magnus 2000: −12.30%, 95% CI −25.82 to 1.22; Wolfhagen 1997: −62%, 95% CI −89.42 to −34.58, pooled: ‐35.66%, 95% CI ‐84.28 to 12.96) (Analysis 10.4; Analysis 10.5). The result remained stable in the sensitivity analysis under the fixed‐effects model (Analysis 10.6): ‐22.02%, 95% CI‐34.15 to ‐9.90.

10.4. Analysis.

Comparison 10: Naltrexone versus placebo, Outcome 4: B) % difference for pruritus on VAS scale (0‐10 cm) in UP and CP participants

10.5. Analysis.

Comparison 10: Naltrexone versus placebo, Outcome 5: B) Subgroup analysis by nature of pruritus and study design; % difference for pruritus on VAS scale (0‐10 cm)

10.6. Analysis.

Comparison 10: Naltrexone versus placebo, Outcome 6: B) Sensitivity analysis: fixed‐effects model; % difference for pruritus on VAS scale (0‐10) in UP and CP participants

Semi‐antibiotic rifampicin/rifampin versus active control or placebo

Three studies including 45 participants researched the treatment of CP with the semi‐antibiotic rifampicin, comparing it to placebo in Ghent 1988 and Podesta 1991a or to phenobarbitone as a standard treatment in Bachs 1989.

The pooled estimate of the two studies researching rifampicin comparing it to placebo indicated that it may improve pruritus in participants suffering from CP (Table 11; Analysis 11.1; two studies: Ghent 1988; Podesta 1991a, 21 participants): MD of −42.00 mm (95% CI −87.31 to 3.31), certainty of evidence: very low. We downgraded the certainty of evidence because of very serious inconsistency and very serious imprecision. The result became statistically significant in the sensitivity analysis under the fixed‐effects model (Analysis 11.2, MD −24.64 mm, 95% CI −31.08 to ‐18.21). Improvement of pruritus remained stable when including Bachs 1989 in the analysis (Analysis 11.3): SMD −1.84, 95% CI −2.82 to −0.87; three studies, 71 participants. The results were consistent, but the 95% CI decreased considerably when using the fixed‐effects model for sensitivity analysis (SMD −1.73, 95% CI −2.45 to −1.02) (Analysis 11.4). We could only estimate the effect on the VAS 0 to 100 (mm) for the studies from Ghent 1988 and Podesta 1991a.

11.1. Analysis.

Comparison 11: Rifampicin versus placebo or standard medication, Outcome 1: A) Pruritus on VAS scale (0‐100 mm) in CP participants; cross‐over design

11.2. Analysis.

Comparison 11: Rifampicin versus placebo or standard medication, Outcome 2: A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐100 mm) in CP participants; cross‐over design

11.3. Analysis.

Comparison 11: Rifampicin versus placebo or standard medication, Outcome 3: B) Subgroup analysis by control; SMD: pruritus on different scales; CP participants; cross‐over design

11.4. Analysis.

Comparison 11: Rifampicin versus placebo or standard medication, Outcome 4: B) Sensitivity analysis: fixed‐effects model; subgroup analysis by control; SMD: pruritus on different scales; CP patients; cross‐over design

Flumecinol versus placebo

Two studies including 69 participants researched the treatment of CP with flumecinol comparing it to placebo in Turner 1994b and Turner 1994a.

The pooled RR 2.20 (95% CI 0.42 to 11.60); two RCTs, N = 69, certainty of evidence: very low; (Table 12; Analysis 12.1) shows that flumecinol tends to be effective compared with placebo, but with no statistically significant effect (P = 0.26). We downgraded the certainty of evidence because of serious inconsistency and very serious imprecision. However, when using the fixed‐effects model for sensitivity analysis, the 95% CI decreased considerably (RR 1.89, 95% CI 1.05 to 3.39) (Analysis 12.2). In addition, participants were asked if their itch had improved. Our subgroup analysis (Analysis 12.3) revealed that the high‐dose administration of flumecinol (300 mg/d; N = 19, Turner 1994b) could be more effective than the low‐dose administration (600 mg/week; N = 50) (Turner 1994a).

12.1. Analysis.

Comparison 12: Flumecinol versus placebo, Outcome 1: A) Pruritus: significant improvement (yes/no); CP participants; parallel‐group design

12.2. Analysis.

Comparison 12: Flumecinol versus placebo, Outcome 2: A) Sensitivity analysis: fixed‐effects model; pruritus: significant improvement (yes/no); CP participants; parallel‐group design

12.3. Analysis.

Comparison 12: Flumecinol versus placebo, Outcome 3: A) Subgroup analysis by dosage; pruritus: significant improvement (yes/no); CP participants; parallel‐group design

Bile acid sequestrants (cholestyramine, colesevelam) versus active control or placebo

Duncan 1984 used a cross‐over design and researched eight participants with CP, comparing the effect of cholestyramine, terfenadine, chlorpheniramine and placebo. The study reported some positive effect for cholestyramine and for terfenadine, as well.

The randomised, double‐blind, trial by Kuiper 2010 aimed to assess the efficacy of colesevelam versus placebo in participants with CP. Data showed no difference in pruritus score between participants treated with colesevelam and participants receiving placebo (P = 1.00 for the VAS day score and P = 0.74 for the VAS evening score; predefined primary endpoint = proportion of participants with at least a 40% reduction in pruritus VAS scores).

Antidepressants (sertraline) versus active control or placebo

Mayo 2007 enrolled 12 participants suffering from CP in a randomised, double‐blind, placebo‐controlled trial. Participants taking sertraline improved by a mean of 1.86 cm on the VAS 0‐10 (cm), whereas participants taking placebo worsened by 0.38. This resulted in a difference of 2.24 in favour of the intervention group (P = 0.009).

Ataei 2019 enrolled 36 participants suffering from CP received in a randomised, double‐blind, comparative trial. Participants taking sertraline improved by a mean of 2.84 cm (before treatment 6.17 (SD 1.415), post treatment 3.33 (SD 1.68)) and participants taking rifampicin improved by a mean of 2.62 (before treatment 6.06 (SD 1.552), post treatment 3.344 (SD 2.75)) on the VAS 0‐10 (cm) with no statistically significant difference between the groups (P = 0.74).

Anaesthetic propofol versus placebo

In a randomised, double‐blind, placebo‐controlled cross‐over trial including 10 participants with CP (Borgeat 1993), investigators described treatment with propofol as successful (defined by authors as a decrease of pruritus of at least 4 points on a verbal rating scale from 0 to 10) in 17 of 20 (85%) doses of propofol, compared to 2 of 20 (10%) doses in the placebo group (P < 0.01). Data did not allow further statistical analysis.

Local anaesthetic lidocaine versus placebo

A randomised, double‐blind, placebo‐controlled study investigated the efficacy of lidocaine on treatment‐resistant pruritus in 18 participants suffering from CP (Villamil 2005). Lidocaine administration resulted in a statistically significant reduction of pruritus severity only at day two (VAS 0‐100 (mm) MD 39.1 (95% CI 15.7 to 62.5) versus 70.8 (95% CI 62.7 to 78.9)) and day three (48.7 (95% CI 25.4 to 72) versus 72.0 (95% CI 60.3 to 83.7)) when compared with placebo administration (P < 0.05). The treatment group, but not the placebo group, improved from baseline (MD of treatment group about 26; P < 0.05).

Maralixibat versus placebo

Mayo 2019 enrolled 66 participants with in a three‐armed RCT receiving oral maralixibat (10 or 20 mg) once per day or placebo for 13 weeks. The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/ET (early termination). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (–26.5; 95% CI, –31.8 to–21.2) and placebo (–23.4; 95% CI, –30.3 to –16.4). The difference between groups was not statistically significant (P = 0.48).

Summary of treatments for CP

As we could not meta‐analyse the data across the comparisons due to heterogeneity of data, we have summarised and ranked MDs effect estimates, as follows:

• Opioid antagonist (naltrexone): VAS 0‐10 (cm) MD −2.42, 95% CI −3.90 to −0.94, certainty of evidence: low.

• Flumecinol: RR 2.20, 95% CI 0.42 to 11.60; two RCTs, N = 69, certainty of evidence: very low.

• Semi‐antibiotic rifampicin/rifampin: VAS 0‐100 (mm) MD −42.00, 95% CI −87.31 to 3.31, certainty of evidence: very low.

• Antidepressant (sertraline): VAS 0‐10 (cm) MD −2.24, (no confidence interval reported), one RCT.

Other treatments compared to placebo with contradictory results, methodological concerns or insufficient benefit included bile acid sequestrants, anaesthetic propofol, and maralixibat.

Palliative care participants with pruritus of different origin

Selective serotonin reuptake inhibitor (SSRI) paroxetine versus placebo

One study researched the effect of the selective serotonin reuptake inhibitor paroxetine (SSRI) on pruritus in palliative care patients (Zylicz 2003). In this randomised, controlled, cross‐over study, paroxetine showed an antipruritic effect in palliative care participants with opioid‐induced, paraneoplastic or haematologic pruritus. Twenty‐four of the 26 participants (two dropouts) treated with paroxetine (5.2, SE 0.32) had lower pruritus intensity scores on the 10‐point numerical analogue scale (NAS) over the seven treatment periods when compared to participants receiving placebo (6.0, SE 0.32). The MD between paroxetine and placebo after one week of treatment was −0.78 points (95% CI −1.19 to −0.37; one RCT, N = 48, certainty of evidence: low) (Summary of findings table 13, Figure 1) and −1.35 points (95% CI −2.11 to −0.59) on day three. We downgraded the certainty of evidence because of very serious imprecision. Nine of 24 of participants (37.5%) had a pruritus reduction of at least 50%. Investigators typically observed the onset of antipruritic action after two or three days, irrespective of the order of treatment. This was the only study that specifically researched patients treated in palliative care units or palliative care settings.

Participants with HIV‐associated pruritus

Hydroxyzine hydrochloride, pentoxifylline, triamcinolone, and indomethacin versus active control

A randomised parallel‐group study in 40 participants examined the four different therapies: hydroxyzine hydrochloride, pentoxifylline, triamcinolone and indomethacin in HIV participants suffering from pruritus (Smith 1997a). Results showed that participants placed on indomethacin obtained a median relief of 2.5 points on a 5‐point verbal rating scale. However, it is uncertain whether drug treatment with hydroxyzine hydrochloride, pentoxifylline, triamcinolone or indomethacin reduces pruritus because the certainty of evidence was very low due to a small sample size and lack of blinding.

Secondary outcomes

Only a few of the included studies examined the secondary outcomes quality of life, patient satisfaction and depression (Table 19).

Quality of life

Fourteen studies measured quality of life as a secondary outcome (Fishbane 2020a; Fishbane 2020b; Fouroutan  2017; Gobo‐Oliveira 2018; Kuiper 2010; Mathur 2017; Mayo 2019; Najmeh 2019; Sja'bani 1997; Somkearti 2021; Spencer 2015; Turner 1994a; Turner 1994b; Yue 2015).

GABA‐analogues

Fouroutan  2017 evaluated quality of life (Dermatology life quality index) in participants suffering from UP receiving pregabalin or doxepin: baseline scores were 3.8 (SD 1.8) for the pregabalin group and 3.6 (SD 1.4) for the doxepin group, respectively; P = 0.551. After four weeks of treatment, scores were improved in both groups (pregabalin: 1.2 (SD 1.5), doxepin: 2.2 (SD 1.4); P = 0.007). Najmeh 2019 reported quality of life improved in participants treated with pregabalin compared to the ketotifen (P < 0.05): pregabalin: 7.42 (SEM 1.21) to 3 (SEM 1.19); ketotifen: 5.85 (SEM 1.20) to 3.71 (SEM 1.19). In the study (Gobo‐Oliveira 2018) comparing gabapentin versus dexchlorpheniramine in participants with UP, both groups showed improved quality of life measures (Dermatology life quality index) with reduction by 50% from 2 (IQR 1‐3) to 1 (IQR 0‐1) in the gabapentin group and reduction from 2 (IQR 1‐4) to 0 (IQR 0‐1) in the dexchlorpheniramine group.

κ‐opioid agonists

Different studies investigated quality of life in participants treated with kappa‐opioid agonists. Participants receiving difelikefalin or placebo for the treatment of UP had improved quality of life, measured via the Skindex‐10 Scale (lower score = better): ‐17.1 (SEM 1.3) versus ‐12.0 (SEM 1.2); P < 0.001 (Fishbane 2020a). Similar results were reported by Fishbane 2020b, where all difelikefalin participants had reduced scores of ‐16.4 (SEM 1.3) versus ‐8.2 (SEM 2.0) in the placebo group; P < 0.001. Also, improved scores on the Scindex‐10 scale were reported by Spencer 2015 (P = 0.031) with no specified values in the abstract‐publication. Participants with UP treated with nalbuphine or placebo had no statistically significant differences on the overall Skindex‐10 scale between the groups (Mathur 2017). Only in the disease domain of the scale bothersomeness of itching (0–18), a difference between the nalbuphine 120 mg group and placebo could be found: –7.1 (SD 4.8) versus ‐5.4 (SD 5.0); P < 0.05.

Other treatments

In participants receiving maralixibat for treatment of CP (Mayo 2019), quality of life measured on the Primary biliary cirrhosis (PBC)‐40 scale was not different when compared with the placebo group.

In participants receiving colesevelam for treatment of CP, Kuiper 2010 found no changes with respect to the domains of physical functioning (P = 0.67), role physical functioning (P = 0.50), bodily pain (P = 1.00), general health (P = 0.48), vitality (P = 0.90), social functioning (P = 0.37), emotional functioning (P = 0.17) or mental health (P = 0.26). Results were based on the Short‐Form 36 Health Survey in the colesevelam group before and after treatment. The authors reported only P values.

For participants receiving low‐dose flumecinol for CP (Turner 1994a), the difference in median improvement in quality of life for flumecinol versus placebo, measured via the VAS 0‐100 (mm) (lower score = better), was 5.0 (95% CI 0.4 to 13.0, P = 0.02; one RCT, N = 50, certainty of evidence: moderate), in favour of flumecinol. The higher dose of flumecinol did not improve quality of life. The difference in median improvement between the two groups was 3.5 mm (95% CI −5.9 to 24.9) (Turner 1994b).

Yue 2015 assessed health‐related quality of life with the Mental Component Summary scale (MCS) from the Short‐Form 12 Health Survey (SF‐12; version 2, 0 to 100, higher scores = better quality of life). At week 12, the health‐related quality of life in UP participants was 47.3 (SD 11.6), 42.8 (SD 13.1) and 42.5 (SD 8.7) for pregabalin, ondansetron and placebo, respectively. The baseline values were similar between groups and the mean change from baseline versus placebo was larger in pregabalin (4.1, 95% CI 2.9 to 5.3) than in ondansetron (1.2, 95% CI ‐0.1 to 2.5).

Sja'bani 1997 did not specify the scale which was used for quality of life measurements.

Somkearti 2021 stated that there was no difference in QoL between the zinc sulphate and placebo group.

Patient satisfaction

Only one of the 91 included studies assessed patient satisfaction with the treatment regimen (Zylicz 2003). Using a non‐validated 7‐point scale, where 0 meant indifferent, −3 meant extremely poor, and 3 meant excellent, participants treated with paroxetine had, on average, higher satisfaction scores (mean 0.41, SE = 0.36) when compared to participants who received placebo (mean −0.66, SE = 0.36), regardless of the order in which they were received. The MD was −1.08 points (95% CI 0.18 to 1.98; one RCT, N = 48, certainty of evidence: low) in favour of paroxetine. We downgraded the certainty of evidence because of very serious imprecision (Summary of Findings Table 13 (Figure 1)).

Depression

Three studies examined depression as a secondary outcome (Bergasa 2006; Mathur 2017; Mayo 2007), measuring it with the Hamilton Depression Rating Scale, the Structured Clinical Interview Questionnaire (SCID) (Bergasa 2006), the Hospital Anxiety and Depression scale (HADS) (Mathur 2017), and the 30‐item Inventory of Depressive Symptomatology‐Self‐Report (IDS‐SR₃₀) (Mayo 2007).

Using the 17‐item Hamilton Rating Scale, Bergasa 2006 only evaluated the psychiatric state of the study participants at baseline and found eight participants scoring in the range of mild depression, three in the range of moderate depression, and two in the range of none to minimal depression. Data on the full psychiatric evaluation were available for 13 of the 16 participants.

Mayo 2007 comparing the effects of sertraline with placebo found that all four participants with moderate or severe depression improved with sertraline (12 participants included). Participants with mild depression symptoms, however, did not reliably improve their IDS‐SR₃₀ score with sertraline. One of these participants also improved with placebo. Both the VAS and IDS‐SR₃₀ improved with increasing doses of sertraline, but the change in IDS‐SR₃₀ did not completely explain the change in VAS.

Mathur 2017, comparing the effects of nalbuphine with placebo, used the Hospital Anxiety and Depression scale (HADS) and found no differences between the groups.

Due to the absence of satisfactory data, the feasibility of pooling the secondary outcomes data was limited. For detailed results, please see the 'Secondary outcomes' table (Table 19).

Adverse events

Twenty‐six (29%) included studies collected no data on adverse events (Ashmore 2000; Aubia 1980; Begum 2004; Bhaduri 2006; Chourdakis 2019; De Marchi 1992; Forouhari 2022; Ghent 1988; Ghorbani Birgani 2011; Kebar 2020; Lahiji 2018; Mahmudpour 2017; Mirnezami 2013; Mohamed 2012; Mortazavi  2017; Najmeh 2019; Pakfetrat 2018; Pederson 1980; Podesta 1991a; Rivory 1984; Shayanpour 2019; Spencer 2015; Subach 2001; Tapia 1977; Tol 2010; Van Leusen 1978). Eleven studies (12%) did not observe any adverse events (Ghanei 2012; Mapar 2015; Najafabadi 2012; Nakhaee 2015; Özaykan 2001; Omidian 2013; Shirazian 2013; Silva 1994; Turner 1994a; Turner 1994b; Young 2009).

Twelve (13%) studies described adverse events in the intervention group leading to withdrawal (Kumagai 2010; Legroux‐Crespel 2004; Murphy 2003; Nasrollahi 2007; Pauli‐Magnus 2000; Pour‐Reza‐Gholi 2007; Rossi 2019; Terg 2002; Wikström 2005a; Wikström 2005b; Yue 2015; Zylicz 2003). In contrast, only six studies found adverse events in the placebo groups or the standard medication group (Amirkhanlou 2016; Kumagai 2010; Legroux‐Crespel 2004; Pauli‐Magnus 2000; Wikström 2005a; Yue 2015).

Most adverse events were mild or moderate. Two interventions also showed multiple major adverse events (naltrexone and nalfurafine). We have summarised the different adverse events and the number of withdrawals for each study and intervention in two tables (see Table 20; Table 21: 'Adverse events according to the different studies'). In the following, we will focus on adverse events for the drugs that we included in the Summary of findings tables. We chose 'risk for at least one adverse event per participant' as a pragmatic outcome for our meta‐analyses.

GABA‐analogues

Gabapentin (oral) versus placebo

Bergasa 2006 was the only study that was appropriate for the analysis of adverse events. The RR for experiencing at least one adverse event was 2.63 (95% CI 0.76 to 9.05; one RCT, N = 15, certainty of evidence: low; Table 1) in favour of the placebo group (P = 0.13). We downgraded the certainty of evidence because of very serious imprecision. Common adverse events were somnolence, fatigue, dizziness and nausea (Gunal 2004; Naghibi 2007; Naini 2007; Nofal 2016).

Gabapentin (topical) versus vehicle

One study (Aquino 2020) reported no significant difference between treatment with topical gabapentin or vehicle, but did not report specifically the number of adverse events.

Gabapentin versus pregabalin

Two studies reported adverse events (Ravindran 2020; Solak 2012). The RR for experiencing at least one adverse event was 4.70 (95% CI 0.21 to 104.14; two RCTs, N = 122, certainty of evidence: very low; Table 2; Analysis 2.2) in favour of the pregabalin group (P = 0.13). We downgraded the certainty of evidence because of serious risk of bias, very serious inconsistency, and very serious imprecision. The pooled estimate became statistically significant in the sensitivity analysis (Analysis 2.3) under the fixed‐effects model. Common adverse events were somnolence, fatigue, dizziness and nausea.

2.2. Analysis.

Comparison 2: Gabapentin versus pregabalin, Outcome 2: B) Risk for at least one adverse drug reaction (ADR) per participant in UP participants; parallel‐group and cross‐over design

2.3. Analysis.

Comparison 2: Gabapentin versus pregabalin, Outcome 3: B) Sensitivity analyses; risk for at least one adverse drug reaction (ADR) per participant in UP participants; parallel‐group and cross‐over design

κ‐opioid agonists versus placebo

The RR for experiencing at least one adverse event per participant was 1.73 (95% CI 1.20 to 2.48; five RCTs, N = 1344, certainty of evidence: low; Table 3; Analysis 3.3) to the disadvantage of kappa‐opioid agonists compared with placebo. We downgraded the certainty of evidence because of serious inconsistency and serious imprecision. The results slightly changed when using the fixed‐effects model (RR 1.47, 95% CI 1.28 to 1.68; Analysis 3.4). Common adverse events were nasopharyngitis, insomnia, headaches, somnolence, and constipation for nalfurafine (Kumada 2017; Kumagai 2010; Wikström 2005a; Wikström 2005b), diarrhoea, dizziness, and vomiting for difelikefalin (Fishbane 2020a; Fishbane 2020b), and nausea, vomiting and somnolence for nalbuphine (Mathur 2017).

3.3. Analysis.

Comparison 3: Kappa‐opioid agonist versus placebo, Outcome 3: B) Risk for at least one adverse drug reaction (ADR) per participant in UP participants; parallel‐group and cross‐over design

3.4. Analysis.

Comparison 3: Kappa‐opioid agonist versus placebo, Outcome 4: B) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant; UP participants; parallel‐group and cross‐over design

Serotonin 5‐HT₃ antagonist ondansetron versus placebo

We included three studies for the analysis of adverse events (Murphy 2003; O'Donohue 2005; Yue 2015). The meta‐analysis showed no difference between the groups (RR 2.54, 95% CI 0.38 to 16.78; three RCTs, N = 174) (Analysis 4.4; Analysis 4.5), and there was a noticeable increase of the 95% CI when using the fixed‐effects model for the sensitivity analysis (RR 2.07, 95% CI 0.87 to 4.93) (Analysis 4.6). Very few adverse events were reported for UP patients resulting in a RR of 7.50 and a wide 95% CI (0.97 to 58.07, two RCTs, N = 155, certainty of evidence: very low) (Analysis 4.5; Table 4). We downgraded the certainty of evidence because of very serious imprecision and serious risk of bias.

4.4. Analysis.

Comparison 4: Ondansetron versus placebo or standard medication, Outcome 4: B) Risk for at least one adverse event per participant in UP and CP participants

4.5. Analysis.

Comparison 4: Ondansetron versus placebo or standard medication, Outcome 5: B) Subgroup analysis by nature of pruritus and study design; risk for at least one adverse event per participant

4.6. Analysis.

Comparison 4: Ondansetron versus placebo or standard medication, Outcome 6: B) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant in UP and CP participants

Leukotriene receptor antagonist montelukast versus placebo

Only major adverse events were reported (Nasrollahi 2007) or adverse events were not reported at all (Mahmudpour 2017).

Zinc sulphate versus placebo

Studies reported no adverse events or similar adverse events for zinc sulphate or placebo during a four‐week or an eight‐week intervention period (Mapar 2015; Najafabadi 2012; Somkearti 2021).

Oral and topical mast cell stabiliser cromolyn sodium versus placebo

Adverse events were rare in both groups, but they showed a conflicting pattern (I² = 84%) that indicated a statistically non‐significant (P = 0.08) higher risk of adverse events (burning sensation) for the topical treatment (Feily 2012) compared with vehicle (RR 13.00, 95% 0.76 to 220.96; one RCT, N = 60). Interestingly, the risk for at least one adverse event per participant was lower (but not statistically significant, P = 0.08) for the oral administration (Vessal 2010) compared with placebo (RR 0.16, 95% CI 0.02 to 1.22; one RCT, N = 62) (Table 8; Analysis 8.4; Analysis 8.5: two RCTs, N = 122, certainty of evidence: very low). We downgraded the certainty of evidence because of very serious inconsistency and serious imprecision. The fixed‐effects model had a considerably decreased 95% CI (Analysis 8.6).

8.4. Analysis.

Comparison 8: Cromolyn sodium versus placebo, Outcome 4: B) Risk for at least one adverse event per participant; UP participants; parallel‐group design

8.5. Analysis.

Comparison 8: Cromolyn sodium versus placebo, Outcome 5: B) Subgroup analysis by route of administration; risk for at least one adverse event per participant; UP participants; parallel‐group design

8.6. Analysis.

Comparison 8: Cromolyn sodium versus placebo, Outcome 6: B) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant; UP participants; parallel‐group design

Topical capsaicin versus placebo

The pooled RR for experiencing at least one adverse event was 3.69 (95% CI 1.17 to 11.67, 95% CI 2.05 to 10.51; three RCTs, N = 116, certainty of evidence: low) in favour of the vehicle group (Table 9; Analysis 9.4). However, participants mostly reported mild skin burning, which is part of the intended mechanism. We downgraded the certainty of evidence because of very serious imprecision. The results changed slightly when using the fixed‐effects model (RR 4.64; 95% CI 2.05 to 10.51) (Analysis 9.5).

9.4. Analysis.

Comparison 9: Topical capsaicin versus vehicle, Outcome 4: B) Risk for at least one adverse event per participant; UP participants, cross‐over design

9.5. Analysis.

Comparison 9: Topical capsaicin versus vehicle, Outcome 5: B) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant; UP participants; cross‐over design

Opioid antagonist naltrexone versus placebo

The overall effect of RR 3.85 (95% CI 1.52 to 9.76; three RCTs, N = 116, certainty of evidence: low) emphasises the increased risk for at least one adverse event for participants under naltrexone compared to placebo (Table 10; Analysis 10.7; Analysis 10.8). We downgraded the certainty of evidence because of very serious imprecision. The fixed‐effects model had a considerably decreased 95% CI (Analysis 10.9).

10.7. Analysis.

Comparison 10: Naltrexone versus placebo, Outcome 7: C) Risk for at least one adverse event per participant in UP and CP participants; cross‐over design

10.8. Analysis.

Comparison 10: Naltrexone versus placebo, Outcome 8: C) Subgroup analysis by nature of pruritus; risk for at least one adverse event per participant; cross‐over design

10.9. Analysis.

Comparison 10: Naltrexone versus placebo, Outcome 9: C) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant; UP and CP patients; cross‐over design

Naltrexone in UP patients

The number of participants with at least one adverse event was higher in the naltrexone group in participants with UP compared with placebo (RR 9.62; two RCTs, N = 76). However, this result was very imprecise as the 95% CI was very wide (1.90 to 48.65) (Pauli‐Magnus 2000; Peer 1996; Analysis 10.8).

Naltrexone in CP patients

We could only integrate the adverse events' outcome of Terg 2002 in our meta‐analysis, showing an RR of 2.67 (95% CI 1.32 to 5.39; N = 40) in favour of the placebo group (Analysis 10.8).

Semi‐antibiotic rifampicin versus active control

We could only use Bachs 1989 to analyse the RR for experiencing at least one adverse event. The result was not statistically significant (RR 0.29, 95% CI 0.03 to 2.51; one RCT, N = 39, certainty of evidence: very low) (Table 11). We downgraded the certainty of evidence because of very serious risk of bias and very serious imprecision. Overall, investigators observed very few adverse events for rifampicin compared to placebo (Table 21).

Flumecinol versus placebo

No adverse events were attributable to the trial medication according to the authors (Turner 1994a; Turner 1994b), who reported no adverse events when flumecinol was compared to placebo (Table 12).

Selective serotonin reuptake inhibitor (SSRI) paroxetine versus placebo

On a 0 to 10 numerical analogue scale (NAS), participants treated with paroxetine compared with placebo suffered slightly more from nausea (0.46 points, 95% CI 0.05 to 0.87) and sleepiness (0.70 points, 95% CI 0.18 to 1.22) but not from vomiting (Summary of finding table 13 (Figure 1): −0.18 points, 95% CI −0.44 to 0.08, N = 52, certainty of evidence: low). We downgraded the certainty of evidence for nausea, vomiting and sleepiness because of very serious imprecision. Two participants discontinued treatment because of severe adverse events (nausea and vomiting), presumably because there was no opportunity to titrate the dose to the effect of the medication in this trial.

Discussion

Summary of main results

We identified 91 studies assessing the effects of 51 different interventions for pruritus of multiple origin in 4652 participants with advanced disease. Forty‐two studies with 2839 participants were new to this update.

The kind of pruritus most frequently researched was UP (N = 3894 participants, 84%), followed by CP (N = 692, 15%). For now, only one RCT has researched pruritus as a symptom in inpatients of two palliative care centres (Zylicz 2003). All other studies focused on different kinds of pruritus based on the underlying disease of the participants. Furthermore, one included study focused on HIV‐related pruritus (Smith 1997a). The main results of this review were reported according to the structure resulting from these findings.

Participants with UP

GABA analogues (gabapentin and pregabalin) compared to placebo showed the clinically most substantial improvement of pruritus (Table 1, Analysis 1.1); certainty of evidence: moderate. Authors reported some adverse events like dizziness or somnolence for gabapentin, but the certainty of evidence was low, and the results were not statistically significant (Table 20; Table 21; Table 1). In head‐to‐head comparison of gabapentin and pregabalin (Table 2; Analysis 2.1), studies did not show an effect favouring one of the two substances; certainty of evidence: low. One study (Aquino 2020) showed a beneficial effect of topical gabapentin. Seven studies (Amirkhanlou 2016; Gobo‐Oliveira 2018; Kebar 2020; Marin 2013; Najmeh 2019; Noshad 2011; Suwanpidokkul 2007) compared gabapentin with different antihistamines showing superiority of gabapentin in most cases.

Kappa‐opioid agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduce pruritus, but the effect is small (Table 3, Analysis 3.1; Analysis 3.2); certainty of evidence: high. The risk for at least one adverse event (most frequently insomnia) was also slightly higher (certainty of evidence: low) (Table 3).

Montelukast compared to placebo did substantially reduce UP (Table 5; Analysis 5.1), but the certainty of evidence was rated very low because the homogeneity was difficult to assess due to well validated but different itch scoring methods. More studies are needed to evaluate montelukast as treatment option for UP.

Fish‐oil/omega‐3 fatty acids compared to placebo can reduce UP (Table 6, Analysis 6.1); certainty of evidence: low. There were no relevant adverse events reported. Ghanei 2012 evaluated the efficacy of omega‐3 fatty acids. Though there were statistically significant group differences, the wide confidence intervals due to the small sample size and the low methodological quality of the trial confer some uncertainty of the findings. However, cross‐over studies confirm a positive effect of fish‐oil/omega‐3 fatty acids on pruritus (Forouhari 2022; Lahiji 2018; Mortazavi  2017; Shayanpour 2019). Mortazavi  2017 was an abstract only publication which did not report essential information for inclusion in the meta‐analysis.

Cromolyn sodium (orally administered) that Vessal 2010 tested may be more effective than the topical use featured in Feily 2012 (certainty evidence: very low, Analysis 8.2; Table 8); the topical use is associated with more adverse events (skin burning). These rather small studies did not report adverse events, except skin burning in patients receiving topical cromolyn sodium (Feily 2012).

Topical capsaicin compared to vehicle (placebo) did reduce UP (Table 9, Analysis 8.1; Analysis 8.2); certainty of evidence: low. A common minor adverse event of topical capsaicin was a transient burning sensation and local erythema with initial application, and the risk for at least one adverse event per participant was considerably increased (Table 9; Table 21); certainty of evidence: low. Three of the studies demonstrated methodological flaws such as inappropriate designs leading to carry‐over effects, inadequate depiction of data and failure to provide appropriate statistical analyses (Breneman 1992a; Cho 1997; Tarng 1996).

Additional studies investigated systemic interventions like erythropoietin (De Marchi 1992), thalidomide (Silva 1994), activated oral charcoal (Pederson 1980), and doxepin (Pour‐Reza‐Gholi 2007), all versus placebo. All of these interventions could have a positive effect on UP. However, the sample sizes were small (16 to 29 participants) and,in four of the six studies, methodological quality was limited (De Marchi 1992; Nasrollahi 2007; Pederson 1980; Silva 1994).

Seven studies investigated the effect of topical agents on UP. Whereas tacrolimus ointment was not more effective than the vehicle (placebo) in relieving UP (Duque 2005), pramoxine lotion tended to reduce pruritus to a greater degree than the control lotion (Young 2009). There was conflicting data on treatment with pimecrolimus crème (Ghorbani 2012; Ghorbani Birgani 2011) when compared to active control or placebo. Adverse events for tacrolimus were minor, and there were none for pramoxine hydrochloride. However, both studies were at high risk of bias. Thus, evidence for the use of these topical applications is limited. Another study examined avena sativa and vinegar solution as topical agents (Nakhaee 2015). Both treatments and placebo reduced pruritus. The evidence of the study is very uncertain because of the small sample size (N = 25) and the impossibility of blinding. Also, nicotinamide, ergocalciferol (Omidian 2013; Shirazian 2013), and zinc sulphate (Table 7) tended to be ineffective for pruritus treatment when compared to placebo.

Participants with CP

In contrast, the findings in CP participants indicate that gabapentin appears to worsen pruritus (Bergasa 2006). On the other hand, the authors also observed a strong placebo effect, prompting them to discuss whether gabapentin possibly interferes with the placebo effect (possibly an association of the placebo intervention with dopamine release).

Three studies explored the effect of rifampicin (Bachs 1989; Ghent 1988; Podesta 1991a). The quantitative results indicate that rifampicin could be effective for treating CP when compared with a placebo or phenobarbitone. However, the heterogeneity was very high (I² = 95%) when using the random‐effects model, leading to an extremely wide 95% CI that reversed statistical significance and impeded the interpretability of results (though the mean effect was large) (Analysis 11.1). The certainty of evidence was judged as very low for pruritus and for the adverse event outcome (Table 11).

Mayo 2007 described the SSRI sertraline as effective and well‐tolerated in participants with CP when compared with a placebo. However, the sample size of 12 participants was very small, and the blinding of outcome assessment was somewhat precarious. Ataei 2019 enrolled 36 participants comparing sertraline with rifampicin. Both interventions reduced pruritus with no statistically significant difference between the groups. More studies are needed to evaluate sertraline as a treatment option for CP.

Two studies researched flumecinol with two different dosages compared to placebo in CP participants (Turner 1994a; Turner 1994b). The results of both studies only reached statistical significance in our analysis when we combined them. However, the certainty of evidence remains very low for this comparison (Table 12). The results suggested that there could be a dose‐response‐relationship, but the small sample sizes impeded generalisation and led to a wide 95% CI. Authors reported no adverse events for flumecinol.

Two studies investigated the effect of anaesthetics: Borgeat 1993 assessed propofol compared to placebo in 12 participants, and Villamil 2005 studied lidocaine compared to placebo in 18 participants. Both trials reported an amelioration of pruritus for participants treated with propofol and lidocaine, but we cannot draw conclusions since the sample sizes were small and the studies were not free of bias. Adverse events reported were minor. However, the applicability of lidocaine as an alternative therapy for CP is limited because of the necessity of hospital or inpatient treatment of the patients concerned.

Participants with advanced diseases and UP or CP

Three naltrexone studies focused on UP (Legroux‐Crespel 2004; Peer 1996; Pauli‐Magnus 2000) comparing to active control or placebo, and two evaluated naltrexone for CP (Terg 2002; Wolfhagen 1997) comparing to placebo. We analysed the percent change of pruritus in CP and UP participants in a subgroup analysis, finding a larger effect in CP participants. However, the results of the studies pertaining to UP are conflicting. For at least Pauli‐Magnus 2000 and Peer 1996, we cannot explain differences by variations in participant compliance, naltrexone dose, study design or methodological quality. Moreover, readers should interpret the results of Legroux‐Crespel 2004 cautiously because of missing data, high dropout rates and high risk of bias. Concerning CP, meta‐analysis favoured naltrexone over placebo (Analysis 10.1). Still, the study population included was quite small (16 and 20 participants in Wolfhagen 1997 and Terg 2002, respectively), and participants on naltrexone had the highest incidence of adverse events (low‐certainty evidence) (Table 10).

Duncan 1984 and Silverberg 1977 studied the bile acid sequestrant cholestyramine for CP and UP, respectively. The results tended to favour the cholestyramine group for UP and CP when compared to placebo. However, both studies suffered from very small sample sizes (8 and 10 participants), and they were of low methodological quality. Thus, the validity of the results is very limited.

Ondansetron was applied for either UP or CP. Four studies were included in meta‐analysis (Analysis 4.1) showing no advantage of ondansetron over placebo, either for use in CP (O'Donohue 2005) or for UP (Ashmore 2000; Murphy 2003). One study researching ondansetron for treatment of UP found a benefit for participants treated with ondansetron compared to participants treated with the standard medication cyproheptadine (Özaykan 2001). In another RCT, the differences were marginal between ondansetron and placebo and indicated a minimal effect in favour of ondansetron (Yue 2015). Interestingly, in all studies comparing ondansetron with placebo, the placebo group showed an improvement in pruritus, which was even statistically significant in one study (Murphy 2003). Overall, ondansetron may be not effective for treatment of UP or CP. Adverse events hardly seem to differ between groups (certainty of evidence: very low) (Table 4).

Palliative care patients with pruritus of different origin

Most 'palliative care' participants, as defined in the Methods, were treated on normal wards, perhaps because many hospitals still do not have a palliative care ward or patients did not have palliative care needs in the early phase of their disease. There were only 26 participants including two dropouts who received treatment on palliative care wards (Zylicz 2003). The study indicates that paroxetine compared to placebo may be effective but also may increase nausea and sleepiness (certainty of evidence: low for all outcomes; Summary of findings table 13 (Figure 1)). Still, the number of participants included in this study was quite small, the treatment period was brief, and there was no follow‐up.

Participants with HIV‐associated pruritus

Smith 1997a compared four different interventions to a placebo for pruritus in 40 participants with HIV. Since authors provided no information about blinding and additional data were missing, we assessed the risk of bias to be high, and we cannot make conclusive recommendations based on the study results.

Overall completeness and applicability of evidence

This review included 91 RCTs. Only one study researched pruritus in palliative care patients who received palliative care. According to the presumed definition of palliative care patients as 'adult patients in any setting, receiving palliative care or suffering an incurable progressive medical condition', we also included studies researching pruritus in participants with advanced and incurable diseases in different settings. Thus, included studies explored a total of 51 different interventions for treatment of four different groups of patients suffering from pruritus of different origins (Table 17; Table 18). Due to the diversity of the interventions and the small number of studies per intervention, we could not compare the effectiveness of all interventions. As the overall quality of studies varied, missing data in several studies did not allow for including data from all studies in a single meta‐analysis. We had to describe the results of several studies as a narrative summary. Due to the diversity and different character of pruritus and the patient groups being researched, the applicability of evidence is restricted to the particular patient group targeted by the intervention.

Quality of the evidence

The summary of findings tables, structured according to the GRADE system (Schünemann 2013), show that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa‐opioid agonist versus placebo and moderate for GABA‐analogues. This means we are highly or moderately confident in the effect estimate: high: further research is very unlikely to change our confidence in the estimate of effect; moderate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Certainty of evidence was low for naltrexone, fish‐oil/omega‐3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. This means that our confidence in the effect estimate is limited, and the true effect may be substantially different from the estimate of the effect. Risk of bias, inconsistency, and imprecision were the main factors for downgrading the certainty of evidence for the primary outcome (Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10; Table 11; Table 12; Summary of findings table 13 (Figure 1)).

Concerning the risk of experiencing at least one adverse event per participant, the certainty of evidence was low for naltrexone, topical capsaicin, GABA‐analogues, kappa‐opioid agonists and very low for ondansetron, rifampicin and cromolyn sodium. For paroxetine, we rated the certainty of evidence as low for nausea, vomiting and sleepiness. We mostly downgraded the certainty of evidence because of serious/very serious imprecision.

Potential biases in the review process

Previous reviews have reported difficulties in defining the population of palliative care patients. Therefore, we used the definition 'adult patients in any setting, receiving palliative care or suffering an incurable progressive medical condition', which has previously been used in other Cochrane reviews (Murray‐Brown 2015; Storrar 2014). However, it is still difficult to identify the patients or patient groups that are appropriate for inclusion in a systematic review on palliative care topics, as there is still a lack of original studies, particularly RCTs, in palliative care. In a survey of 25 Cochrane reviews in palliative care (Wee 2008), the authors concluded that “Cochrane reviews in palliative care [...] fail to provide good evidence for clinical practice because the primary studies are few, small, clinically heterogeneous, and of poor quality and external validity”. Nevertheless, data on palliative care patients may be hidden in studies not described as palliative care topics. Therefore, it is possible that we failed to identify some published or unpublished trials including palliative care patients for this review.

We decided to downgrade our certainty of evidence judgements using the GRADE‐system on high, but not unclear risk of bias. This may have resulted in a level of overestimation of the certainty of evidence.

In this update, we performed a comprehensive literature search, specified inclusion and exclusion criteria and conducted meta‐analysis where possible. We updated MEDLINE, Embase and CENTRAL (June 2016 to July 2022), checked reference lists of all relevant trials and searched registers of ongoing trials. We included 19 studies from another Cochrane review (Hercz 2020), which might have biased the review process because other authors were involved in data extraction from the studies and assessment of risk of bias. Since Hercz 2020 did not include patient satisfaction and depression as secondary endpoints, we checked all included studies, but could not find additional data on these endpoints.

In order to avoid duplicate publication bias, it was crucial to identify all redundant and multiple publications, which can lead to overestimation of intervention effects. We found one study whose data overlapped substantially with an included study and therefore excluded it (Borgeat 1994).

In the original review and in the first update, we imposed no language restriction. As a result, we identified a Turkish language study that we had translated before data extraction (Özaykan 2001). We accept possible lack of clarity due to translation.

The title of this review suggests that a variety of patients with different underlying diseases were included. However, the vast majority of participants suffered from UP (N = 3894, 84%) pruritus, and only 26 participants were treated in palliative care settings.

Choosing the adverse event outcome 'risk for at least one adverse event per participant' for meta‐analysis was a pragmatic decision in order to give a quantitative overview. In many cases, the number of adverse events exceeded the number of participants, making the results of statistical analyses incoherent. On the one hand, one participant may experience several adverse events simultaneously. On the other hand, especially in the cross‐over studies, the data do not allow us to identify which participant in which group of the study experienced the adverse event. Therefore, it was not possible to allocate the adverse events described in the studies to an individual or to adequately calculate the number of adverse events in relation to the factual number of participants included. Table 20 and Table 21 describe all different types of adverse events more precisely.

The results of the risk of bias assessment emphasise the challenge and difficulty of conducting large high‐quality RCTs with 200 or more participants with advanced disease per treatment arm. Though other Cochrane Reviews have used this cut‐off, which seems reasonable, it may be somewhat arbitrary. Moreover, the sample size is also indirectly addressed by the 'imprecision' item of GRADE. It is difficult to decide on the extent of bias at the outcome level. On the one hand, participants and personnel in 70 (77%) studies were adequately blinded. However, the outcome assessment was only blinded in 26 studies (29%). The latter in particular could have contributed to bias when assessing the intensity of pruritus or adverse events. The quality of evidence at the outcome level can be found in the Summary of findings tables for the all comparisons.

Agreements and disagreements with other studies or reviews

The Cochrane review “Interventions for itch in people with advanced chronic kidney disease” (Hercz 2020), unlike our review, includes non‐pharmacological/complementary interventions and only participants with UP. Their key conclusions in regard to UP are congruent with the conclusions in this review: substantial benefit of GABA‐analogues when compared to placebo and benefit of kappa‐opioid agonists when compared to placebo in participants suffering from UP. In addition, we could include some new studies e.g. on difelikefalin (kappa‐opoid agonist). While there is some overlap of Hercz 2020 and this review in regard to pharmacological interventions for UP, it did not cover participants suffering from other origins of pruritus e.g. CP and malignant disease.

Another Cochrane review on “Interventions for chronic pruritus of unknown origin” (Andrade 2020) included one study on the neurokinin 1 receptor (NK1R) antagonist serlopitant suggesting that serlopitant may reduce pruritus intensity when compared with placebo (quality of evidence: low). Participants of this study were healthy individuals, therefore, there is no overlap with this review. Future studies should investigate the effect of serlopitant in palliative care patients.

Furthermore, we found reviews and systematic reviews on the following interventions for pruritus, and we compared the results to the results of this review.

• GABA‐analogues (Eusebio‐Alpapara 2020): In agreement with our conclusion, GABA‐analogues are effective for reduction of UP. The authors did not include Naini 2007 in their meta‐analysis, which did not affect the conclusion.

• Kappa‐opioid agonists (Inui 2015): In contrast to our review, this review included only studies on nalfurafine while our review also included other kappa‐opioid agonists (difelikefalin, nalbuphine). In addition, the authors included a long‐term study that showed the efficacy of nalfurafine hydrochloride over one year without resulting in abuse liability of nalfurafine (Ueno 2013). Our analysis suggests that the effect of kappa‐opioid agonists should not be overestimated (Analysis 3.1).

• Rifampicin (Khurana 2006; Tandon 2007): In accordance with the results of our review, meta‐analyses of prospective RCTs revealed that rifampicin might be effective and has tolerable adverse events as short‐term treatment for pruritus (Khurana 2006; Tandon 2007).

• Systemic μ‐opioid receptor antagonists (Phan 2010): reviewed the use of systemic μ‐opioid receptor antagonists in the treatment of various forms of chronic pruritus; the included RCTs in participants with advanced diseases were similar to the RCTs included in this review.

• Topical capsaicin (Gooding 2010): explored the effect of topical capsaicin. Since it was conducted in 2010, the review did not include the Makhlough 2010 study on topical capsaicin; however, the overall results were comparable with our findings.

• Using fish oil/omega‐3 fatty acids for UP was reviewed by Panahi 2016. The review included two studies which did not have pruritus as the primary endpoint; therefore, they were excluded by us. This review included two studies which were published after 2016. The author's conclusion that fish‐oil/omega‐3 fatty acids may improve UP is in agreement with our conclusion.

We found reviews and systematic reviews on the following different origins of pruritus.

• UP: Simonsen 2017 conducted a systematic literature search on interventions against UP and found several studies which were also included in this review. Conclusions on the effectiveness of GABA‐analgues mirror the conclusions of this review. Simonsen and colleagues did not conduct meta‐analysis due to heterogeneity of the studies. However, we decided that meta‐analyses were feasible under careful consideration of study design and study limitations.

• CP: Düll 2019 summarised recent epidemiological data suggesting that cholestatic pruritus is a common and relevant symptom. The narrative review referred to guideline of the European Association for the Study of the Liver on the management of cholestatic liver disease (EASL 2009) which recommends cholestyramine, rifampicin, naltrexone and sertraline for patients with CP which is in agreement with the results of this review, although the quality of the evidence differs between the interventions from very low to low (Table 10; Table 11; Table 12).

Authors' conclusions

Implications for practice.

Several interventions for different origins of pruritus show different effectiveness in reducing pruritus.

For adult palliative care patients with pruritus

For the treatment of uraemic pruritus (UP) GABA‐analogues (gabapentin and pregabalin) had the most substantial effect (quality of evidence: moderate). The effects of other treatments were moderate or minor with differing quality of evidence: kappa‐opioid agonists (difelikefalin, nalbuphine, nalfurafine), montelukast, fish‐oil/omega‐3 fatty acids, cromolyn sodium (oral rather than topical) and topical capsaicin.

For the treatment of cholestatic pruritus (CP), rifampicin and flumecinol could be effective, but the certainty of evidence was very low. The opioid antagonist naltrexone offered a therapeutic alternative for participants suffering from UP or CP. However, this drug is sometimes inappropriate in a palliative care population that suffers from pain because of the risk of loss of analgesia at higher doses of naltrexone (Higginson 1997; Potter 2003; Walsh 2000). Ondansetron tended to have only a very small or no effect for treatment of UP or CP, and the results for cholestyramine, thalidomide, lidocaine and sertraline were very limited due to the small sample sizes.

Paroxetine showed promise in palliative care patients, although evidence was only available from one study. Overall, most of the drugs were associated with few and mild adverse events. Naltrexone showed the most adverse events.

For patients suffering from pruritus associated with HIV infection, we could not draw any distinct conclusions, as the evidence was of very low certainty. Indomethacin was described as the most effective drug, but the results cannot be generalised.

For clinicians

The varying pathogenesis of pruritus in different disorders means that a universally accepted therapy is difficult to establish. Therapy for pruritus is challenging and requires an individualistic approach. Therefore, identifying the underlying cause of pruritus is still of prime importance in order to develop tailored treatment plans. Especially in palliative care, patients with pruritus may have more than one origin for pruritus. The fact that itch affects the skin, immune system, and the peripheral and central nervous system means that complex and combinatory pathways are likely to be more effective than a single‐line approach.

For policy‐makers

Two factors could be taken into account for policymaking. First, many drugs presented here were used off‐label. The off‐label use of drugs is a typical and well‐known phenomenon in palliative care. Second, treatments for pruritus are not necessarily bound to the pharmaceutical law (e.g. fish‐oil/omega‐3 fatty acid). This influences time and costs of RCTs.

For funders

Funders could consider supporting high‐quality RCTs with 50 or more participants per treatment arm. Most of the investigated drugs showed a positive tendency in reducing pruritus, but these results need to be confirmed in further RCTs (e.g. gabapentin, cromolyn sodium; see also below).

Implications for research.

For GABA analogues, the effect is large and certainty of evidence is moderate in UP patients. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. However, these results are only valid for UP patients. The conflicting results for CP participants should be clarified in a future RCT with an adequate sample size (at least 50 participants per treatment arm) (Anand 2013). Furthermore, GABA‐analogues could be promising substances for trials investigating other origins of pruritus (e.g. unspecific pruritus in palliative care). For kappa‐opioid agonists (difelikefalin, nalbuphine, nalfurafine), the certainty of evidence is high and further RCTs are unlikely to change the results of slightly decreasing pruritus.

In the future, larger studies would help delineate the efficacy of the available and proposed antipruritics. Studies in the field of palliative care are especially lacking, and the certainty of evidence for interventions targeting palliative care patients is low. Therefore, well‐designed, preferably placebo‐controlled and randomised treatment trials are needed to further verify the effectiveness of many antipruritic agents currently in use. Ideally, these RCTs should at least include 50 participants per treatment arm (depends also on sample size calculation).

Measurement (endpoints)

Most authors used a simple 10 cm or 100 mm VAS to assess pruritus. The VAS should be the minimum standard for assessing pruritus (e.g. in addition to the Duo scale, satisfaction and quality of life). One advantage of the VAS is that the results can be easily pooled and interpreted in meta‐analyses.

What's new

Date	Event	Description
22 March 2023	New citation required but conclusions have not changed	i. Summary of the differences between the update and the current published version. We included 42 new studies and removed one study (Pakfetrat 2014) from the update 2016 because it met the exclusion criteria (complementary treatment) We updated the Study flow diagram; 'Characteristics of studies' table; Risk of bias table; Additional tables (1‐5); Meta‐analyses: one comparison deleted (because studies were too heterogenous and abstract‐only publication had high risk of bias), three additional comparisons; subgroup analyses and sensitivity analyses for the primary and the secondary outcomes; 'Summary of findings' tables three additional comparisons. ii. Date and year of the last search: 6 July 2022. iii. Forty‐two new included studies iv. Participants involved in this review update (N   =   4652): 1813 participants from the first update (Siemens 2016); one study was excluded Pakfetrat 2014 (N = 100 participants) because complementary treatment (tumeric); three participants were miscounted. 2839 additional participants: Aquino 2020 (N = 30); Ataei 2019 (N = 36); Aubia 1980 (N = 13); Begum 2004 (N = 22); Bhaduri 2006 (N = 78); Chourdakis 2019 (N = 20); Fishbane 2020a (N = 378); Fishbane 2020b (N = 174); Forouhari 2022 (N = 40); Fouroutan  2017 (N = 90); Gholyaf 2020 (N = 77); Ghorbani 2012 (N = 60); Ghorbani Birgani 2011 (N = 60); Gobo‐Oliveira 2018 (N = 60); Kebar 2020 (N = 32); Kumada 2017 (N = 317); Lahiji 2018 (N = 40); Mahmudpour 2017 (N = 80); Marin 2013 (N = 36); Mathur 2017 (N = 373); Mayo 2019 (N = 66); Mirnezami 2013 (N = 70); Mohamed 2012 (N = 45); Mortazavi  2017 (N = 20); Naghibi 2007 (N = 20); Najmeh 2019 (N = 30); Nofal 2016 (N = 54); Noshad 2011 (N = 40); Pakfetrat 2018 (N = 50); Ravindran 2020 (N = 50); Rivory 1984 (N = 13); Rossi 2019 (N = 21); Shayanpour 2019 (N = 64); Sja'bani 1997 (N = 29); Solak 2012 (N = 50); Somkearti 2021 (N = 55); Spencer 2015 (N = 65); Subach 2001 (N = 23); Suwanpidokkul 2007 (N = 19); Tapia 1977 (N = 20); Tol 2010 (N = 14); Van Leusen 1978 (N = 5). v. New meta‐analyses as a result of our new findings and general revision: We updated all meta‐analyses: subgroup analyses and sensitivity analyses for the primary and the secondary outcomes. New comparisons added to Data synthesis and Summary of findings tables: GABA‐analogues versus placebo (renamed from 'gabapentin versus placebo') Gabapentin versus pregabalin Kappa‐opioid agonists versus placebo (renamed from 'nalfurafine versus placebo'): two substances (nalbuphine, difelikefalin) added Montelukast versus placebo Fish‐oil/omega‐3 fatty acids versus placebo One comparison was omitted ('gabapentin versus antihistamines') because studies were too heterogenous and abstract‐only publication had high risk of bias (Marin 2013; Suwanpidokkul 2007). New scales (Skindex‐10, PBC‐10, DLQI, HADS) measuring quality of life and depression were added to the 'methods section'. Studies with > 10 years where no changes were made in the registry were deleted from 'ongoing studies'. Risk of bias results were added in the forest plot figures. Complementary intervention 'tumeric' was deleted because the intervention met exclusion criteria. vi. Conclusion The conclusion has been slightly altered without changing the main statement: new effective substances. Previous readers of the review should re‐read this update.
22 March 2023	New search has been performed	This review has been updated. We included results of a new search and updated the 'Risk of bias table, the 'Summary of findings' tables and the meta‐analyses.

History

Protocol first published: Issue 1, 2010
Review first published: Issue 6, 2013

Date	Event	Description
9 June 2016	New citation required but conclusions have not changed	i. Summary of the differences between the update and the current published version. We optimised the search strategies. We included 10 new studies. We updated the study flow diagram; 'Characteristics of studies' table; 'Risk of bias' table; additional tables (1‐5); meta‐analyses: one comparison deleted (only one study), three additional comparisons; subgroup analyses and sensitivity analyses for the primary and the secondary outcomes; 'Summary of findings' tables three additional comparisons; integration of secondary outcomes. ii. Date and year of the last search: 9 June 2016. iii. Ten new included studies after reading the full text: Amirkhanlou 2016; Feily 2012; Ghanei 2012; Mapar 2015; Najafabadi 2012; Nakhaee 2015; Omidian 2013; Pakfetrat 2014; Shirazian 2013; Yue 2015. iv. Participants involved in this review update (N = 1916): 1289 participants from the first version of this review (Xander 2013): (the original review reported 1286 participants because 23 instead of 26 participants from Zylicz 2003 were added to the total number of participants); 627 additional participants: Amirkhanlou 2016 (N = 52); Feily 2012 (N = 60); Ghanei 2012 (N = 22); Mapar 2015 (N = 40); Najafabadi 2012 (N = 40); Nakhaee 2015 (N = 25); Omidian 2013 (N = 50); Pakfetrat 2014 (N = 100); Shirazian 2013 (N = 50); Yue 2015 (N = 188). v. New meta‐analyses as a result of our new findings and general revision: We updated all meta‐analyses: subgroup analyses and sensitivity analyses for the primary and the secondary outcomes. We added three comparisons: cromolyn sodium versus placebo (Feily 2012; Vessal 2010), flumecinol versus placebo (Turner 1994a; Turner 1994b) and zinc sulphate versus placebo (Mapar 2015; Najafabadi 2012) vi. Conclusion The conclusion has been slightly altered without changing the main statement. Previous readers of the review should re‐read this update.
9 June 2016	New search has been performed	This review has been updated. We included results of a new search and updated the 'Risk of bias table, the 'Summary of findings' tables and the meta‐analyses.

Notes

Because this review does not comply with Cochrane’s Conflict of Interest Policy (compare 'declaration of interest'), the review will be updated in 2024 with an author team complying with the policy.

Appendices

Appendix 1. MEDLINE search strategy via Ovid

1. exp Pruritus/

2. (prurit* or itch* or scratch*).ti.

3. ((prurit* or itch* or scratch*) adj10 (prevent* or stop* or alleviat* or relief* or reliev*)).mp.

4. 1 or 2 or 3

5. ((advance* or late or last or end or final) adj4 (stage* or phase*)).mp.

6. (palliat* or terminal* or endstage or end‐stage or hospice* or (end adj3 life) or (care adj3 dying)).mp.

7. ((advance* or progressi* or terminal*) adj6 (ill* or disease* or condition*)).mp.

8. (terminal* adj6 (care or therap* or treat*)).mp.

9. (hospice or (nursing adj3 home*)).mp.

10. exp Palliative Care/ or Palliative Medicine/ or Terminal Care/ or Terminally Ill/ or Hospice Care/ or "Hospice and Palliative Care Nursing"/ or exp Home Care Services/ or exp Hospitals, Special/ or Attitude to Death/ or exp Medicare/ or Patient Care/ or Nursing Homes/ or Homes for the Aged/

11. 5 or 6 or 7 or 8 or 9 or 10

12. 4 and 11

13. randomized controlled trial.pt.

14. controlled clinical trial.pt.

15. randomized.ab.

16. placebo.ab.

17. drug therapy.fs.

18. randomly.ab.

19. trial.ab.

20. groups.ab.

21. 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20

22. exp animals/ not humans.sh.

23. 21 not 22

24. 12 and 23

‐v

Appendix 2. Embase search strategy via Ovid

1. exp Pruritus/

2. pruri$.tw.

3. itch$.tw.

4. scratch.tw.

5. ((pruri$ or itch$ or scratch$) adj5 prevent$).tw.

6. or/1‐5

7. exp Antipruritic Agent/

8. antipruritic$.tw.

9. (Antipruritic Agent or Pruritus or anti‐pruritic$).mp.

10. anti‐pruritic$.tw.

11. exp Drug Therapy/

12. drug therapy combination$.mp.

13. exp Drug Combination/

14. prevention control.mp.

15. (pharmacol$ adj3 (therap$ or treat$ or intervent$)).mp.

16. (pharmaceutic$ adj3 (therap$ or treat$ or intervent$)).mp.

17. (drug$ adj3 prevent$).mp.

18. pharmaceutic aid$.mp.

19. exp "Pharmaceutical Vehicles and Additives"/

20. or/7‐19

21. (endstage or end‐stage).mp.

22. progressive.mp.

23. (terminal$ adj3 ill$).mp.

24. palliative care.mp.

25. exp Palliative Therapy/

26. (palliativ$ adj3 car$).mp.

27. (palliative adj3 therap$).mp.

28. (palliative adj3 treat$).mp.

29. (terminal adj3 care).mp.

30. (terminal adj3 disease).mp.

31. (terminal adj3 treat$).mp.

32. (end adj3 life adj3 care).mp.

33. exp Home Care/

34. hospice care.mp.

35. exp Psychological Aspect/

36. exp Terminal Disease/

37. exp Terminal Care/

38. exp Terminally ill Patient/

39. exp Medicare/

40. exp Hospice/

41. exp Hospice Care/

42. exp Hospice Patient/

43. exp Patient Care/

44. (hospice adj3 care).mp.

45. hospice$.mp.

46. exp hospice nursing/

47. exp hospital patient/

48. exp nursing home/

49. exp nursing home patient/

50. exp home for the aged/

51. ("nursing adj2 home$" or "home for the aged" or "old age home$").mp.

52. or/21‐51

53. 6 and 20 and 52

54. random$.tw.

55. factorial$.tw.

56. crossover$.tw.

57. cross over$.tw.

58. cross‐over$.tw.

59. placebo$.tw.

60. (doubl$ adj blind$).tw.

61. (singl$ adj blind$).tw.

62. assign$.tw.

63. allocat$.tw.

64. volunteer$.tw.

65. Crossover Procedure/

66. double‐blind procedure.tw.

67. Randomized Controlled Trial/

68. Single Blind Procedure/

69. or/54‐68

70. (animal/ or nonhuman/) not human/

71. 69 not 70

72. 53 and 71

Appendix 3. Cochrane Central Register of Controlled Trials (CENTRAL) search strategy via The Cochrane Library

#1 [mh pruritus]

#2 (pruri*):ti,ab,kw

#3 (itch*):ti,ab,kw

#4 (scratch*):ti,ab,kw

#5 (antipruritic*):ti,ab,kw

#6 {or #1‐#5}

#7 (drug therap*):ti,ab,kw

#8 (pharmacologic* therap*):ti,ab,kw

#9 (pharmacologic* treat*):ti,ab,kw

#10 (pharmaceutic* therap*):ti,ab,kw

#11 (pharmaceutic* treat*):ti,ab,kw

#12 {or #7‐#11}

#13 (advanced disease*):ti,ab,kw

#14 (palliative care):ti,ab,kw

#15 (hospice care):ti,ab,kw

#16 (terminal care):ti,ab,kw

#17 (terminal* ill*):ti,ab,kw

#18 {or #13‐#17}

#19 (#6 and #12)

#20 (#18 and #19)

Appendix 4. MEDLINE search strategy via Ovid, August 2012

mp=title, original title, abstract, name of substance word, subject heading word; ti=title; pt=publication type; ab=abstract; fs=floating subheading; sh=MeSH subject heading

1. exp Pruritus/

2. (prurit* or itch* or scratch*).ti.

3. ((prurit* or itch* or scratch*) adj10 (prevent* or stop* or alleviat* or relief* or reliev*)).mp.

4. 1 or 2 or 3

5. ((advance* or late or last or end or final) adj4 (stage* or phase*)).mp.

6. (palliat* or terminal* or endstage or end‐stage or "end stage" or hospice* or (end adj3 life) or (care adj3 dying)).mp.

7. ((advance* or progressi* or terminal*) adj6 (ill* or disease* or condition*)).mp.

8. (terminal* adj6 (care or therap* or treat*)).mp.

9. exp Palliative Care/ or Terminal Care/ or Terminally Ill/ or Hospice Care/ or exp Home Care Services/ or exp Hospitals, Special/ or Attitude to Death/

10. 5 or 6 or 7 or 8 or 9

11. 4 and 10

For identification of randomised controlled trials (humans or human and animals) the subject search above will be combined with the following search strategy

Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity‐maximizing version (2008 revision); Ovid format

1. randomized controlled trial.pt.

2. controlled clinical trial.pt.

3. randomized.ab.

4. placebo.ab.

5. drug therapy.fs.

6. randomly.ab.

7. trial.ab.

8. groups.ab.

9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8

10. exp animals/ not humans.sh.

11. 9 not 10

Appendix 5. Biosis search strategy via Ovid, August 2012

1. (prurit* or itch* or scratch*).m_titl.

2. ((prurit* or itch* or scratch*) adj10 (prevent* or stop* or alleviat* or relief* or reliev*)).mp.

3. 1 or 2

4. ((advance* or late or last or end or final) adj4 (stage* or phase*)).mp.

5. (palliat* or terminal* or endstage or end‐stage or "end stage" or hospice or (end adj3 life) or (care adj3 dying)).mp.

6. ((advance* or progressi* or terminal*) adj6 (ill* or disease* or condition)).mp.

7. (terminal* adj6 (care or therap* or treat*)).mp.

8. 4 or 5 or 6 or 7

9. 3 and 8

10. (animals not (humans and animals)).sh.

11. 9 not 10

Appendix 6. CINAHL search strategy via EBSCOhost, August 2012

1. MH pruritus

2. MJ prurit* or MJ itch* or MJ scratch*

3. prurit* N10 prevent* or prurit* N10 stop* or prurit* N10 alleviat* or prurit* N10 relief* or prurit* N10 reliev*

4. itch* N10 prevent* or itch* N10 stop* or itch* N10 alleviat* or itch* N10 relief* or itch* N10 reliev*

5. scratch* N10 prevent* or scratch* N10 stop* or scratch* N10 alleviat* or scratch* N10 relief* or scratch* N10 reliev*

6. S1 or S2 or S3 or S4 or S5

7. advance* N4 stage* or advance* N4 phase* or late N4 stage* or late N4 phase* or last N4 stage* or last N4 phase* or end N4 stage* or end N4 phase* or final N4 stage* or final N4 phase*

8. palliat* or terminal* or endstage or end‐ stage or "end stage" or hospice* or end N3 life or care N3 dying

9. advance* N6 ill* or advance* N6 disease* or advance* N6 condition* or progressi* N6 ill* or progressi* N6 disease* or progressi* N6 condition* or terminal* N6 ill* or terminal* N6 disease* or terminal* N6 condition*

10. terminal* N6 care* or terminal* N6 therap* or terminal* N6 treat*

11. MH Palliative Care or MH Terminal Care or MH Terminally Ill or MH Hospice Care or MH Home Care Services or MH Hospitals, Special or MH Attitude to Death

12. S7 or S8 or S9 or S10 or S11

13. S6 and S12

14. animals not (humans and animals)

15. S13 not S14

Appendix 7. Embase search strategy via Ovid August 2012

1. exp Pruritus/

2. pruri$.tw.

3. itch$.tw.

4. scratch.tw.

5. ((pruri$ or itch$ or scratch$) adj5 prevent$).mp.

6. or/1‐5

7. exp Antipruritic Agent/

8. antipruritic$.tw.

9. (Antipruritic Agent or Pruritus or anti‐pruritic$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword]

10. anti‐pruritic$.tw.

11. exp Drug Therapy/

12. drug therapy combination$.mp.

13. exp Drug Combination/

14. prevention control.mp.

15. (pharmacol$ adj3 (therap$ or treat$ or intervent$)).mp.

16. (pharmaceutic$ adj3 (therap$ or treat$ or intervent$)).mp.

17. (drug$ adj3 prevent$).mp.

18. pharmaceutic aid$.mp.

19. exp "Pharmaceutical Vehicles and Additives"/

20. or/7‐19

21. (endstage or end‐stage).mp.

22. progressive.mp.

23. (terminal$ adj3 ill$).mp.

24. palliative care.mp.

25. exp Palliative Therapy/

26. (palliativ$ adj3 car$).mp.

27. (palliative adj3 therap$).mp.

28. (palliative adj3 treat$).mp.

29. (terminal adj3 care).mp.

30. (terminal adj3 disease).mp.

31. (terminal adj3 treat$).mp.

32. (end adj3 life adj3 care).mp.

33. exp Home Care/

34. hospice care.mp.

35. exp Psychological Aspect/

36. exp Terminal Disease/

37. exp Terminal Care/

38. exp Terminally ill Patient/

39. exp Medicare/

40. exp Hospice/

41. exp Hospice Care/

42. exp Hospice Patient/

43. exp Patient Care/

44. (hospice adj3 care).mp.

45. hospice$.mp.

46. exp hospice nursing/

47. exp hospital patient/

48. exp nursing home/

49. exp nursing home patient/

50. exp home for the aged/

51. ("nursing adj2 home$" or "home for the aged" or "old age home$").mp.

52. or/21‐51

53. 6 and 20 and 52

Appendix 8. PsycINFO search strategy via EBSCOhost, August 2012

S1 DE "Pruritus"

S2 MJ prurit* or MJ itch* or MJ scratch*

S3 prurit* N10 prevent* or prurit* N10 stop* or prurit* N10 alleviat* or prurit* N10 relief* or prurit* N10 reliev*

S4 itch* N10 prevent* or itch* N10 stop* or itch* N10 alleviat* or itch* N10 relief* or itch* N10 reliev*

S5 scratch* N10 prevent* or scratch* N10 stop* or scratch* N10 alleviat* or scratch* N10 relief* or scratch* N10 reliev*

S6 S1 or S2 or S3 or S4 or S5

S7 advance* N4 stage* or advance* N4 phase* or late N4 stage* or late N4 phase* or last N4 stage* or last N4 phase* or end N4 stage* or end N4 phase* or final N4 stage* or final N4 phase*

S8 palliat* or terminal* or endstage or end‐ stage or "end stage" or hospice* or end N3 life or care N3 dying

S9 advance* N6 ill* or advance* N6 disease* or advance* N6 condition* or progressi* N6 ill* or progressi* N6 disease* or progressi* N6 condition* or terminal* N6 ill* or terminal* N6 disease* or terminal* N6 condition*

S10 terminal* N6 care* or terminal* N6 therap* or terminal* N6 treat*

S11 MH Palliative Care or MH Terminal Care or MH Terminally Ill or MH Hospice Care or MH Home Care Services or MH Hospitals, Special or MH Attitude to Death

S12 Palliative or Palliative care or Palliative treatment or Terminal care or Terminally ill or Hospice or Hospice care or Home care service or Attitude to death

S13 S7 or S8 or S9 or S10 or S11 or S12

S14 S6 and S13

Appendix 9. Search strategy for The Cochrane Library via Wiley, August 2012

#1 MeSH descriptor Pruritus explode all trees
#2 (pruri*):ti,ab,kw
#3 (itch*):ti,ab,kw
#4 (scratch*):ti,ab,kw
#5 (antipruritic*):ti,ab,kw
#6 (antipruritic* NEXT therap*):ti,ab,kw
#7 (#1 OR #2 OR #3 OR #4 OR#5 OR #6)
#8 (drug therap*):ti,ab,kw
#9 (pharmacologic* therap*):ti,ab,kw
#10 (pharmacologic* treat*):ti,ab,kw
#11 (pharmaceutic* therap*):ti,ab,kw
#12 (pharmaceutic* treat*):ti,ab,kw
#13 (#9 OR #10 OR #11OR #12)
#14 (advanced disease*):ti,ab,kw
#15 (advanced NEXT disease*):ti,ab,kw
#16 (palliative care):ti,ab,kw
#17 (palliative NEXT care):ti,ab,kw
#18 (hospice care):ti,ab,kw
#19 (hospice NEXT care):ti,ab,kw
#20 (terminal care):ti,ab,kw
#21 (terminal NEXT care):ti,ab,kw
#22 (terminal* ill*):ti,ab,kw
#23 (#14 OR #22)
#24 (#7 AND #13)
'#25 (#'23 AND #24)

Data and analyses

Comparison 1. GABA‐analogues versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 A) Pruritus on VAS scale (0‐10 cm) in UP participants	5	297	Mean Difference (IV, Random, 95% CI)	‐5.10 [‐5.65, ‐4.55]
1.2 A) Subgroup analysis by study design; pruritus on VAS scale (0‐10 cm) in UP participants	5	297	Mean Difference (IV, Random, 95% CI)	‐5.10 [‐5.65, ‐4.55]
1.2.1 Cross‐over design	2	90	Mean Difference (IV, Random, 95% CI)	‐5.32 [‐6.47, ‐4.17]
1.2.2 Parallel group‐design	3	207	Mean Difference (IV, Random, 95% CI)	‐5.08 [‐5.82, ‐4.33]
1.3 A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐10 cm); UP participants	5	297	Mean Difference (IV, Fixed, 95% CI)	‐5.05 [‐5.52, ‐4.58]

1.2. Analysis.

Comparison 1: GABA‐analogues versus placebo, Outcome 2: A) Subgroup analysis by study design; pruritus on VAS scale (0‐10 cm) in UP participants

Comparison 2. Gabapentin versus pregabalin.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 A) Pruritus on VAS scale (0‐10 cm) in UP participants; parallel group and cross‐over design	2	100	Mean Difference (IV, Random, 95% CI)	‐0.23 [‐1.29, 0.83]
2.2 B) Risk for at least one adverse drug reaction (ADR) per participant in UP participants; parallel‐group and cross‐over design	2	122	Risk Ratio (M‐H, Random, 95% CI)	4.70 [0.21, 104.14]
2.3 B) Sensitivity analyses; risk for at least one adverse drug reaction (ADR) per participant in UP participants; parallel‐group and cross‐over design	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	2.20 [1.43, 3.38]

Comparison 3. Kappa‐opioid agonist versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 A) Pruritus on VAS scale (0‐10 cm) in UP participants; parallel‐group design; Wikström b: Wikström a (week 2) + period 1 Wikström b	6	1292	Mean Difference (IV, Random, 95% CI)	‐0.96 [‐1.22, ‐0.71]
3.2 A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐10 cm); UP participants	6	1292	Mean Difference (IV, Fixed, 95% CI)	‐0.96 [‐1.22, ‐0.71]
3.3 B) Risk for at least one adverse drug reaction (ADR) per participant in UP participants; parallel‐group and cross‐over design	6	1344	Risk Ratio (M‐H, Random, 95% CI)	1.73 [1.20, 2.48]
3.4 B) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant; UP participants; parallel‐group and cross‐over design	6	1344	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [1.28, 1.68]

Comparison 4. Ondansetron versus placebo or standard medication.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 A) Pruritus on VAS scale (0‐10 cm) in UP and CP participants	4	202	Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.71, 0.58]
4.2 A) Subgroup analysis by nature of pruritus and study design; pruritus on VAS scale (0‐10 cm)	4	202	Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.71, 0.58]
4.2.1 UP patients; cross‐over design	3	183	Mean Difference (IV, Random, 95% CI)	0.05 [‐0.95, 1.06]
4.2.2 CP patients; parallel‐group	1	19	Mean Difference (IV, Random, 95% CI)	0.16 [‐2.34, 2.66]
4.3 A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐10 cm) in UP and CP participants	4	202	Mean Difference (IV, Fixed, 95% CI)	‐0.28 [‐0.46, ‐0.09]
4.4 B) Risk for at least one adverse event per participant in UP and CP participants	3	174	Risk Ratio (M‐H, Random, 95% CI)	2.54 [0.38, 16.78]
4.5 B) Subgroup analysis by nature of pruritus and study design; risk for at least one adverse event per participant	3	174	Risk Ratio (M‐H, Random, 95% CI)	2.54 [0.38, 16.78]
4.5.1 UP; cross‐over design	2	155	Risk Ratio (M‐H, Random, 95% CI)	7.50 [0.97, 58.07]
4.5.2 CP; parallel‐group design	1	19	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.34, 2.32]
4.6 B) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant in UP and CP participants	3	174	Risk Ratio (M‐H, Fixed, 95% CI)	2.07 [0.87, 4.93]

Comparison 5. Montelukast versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 A) Pruritus on different scales; SMD in UP participants; parallel‐group design	2	87	Std. Mean Difference (IV, Random, 95% CI)	‐1.40 [‐1.87, ‐0.92]
5.2 A) Sensitivity analysis: fixed‐effects model; Pruritus on different scales; SMD in UP participants; parallel‐group design	2	87	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.40 [‐1.87, ‐0.92]

Comparison 6. Fish‐oil/Omega‐3 fatty acids versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 A) Pruritus on different scales; SMD in UP participants; parallel‐group design and cross‐over design	4	212	Std. Mean Difference (IV, Random, 95% CI)	‐1.60 [‐1.97, ‐1.22]
6.2 A) Sensitivity analysis: fixed‐effects model; pruritus on different scales; SMD in UP participants; parallel‐group design and cross‐over design	4	212	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.62 [‐1.94, ‐1.31]

Comparison 7. Zinc sulphate versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 A) Pruritus on different scales; SMD in UP participants; parallel‐group design	2	76	Std. Mean Difference (IV, Random, 95% CI)	‐0.13 [‐0.58, 0.32]
7.2 A) Sensitivity analysis: fixed‐effects model; Pruritus on different scales; SMD in UP participants; parallel‐group design	2	76	Std. Mean Difference (IV, Fixed, 95% CI)	‐0.13 [‐0.58, 0.32]

Comparison 8. Cromolyn sodium versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 A) Pruritus on VAS scale (0‐10 cm; values from Feily (2012) multiplied by factor 2); UP participants; parallel‐group design	2	100	Mean Difference (IV, Random, 95% CI)	‐3.27 [‐5.91, ‐0.63]
8.2 A) Subgroup analysis by route of administration; values from Feily (2012) multiplied by factor 2); UP participants; parallel‐group design	2	100	Mean Difference (IV, Random, 95% CI)	‐3.27 [‐5.91, ‐0.63]
8.2.1 Oral CS versus placebo	1	40	Mean Difference (IV, Random, 95% CI)	‐4.70 [‐6.57, ‐2.83]
8.2.2 Topical CS versus placebo	1	60	Mean Difference (IV, Random, 95% CI)	‐2.00 [‐3.37, ‐0.63]
8.3 A) Sensitivity analysis: fixed‐effects model; values from Feily (2012) multiplied by factor 2; UP participants; parallel‐group design	2	100	Mean Difference (IV, Fixed, 95% CI)	‐2.94 [‐4.04, ‐1.83]
8.4 B) Risk for at least one adverse event per participant; UP participants; parallel‐group design	2	122	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.02, 106.52]
8.5 B) Subgroup analysis by route of administration; risk for at least one adverse event per participant; UP participants; parallel‐group design	2	122	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.02, 106.52]
8.5.1 Oral CS versus placebo	1	62	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.02, 1.22]
8.5.2 Topical CS versus placebo	1	60	Risk Ratio (M‐H, Random, 95% CI)	13.00 [0.76, 220.96]
8.6 B) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant; UP participants; parallel‐group design	2	122	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.40, 3.08]

Comparison 9. Topical capsaicin versus vehicle.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 A) Pruritus on different scales; SMD in UP participants; cross‐over design (Cho: 1. iPTH =< 35 pg/mL and 2. iPTH > 35 pg/mL)	2	112	Std. Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.55, ‐0.57]
9.2 A) Subgroup analysis by pruritus scales; SMD; UP participants; cross‐over design (Cho: 1. iPTH =< 35 pg/mL and 2. iPTH > 35 pg/mL)	2	112	Std. Mean Difference (IV, Random, 95% CI)	‐1.06 [‐1.55, ‐0.57]
9.2.1 Topical capsaicin versus placebo on 4‐point scale (1‐4)	1	44	Std. Mean Difference (IV, Random, 95% CI)	‐1.22 [‐2.32, ‐0.11]
9.2.2 Topical capsaicin versus placebo on Duo scale (0‐30)	1	68	Std. Mean Difference (IV, Random, 95% CI)	‐1.00 [‐1.43, ‐0.58]
9.3 A) Sensitivity analysis: fixed‐effects model; pruritus on different scales; UP participants; cross‐over design (Cho: 1. iPTH =< 35 pg/mL and 2. iPTH > 35 pg/mL)	2	112	Std. Mean Difference (IV, Fixed, 95% CI)	‐1.02 [‐1.35, ‐0.68]
9.4 B) Risk for at least one adverse event per participant; UP participants, cross‐over design	3	116	Risk Ratio (M‐H, Random, 95% CI)	3.69 [1.17, 11.67]
9.5 B) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant; UP participants; cross‐over design	3	116	Risk Ratio (M‐H, Fixed, 95% CI)	4.64 [2.05, 10.51]

Comparison 10. Naltrexone versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 A) Pruritus on VAS scale (0‐10 cm) in CP participants	2	52	Mean Difference (IV, Random, 95% CI)	‐2.42 [‐3.90, ‐0.94]
10.2 A) Subgroup analysis by study design: pruritus on VAS scale (0‐10 cm) in CP participants	2	52	Mean Difference (IV, Random, 95% CI)	‐2.42 [‐3.90, ‐0.94]
10.2.1 Parallel group‐design	1	16	Mean Difference (IV, Random, 95% CI)	‐3.32 [‐5.01, ‐1.63]
10.2.2 Cross‐over design	1	36	Mean Difference (IV, Random, 95% CI)	‐1.79 [‐2.91, ‐0.67]
10.3 A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐10 cm) in CP participants	2	52	Mean Difference (IV, Fixed, 95% CI)	‐2.26 [‐3.19, ‐1.33]
10.4 B) % difference for pruritus on VAS scale (0‐10 cm) in UP and CP participants	2	48	Mean Difference [%] (IV, Fixed, 95% CI)	‐22.02 [‐34.15, ‐9.90]
10.5 B) Subgroup analysis by nature of pruritus and study design; % difference for pruritus on VAS scale (0‐10 cm)	2	48	Mean Difference [%] (IV, Random, 95% CI)	‐35.66 [‐84.28, 12.96]
10.5.1 CP and parallel‐group design	1	16	Mean Difference [%] (IV, Random, 95% CI)	‐62.00 [‐89.42, ‐34.58]
10.5.2 UP and cross‐over design	1	32	Mean Difference [%] (IV, Random, 95% CI)	‐12.30 [‐25.82, 1.22]
10.6 B) Sensitivity analysis: fixed‐effects model; % difference for pruritus on VAS scale (0‐10) in UP and CP participants	2	48	Mean Difference [%] (IV, Fixed, 95% CI)	‐22.02 [‐34.15, ‐9.90]
10.7 C) Risk for at least one adverse event per participant in UP and CP participants; cross‐over design	3	116	Risk Ratio (M‐H, Random, 95% CI)	3.85 [1.52, 9.76]
10.8 C) Subgroup analysis by nature of pruritus; risk for at least one adverse event per participant; cross‐over design	3	116	Risk Ratio (M‐H, Random, 95% CI)	3.85 [1.52, 9.76]
10.8.1 UP	2	76	Risk Ratio (M‐H, Random, 95% CI)	9.62 [1.90, 48.65]
10.8.2 CP	1	40	Risk Ratio (M‐H, Random, 95% CI)	2.67 [1.32, 5.39]
10.9 C) Sensitivity analysis: fixed‐effects model; risk for at least one adverse event per participant; UP and CP patients; cross‐over design	3	116	Risk Ratio (M‐H, Fixed, 95% CI)	4.07 [2.07, 8.00]

Comparison 11. Rifampicin versus placebo or standard medication.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 A) Pruritus on VAS scale (0‐100 mm) in CP participants; cross‐over design	2	42	Mean Difference (IV, Random, 95% CI)	‐42.00 [‐87.31, 3.31]
11.2 A) Sensitivity analysis: fixed‐effects model; pruritus on VAS scale (0‐100 mm) in CP participants; cross‐over design	2	42	Mean Difference (IV, Fixed, 95% CI)	‐24.64 [‐31.08, ‐18.21]
11.3 B) Subgroup analysis by control; SMD: pruritus on different scales; CP participants; cross‐over design	3	81	Std. Mean Difference (IV, Random, 95% CI)	‐1.84 [‐2.82, ‐0.87]
11.3.1 Rifampin/rifampicin versus phenobarbitone on 4‐point scale (0‐3)	1	39	Std. Mean Difference (IV, Random, 95% CI)	‐1.43 [‐2.39, ‐0.47]
11.3.2 Rifampin/rifampicin versus placebo on VAS scale (0‐100) (Podesta: only first period))	2	42	Std. Mean Difference (IV, Random, 95% CI)	‐2.25 [‐3.99, ‐0.52]
11.4 B) Sensitivity analysis: fixed‐effects model; subgroup analysis by control; SMD: pruritus on different scales; CP patients; cross‐over design	3	81	Std. Mean Difference (IV, Random, 95% CI)	‐1.84 [‐2.82, ‐0.87]
11.4.1 Rifampin/rifampicin versus phenobarbitone on 4‐point scale (0‐3)	1	39	Std. Mean Difference (IV, Random, 95% CI)	‐1.43 [‐2.39, ‐0.47]
11.4.2 Rifampin/rifampicin versus placebo on VAS scale (0‐100) (Podesta: only first period))	2	42	Std. Mean Difference (IV, Random, 95% CI)	‐2.25 [‐3.99, ‐0.52]

Comparison 12. Flumecinol versus placebo.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 A) Pruritus: significant improvement (yes/no); CP participants; parallel‐group design	2	69	Risk Ratio (M‐H, Random, 95% CI)	2.32 [0.54, 10.10]
12.2 A) Sensitivity analysis: fixed‐effects model; pruritus: significant improvement (yes/no); CP participants; parallel‐group design	2	69	Risk Ratio (M‐H, Fixed, 95% CI)	1.89 [1.05, 3.39]
12.3 A) Subgroup analysis by dosage; pruritus: significant improvement (yes/no); CP participants; parallel‐group design	2	69	Risk Ratio (M‐H, Random, 95% CI)	2.32 [0.54, 10.10]
12.3.1 Oral flumecinol 600 mg weekly for three weeks	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.77, 2.59]
12.3.2 Oral flumecinol 300 mg daily for three weeks	1	19	Risk Ratio (M‐H, Random, 95% CI)	6.30 [0.95, 41.78]

Characteristics of studies

Characteristics of included studies [author‐defined order]

Borgeat 1993.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 12 Number of participants evaluable: 10 Withdrawals/dropouts: 2 Reason for exclusion: history of skin disease associated with pruritus Age (years): 21‐79 Sex (male/female): 4/6 Underlying disease(s): pancreatic neoplasia (n = 3), cholangitis (n = 2), PBC (n = 2), hepatic metastasis (n = 2), bile duct neoplasia (n = 1) Participant pool: no information Setting: no information Haemodialysis: NA Baseline pruritus assessment: no information Duration/severity of pruritus: no information Baseline parameters: no information
Interventions	Intervention 1: propofol (1.5 mL/d, when pruritus was > 6/10 on the verbal rating score) Intervention 2: placebo (1.5 mL/d intralipid) Additional medication: no information Route of administration: intravenously Duration of treatment: 2 days (2 days propofol/placebo ‐ 2 days cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: verbal rating score (0 to 10 cm) Adverse events
Notes	Presentation of study results is inappropriate. Study period is very short, and the sample size is very small (N = 10). No declared source of funding COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "Medication was blinded and randomised by our pharmacy, which delivered a set of four coded vials per patient of either propofol or Intralipid".
Allocation concealment (selection bias)	Unclear risk	QUOTE: "[Pharmacy] delivered a set of four coded vials per patient".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Medication was blinded and randomised by our pharmacy". Double‐blind; unclear who was blinded
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	High risk	No information on dropouts; no information on response to placebo
Selective reporting (reporting bias)	Unclear risk	Inclusion and exclusion criteria inadequately described; no data for hallucinations, mood changes, haemodynamic values
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 12
Other bias	Unclear risk	Poor additional information; small number of participants; very short study period; only two doses of propofol/placebo for each participant; assessment of compliance not stated

Van Leusen 1978.

Study characteristics
Methods	Study design: cross‐over RCT Time frame: not reported Duration of study/follow‐up: 4 weeks (unknown washout period)
Participants	Setting: single‐centre (inpatients) Country: Netherlands Inclusion criteria: ESRD on HD Number: 5 Mean age ± SD (years): not reported Sex: not reported Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Treatment group Cholestyramine (oral): 5 mg twice/day for 4 weeks Control group Placebo (oral methylcellulose): twice/day for 4 weeks
Outcomes	Pruritus: 4‐point itch severity scale before and after both interventions for each individual patient recorded
Notes	No funding source declared COI: no author COI statements provided Correspondence: Municipal Hospital, Arnhem Netherlands
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "randomly assigned"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts
Selective reporting (reporting bias)	Low risk	Results clearly reported
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 10
Other bias	Unclear risk	Washout period unclear; no evidence of publication or funding bias

Aquino 2020.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: uremic Number of participants randomised: 30 Topical gabapentin: 15 Placebo: 15 Withdrawals/dropouts: 2 Topical gabapentin: 1 Placebo: 1 Age (mean ± SD): Intervention group: 46.1 ± 13.4 Placebo group: 41.2 ± 11.6 Sex (male/female): Intervention group: 12/3 Placebo group: 14/1 Underlying desease(s): ESRD Setting: HD Unit Haemodialysis: not specified
Interventions	Intervention 1: topical 6% gabapentin permeation cream Intervention 2 (placebo): plain permeation cream Route of administration: topical Duration of treatment: 2 weeks/daily Follow‐up: none
Outcomes	Pruritus assessment: VAS (change pruritis scores from baseline to 1 and 2 weeks) Additional outcomes: Acute adverse events 5‐D itch scale (change pruritus scores from baseline to 2 weeks)
Notes	Funding: authors declared no source of funding. COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Patients were allocated to either the exp group or the control group via block randomization."
Allocation concealment (selection bias)	Low risk	QUOTE: "Each topical formulation was packed in a white jar (labelled A or B) ...identical, odorless white cream. The label designation was kept from the assessors and the subjects until the end of study."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "The authors conducted a randomized, double‐blind vehicle‐controlled study."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Each topical formulation was packed in a white jar (labelled A or B) ...identical, odorless white cream. The label designation was kept from the assessors and the subjects until the end of study."
Incomplete outcome data (attrition bias) All outcomes	Low risk	QUOTE: "2 patients were lost to follow‐up, one from each group. All 30 were included in ITT. Missing data were handled using the last‐observer‐carried‐forward (LOCF) method."
Selective reporting (reporting bias)	Unclear risk	No protocol cited
Size of study (possible biases confounded by small size)	High risk	< 50 participants
Other bias	Low risk	The study appeared to be free of other sources of bias.

Ashmore 2000.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants on haemodialysis with ESRD and pruritus Number of participants randomised: 19 Number of participants evaluable: 16 Withdrawals/dropouts: 3 Reason for dropout: non‐compliance Age (years): range 28‐77 (mean 60) for the participants completing the study Sex (male/female): 11/8; participants completing the study: 10/6 Underlying disease(s): chronic renal failure of unknown cause (n = 3), hypertensive nephrosclerosis (n = 3), immunoglobulin A nephropathy (n = 2), nephrotic syndrome (n = 2), connective tissue disease (n = 1), diabetic nephropathy (n = 1), Henoch‐Schönlein purpura (n = 1), obstructive uropathy (n = 1), systemic lupus erythaematosus (n = 1), adult polycystic kidney disease (n = 1) Participant pool: single‐centre Setting: inpatient Haemodialysis: median of 20 months (1 to 53 months) Duration/severity of pruritus: no information Baseline parameters: Symptom score (measured by antihistamine escape medication): Before ondansetron treatment: 21% (IQR 8.5 to 61) Before placebo treatment: 52.5% (IQR 0 to 88.3) Pruritus score (measured by VAS 10 cm): Before ondansetron treatment: 5.3 (IQR 3.4 to 6.3) Before placebo treatment: 3.7 (IQR 3.0 to 4.6)
Interventions	Intervention 1: ondansetron (8 mg 3x/d) Intervention 2: placebo Additional medication: antihistamines as escape medication chlorpheniramine (n = 9), terfenadine (n = 4), hydroxyzine (n = 3), iron supplements (n = 16), erythropoietin (n = 15), crotamiton cream (n = 9), H2‐receptor antagonist (n = 5) Route of administration: oral Duration of treatment: 2 weeks: washout 1 (day 1‐7) ‐ ondansetron/placebo (8‐21) ‐ washout 2 (22‐28) ‐ cross‐over (29‐42) Follow‐up: no information
Outcomes	Symptom relief (measured by antihistamine escape medication) Pruritus relief (measured by VAS 10‐cm) Additional outcomes: serum calcium, phosphate, magnesium, urea, creatinine levels, bilirubin, alanine transaminase, alkaline phosphatase, haemoglobin, ferritin, parathyroid hormone
Notes	Funding: supported in part by a grant from Glaxo Group Research and in part by the Yorkshire Kidney Research Fund COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "We randomly assigned 16 haemodialysis patients. . ." Participants were randomised to receive active drug or placebo. . ." Method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Participants were randomised. . . in a double‐blind cross‐over study."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data, (3 participants withdrawn due to protocol violation), then PP analysis; no intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 19
Other bias	Unclear risk	Partly sponsored by Glaxo Smith Kline

Bachs 1989.

Study characteristics
Methods	RCT Comparative trial Cross‐over design
Participants	Pruritus: CP Description: participants with clinical, biochemical, immunological, and histological features of primary biliary cirrhosis (PBC) and pruritus Number of participants randomised: 22 Number of participants evaluable: 17 Rifampicin: 21 Phenobarbitone: 18 Withdrawals/dropouts: Rifampicin: 1 Phenobarbitone: 4 Reason for dropouts: Rifampicin: development of anaemia and renal failure Phenobarbitone: rash (n = 3), 1 participant refused the drug Age (mean ± SD): 49.7 years ± 8.4 Sex (male/female): 0/22 Underlying disease(s): PBC Participant pool: no information Setting: outpatient Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: no information Baseline parameters: Pruritus score (measured by a 4‐point scale; 0 = no itching, 3 = continuous pruritus): Rifampicin: 2.4 (SD 0.6) Phenobarbitone: 1.8 (SD 1.2)
Interventions	Intervention 1: rifampicin (10 mg/kg) Intervention 2: phenobarbitone (3 mg/kg) Additional medication: stopped 1 month prior the study Route of administration: oral Duration of treatment: 2 weeks (2 weeks rifampicin/phenobarbitone ‐ 30 days washout ‐ 2 weeks cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: 4‐point scale Adverse events Additional outcomes: fasting serum concentrations of bile acids, alkaline phosphatase, and gamma‐glutamyl‐transpeptidase decreased with rifampicin but not with phenobarbitone
Notes	Funding: grant support from Cancer Research Campaign, Medical Research Council, and United Birmingham Hospitals Endowment COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "The order of treatment was randomised."
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	High risk	No information provided, probably no blinding
Blinding of outcome assessment (detection bias) All outcomes	High risk	No information provided, probably no blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data; unclear if intention‐to‐treat analysis was used
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting although no results on cholesterol given
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 22
Other bias	Low risk	No indication

Bergasa 2006.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 16 Number of participants evaluable: 13 Gabapentin: 7 Placebo: 6 Number of participants enrolled: 15 (1 withdrawal prior to randomisation) Gabapentin: 8 Placebo: 7 Withdrawals/dropouts: 3 Gabapentin: 1 Placebo: 1 Prior to randomisation: 1 Reason for dropout: Gabapentin: vomiting Placebo: persistent severe pruritus within 2 weeks Prior to randomisation: participant did not want to be hospitalised Age (years): median: 49 (range 44 to 63) Sex (male/female): 0/16 Underlying disease(s): PBC (n = 9), chronic liver disease secondary to infection with hepatitis C (n = 6), PSC (n = 1) Participant pool: single‐centre Setting: inpatient Haemodialysis: NA Duration/severity of pruritus:1‐12 years, except one participant for whom it was 4 months; antipruritic drugs had not provided satisfactory relief Baseline parameters: no information
Interventions	Intervention 1: gabapentin (starting dose of 300 mg/d (100 mg, 3x/d), increased if necessary and in the absence of side effects by 300 mg (100 mg, 3x/d) every 3 days to a maximum of 2400 mg/d or until pruritus relief) Intervention 2: placebo Additional medication: Antipruritic drugs were discontinued 5 days before collecting baseline data. Participants who took antihistamines to sleep were kept on those doses. Route of administration: oral Duration of treatment: 4 weeks Follow‐up: no information
Outcomes	Pruritus assessment: VAS Hourly scratching activity (HSA) Interviews Adverse events Additional outcomes: At baseline: complete blood count, coagulation, comprehensive metabolic panels Dermatological evaluation: None of the participants had a dermatological disease associated with pruritus. Psychiatric evaluation: Hamilton depression rating scale and Structured Clinical Interview Questionnaire; the results of the psychiatric evaluations suggested that liver disease and pruritus might have contributed to the depressive symptomatology of the subject.
Notes	Gabapentin was discontinued in 5 participants during the study and 2 more after completing the study; 2 participants took gabapentin after completing treatment with placebo; 1 dropped because of side effects. Funding: supported by 1RO3DK 55618‐01A1 and GCRC grant RR00645 COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE:"[R]andomised to receive the placebo or the active drug according to a randomisation code generated and kept at the research pharmacy."
Allocation concealment (selection bias)	Low risk	QUOTE: "[A]ccording to a randomisation code generated and kept at the research pharmacy."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "The study was a double‐blind. . ."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	Gabapentin was discontinued in 5 participants; unclear if used intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 16
Other bias	Unclear risk	Washout period only 5 days; co‐medication with antihistamines

Breneman 1992a.

Study characteristics
Methods	RCT Placebo‐controlled Probably parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 7 Number of participants evaluable: 5 (4 completed the entire 6‐week trial; 1 additional withdrawal after 5 weeks of treatment) Withdrawals/dropouts: 2 + 1 Reason for dropout: worsening medical status (1 + 1), insufficient improvement (1) Age (years): 20‐78 Sex (male/female): 3/4 Underlying disease(s): no information Participant pool: no information Setting: inpatient Haemodialysis: at least 1 month Baseline pruritus assessment: yes Duration/severity of pruritus: no information on duration; moderate‐to‐severe Baseline parameters: Pruritus score (measured by 4‐point score; 1 = no itching, 4 = severe itching interfering with daily activities and/or sleep): At least 3 or 4
Interventions	Intervention 1: capsaicin (0.025% 4x/d) Intervention 2: vehicle (4x/d) Additional medication: no information Route of administration: topical (cream) Duration of treatment: 6 weeks Follow‐up: no information
Outcomes	Pruritus assessment: 4‐point score Adverse events
Notes	Study design was inappropriate. Participants were instructed to apply one cream solely on one arm and the other cream only on the other arm; the risk that participants may have mixed up the creams was very high. Sample size was very small. No declared source of funding COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "Therapies were assigned on a random basis". Method of randomisation not stated
Allocation concealment (selection bias)	Unclear risk	Not information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: ". . . in a double‐blinded fashion."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	2/7 participants not evaluated (1: insufficient improvement), 4/7 participants completed full trial, no intention‐to‐treat analysis
Selective reporting (reporting bias)	High risk	Unclear study design; missing participant characteristics
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 7
Other bias	High risk	Very small number of participants included; only 4 of 7 participants completed the trial. Participants were instructed to apply one cream solely on one arm and the cream from the other tube specifically on the other arm; the risk that participants may have mixed up the creams was very high. Assessment of compliance not stated

Cho 1997.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 22 Two subgroups: low‐intact PTH (parathyroid hormone) < 35 pg/mL (n = 10) and high‐intact PTH > 35 pg/mL (n = 12)   Group A (capsaicin ‐ placebo): 12 Group B (placebo ‐ capsaicin): 10 Number of participants evaluable: 22 Withdrawals/dropouts: 0 Reason for dropout: NA Age (mean ± SD): 62 years ± 4 Sex (male/female): 14/8 Underlying disease(s):chronic glomerulonephritis (n = 8), chronic intestinal nephritis (n = 6), ESRD (n = 3), chronic pyelonephritis (n = 2), nephrosclerosis (n = 2), lupus nephritis (n = 1) Participant pool: no information Setting: inpatient Haemodialysis: average duration of 63 ± 14 months; 3 x 4−4.5 h/week Baseline pruritus assessment: yes Duration/severity: no information Baseline parameters: Pruritus score (measured by 4‐point score; 1 if no itching, 2, 3, or 4 if mild, moderate, or severe, respectively): Capsaicin (iPTH < 35 pg/mL): 3.7 (SE 0.2) Placebo (iPTH < 35 pg/mL): 3.0 (SE 0.3) Capsaicin (iPTH > 35 pg/mL): 3.5 (SE 0.2) Placebo (iPTH > 35 pg/mL): 2.8 (SE 0.2)
Interventions	Intervention 1: capsaicin (0.025%, 4 x /d) Intervention 2: vehicle Additional medication: ongoing medications were continued without alterations in dosage; topical agents were discontinued at least 2 weeks prior to the study. Route of administration: topical (cream) Duration of treatment: 4 weeks (4 weeks capsaicin/vehicle ‐ 2 weeks washout ‐ 4 weeks cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: 4‐point score Adverse events Additional outcomes: Intensity of cutaneous burning and/or stinging sensations, dryness of skin, and erythaema Serum calcium, phosphate, and intact PTH levels
Notes	No raw data given. Carry‐over effect because there was no washout period between verum and vehicle phases. No between‐group comparisons were reported separately for the two phases of the cross‐over study. No declared source of funding COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Treatment order was arranged from the computer‐generated random numbers. . ."
Allocation concealment (selection bias)	Low risk	QUOTE: "Treatment order was arranged from the computer‐generated random numbers by one of the co‐authors who did not participate in the observation."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Treatments with either capsaicin 0.025% cream or vehicle base creams [QUOTE:] "were unknown by the observers and patients".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Treatments with either capsaicin 0.025% cream or placebo base cream were unknown by the observers and patients."
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data, all 22 participants evaluated; unclear if used intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	No raw data or between‐group comparisons reported for the two phases of the cross‐over‐study
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 22
Other bias	Unclear risk	Indication for carry‐over effect; self‐assessment of pruritus by participants

De Marchi 1992.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 20 Group 1 (pruritus, erythropoietin ‐ placebo): 5 Group 2 (pruritus, placebo ‐ erythropoietin): 5 Group 3 (no pruritus, erythropoietin ‐ placebo): 5 Group 4 (no pruritus, placebo ‐ erythropoietin): 5 Number of participants evaluable: 9 (from 10 patients because group 3 and 4 had no pruritus) Withdrawals/dropouts: 1 participant before cross‐over Reason for dropout: participant did not respond to erythropoietin Age (mean ± SD) : Group 1/2: 55 years ± 10 Group 3/4: 54 years ± 9 Sex (male/female): Group 1/2: 7/3 Group 3/4: 6/4 Underlying disease(s): no information Participant pool: no information Setting: inpatient Haemodialysis: 3 times weekly Baseline pruritus assessment: yes Duration/severity of pruritus: Group 1/2: generalised for at least 1 year; severe enough to disturb sleep and interfere with daytime activities; unresponsive to commonly used antipruritic drugs Group 3/4: participants with uraemia but without pruritus Baseline parameters: Biochemical parameters (measured by blood samples): Group 1 (pruritus, erythropoietin ‐ placebo): Erythropoietin: histamine 20.8 (SE 4), haemoglobin 3.86 (SE 0.18), hematocrit 0.18 (SE 0.01) Placebo: histamine 4.2 (SE 0.4), haemoglobin 4.48 (SE 0.12), hematocrit 0.21 (SE 0.01) Group 2 (pruritus, placebo ‐ erythropoietin): Erythropoietin: histamine 19.5 (SE 4.1), haemoglobin 3.98 (SE 0.18), hematocrit 0.19 (SE 0.01) Placebo: histamine 20.5 (SE 3.8), haemoglobin 3.98 (SE 0.12), hematocrit 0.19 (SE 0.01) Group 3 (no pruritus, erythropoietin ‐ placebo): Erythropoietin: histamine 4.1 (SE 0.9), haemoglobin 3.92 (SE 0.18), hematocrit 0.19 (SE 0.1) Placebo: histamine 2.6 (SE 0.4), haemoglobin 4.45 (SE 0.12), hematocrit 0.21 (SE 0.01) Group 4 (no pruritus, placebo ‐ erythropoietin): Placebo: histamine 4.3 (SE 0.7), haemoglobin 3.86 (SE 0.12), hematocrit 0.18 (SE 0.01) Erythropoietin: histamine 4.5 (SE 0.8), haemoglobin 3.92 (SE 0.18), hematocrit 0.18 (SE 0.01) Pruritus score(measured by scoring system proposed by Duo, modified by Mettang, maximum score for a 24‐h period: 40 (14 of 40 attributed to the night‐time period)): Group 1 (pruritus, erythropoietin ‐ placebo): Erythropoietin: 25.3 (SE 3) Placebo: 11 (SE 6) Group 2 (pruritus, placebo ‐ erythropoietin): Placebo: 27 (SE 4) Erythropoietin: 27 (SE 4)
Interventions	Intervention 1: erythropoietin (36 units/kg body weight 3 times a week) Intervention 2: placebo Additional medication: no information Route of administration: intravenous Duration of treatment: 5 weeks (2 weeks baseline ‐ 5 weeks erythropoietin/placebo ‐ 5 weeks cross‐over) Follow‐up: baseline, weekly blood samples before and at the end of each 5‐week study
Outcomes	Pruritus assessment: Scoring system proposed by Duo and modified by Mettang (0 to 40) Biochemical parameters (measured by blood samples): histamine, haemoglobin, hematocrit Additional outcomes: plasma histamine levels
Notes	Route of administration not clearly stated No declared source of funding COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"The patients were randomly assigned".
Allocation concealment (selection bias)	Low risk	Code broken only after completion
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind including outcome assessor: QUOTE: "a single investigator who was unaware of the treatment assignments evaluated all patients". Participants and personnel were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessor was blinded.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	One withdrawal; unclear if used intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 20
Other bias	Low risk	No conflicts of interest declared

Duncan 1984.

Study characteristics
Methods	RCT Comparative trial Cross‐over design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 8 Number of participants evaluable: 8 Withdrawals/dropouts: 1 dropout in placebo group Reason for dropouts: nausea and cutaneous burning Age: no information Sex (male/female): no information Underlying disease(s): primary biliary cirrhosis (7), sclerosing cholangitis (1) Participant pool: single‐centre Setting: outpatient Haemodialysis: NA Baseline pruritus assessment: no information Duration/severity of pruritus: no information Baseline parameters: no information
Interventions	Intervention 1: cholestyramine (4 g at night on day 1 and increased if tolerated to 2 x /d on day 3; not further increased) Intervention 2: terfenadine (60 mg at night on day 1 and increased if tolerated to 2 x /d on day 3; increased to 3 x /d on day 5) Intervention 3: chlorpheniramine (4 mg at night on day 1 and increased if tolerated to 2 x /d on day 3; increased to 3 x/d on day 5) Intervention 4: placebo (lactose, 200 mg at night on day 1, increased if tolerated to 2 x /d on day 3; increased to 3 x /d on day 5) Additional medication: all antipruritic drugs were stopped at least 1 week prior to the study. Route of administration: oral Duration of treatment: 2 weeks each (cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: 4‐point score Adverse events Additional outcomes: psychometric testing
Notes	Presentation of the results was inappropriate. Some participants stopped taking one of the trial medications, but there were no data on whether they were excluded from the analysis. No declared source of funding COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "The order of administration of the drugs was randomised, different for each patient, and concealed from the assessor".
Allocation concealment (selection bias)	Unclear risk	QUOTE: "Treatment was supplied in unlabelled bottles by the hospital pharmacy."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Single‐blind; unclear who was blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "The order of administration of the drugs was randomised, different for each patient, and concealed from the assessor".
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not clear if all participants analysed; unclear if used intention‐to‐treat analysis; missing participant data like sex and age
Selective reporting (reporting bias)	High risk	No protocol published
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 8
Other bias	Unclear risk	No washout period in between the treatments; no conflicts of interest declared

Duque 2005.

Study characteristics
Methods	RCT Vehicle‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 22 Tacrolimus: 12 Vehicle: 10 Number of participants evaluable: 20 Withdrawals/dropouts: vehicle (n = 2) Reason for dropout: 1 received a kidney transplant; 1 dropped out after two weeks because of lack of improvement Age (mean ± SD): 59 years ± 13.2 Sex (male/female): no information Underlying disease(s): no information Participant pool: multicentre (2 dialysis centres) Setting: outpatient Haemodialysis: at least 3 months Baseline pruritus assessment: yes Duration/severity of pruritus: no information on duration; frequent and severe itch that was resistant to conventional therapies; initial VAS between 3 and 10 Baseline parameters: Pruritus score (measured by VAS 10‐cm): Tacrolimus: 7.7 Vehicle: 7.5
Interventions	Intervention 1: tacrolimus 0.1% (3 x /week by investigator only on pruritic areas; twice daily by participant; average of four 30 g tubes per participant) Intervention 2: vehicle Additional medication: stopped 2‐4 weeks prior to the study Route of administration: topical Duration of treatment: 4 weeks (4 weeks tacrolimus/placebo ‐ 4 weeks cross‐over) Follow‐up: baseline‐ 4 weeks: 3 x /week ‐ 2 weeks after treatment completion
Outcomes	Pruritus assessment: VAS 10‐cm Skin conditions: measured by 3‐point Lickert scale (0 = no skin signs, 3 = severe excoriations, scaliness, lichenification)
Notes	Supported by: Fujisawa Health Care Inc, Deerfield, Ill COI: Dr Fleischer is on the Speaker’s Bureau of Fujisawa, and Drs Yosipovitch and Fleischer have other research projects that are funded by Fujisawa
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was randomised; method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	2 dropouts in the placebo group; unclear if used intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	Prespecified outcomes not mentioned
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 22
Other bias	Low risk	Conflicts of interest mentioned but negative study

Forouhari 2022.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 40 Omega‐3: 20 Placebo: 20 Withdrawals/dropouts: Placebo: 4; Omega‐3: 3 Age (mean ± SD): omega‐3: 59.00 ± 13.56, placebo: 51.25 ± 15.85 Male sex (%) : omega‐3: 70.6, placebo: 68.8 Underlying disease(s): ESRD Setting: HD unit, outpatient Haemodialysis: not specified
Interventions	Intervention 1: 1 g omega‐3 capsule every eight hours (1 g omega ‐ contained 180 mg of Eicosapentaenoic Acid (EPA) and 120 mg of Docosahexaenoic Acid (DHA) Intervention 2: capsule placebo (liquid parafine) every 8 hours Route of administration: oral Duration of treatment: 4 weeks (4 weeks omega‐3/placebo ‐ 6 weeks washout ‐ 4 weeks cross‐over) Follow‐up: none
Outcomes	Pruritus assessment: VAS Additional outcomes: none
Notes	No delcared source of funding COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation sequence not mentioned
Allocation concealment (selection bias)	Unclear risk	Allocation concealement not mentioned
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Both patients and investigators were blinded to the research."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	The study did not address this outcome.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Reasons for dropping out were not given specifically for each group.
Selective reporting (reporting bias)	Unclear risk	QUOTE from protocol: "Registration timing: retrospective"
Size of study (possible biases confounded by small size)	High risk	< 50 participants
Other bias	High risk	Carry‐over effect

Ghent 1988.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: CP Description: participants with PBC Number of participants randomised: 9 Group A (rifampicin ‐ placebo): 4 Group B (placebo ‐ rifampicin): 5 Number of participants evaluable: 9 Withdrawals/dropouts: 0 Reason for dropout: NA Age (years): 45‐64 Sex (male/female): 1/8 Underlying disease(s): primary biliary cirrhosis Participant pool: single‐centre Setting: outpatient Haemodialysis: NA Baseline pruritus assessment: 1 week baseline record of the pruritus VAS was obtained for 5 subjects prior to the study Duration/severity of pruritus: persistent pruritus Baseline parameters: no information
Interventions	Intervention 1: rifampicin (150 mg 2 x /d for serum bilirubin level > 51 µmol/L (3 mg/dL); 150 mg 3 x /d for serum bilirubin level < 51 µmol/L) Intervention 2: placebo Additional medication: cholestyramine (n = 5) Route of administration: oral Duration of treatment: 2 weeks (2 weeks washout ‐ 2 weeks cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: VAS (0‐100 mm) Adverse events: none observed Additional outcomes: urine analysis, blood count, serum bilirubin, creatinine, alanine transaminases, aspartate transaminases, alkaline phosphatases, fasting total serum bile acids
Notes	Presentation of study results was inappropriate. Funding: supported by the University Hospital Pool Research Fund COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "The order of treatment was random. . .". Method of randomisation not stated
Allocation concealment (selection bias)	Low risk	QUOTE: "The coding of the medication order was done by an independent research pharmacist."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: ". . . in a double‐blind manner."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All completed and analysed; unclear if used intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 9
Other bias	Unclear risk	Small number of participants

Gunal 2004.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 25 Number of participants evaluable: 25 Withdrawals/dropouts: 0 Reason for dropout: NA Age (mean ± SD): 55 ± 11, range 32‐77 years, Sex (male/female): 14/11 Underlying disease(s): ESRD, diabetes (n = 8) Participant pool: single‐centre Setting: inpatient Haemodialysis: duration of 42 ± 33 months Baseline pruritus assessment: yes Duration/severity of pruritus: duration > 8 weeks; not relieved by antihistamines, nicergoline, moisturisers Baseline parameters: Pruritus score (measured by VAS 10‐cm): 8.4 (SD 0.94)
Interventions	Intervention 1: gabapentin (300 mg 3 x /week at the end of haemodialysis sessions) Intervention 2: placebo Additional medication: any medication with presumed antipruritic effects was discontinued 1 week before the study. Route of administration: oral Duration of treatment: 4 weeks (4 weeks gabapentin/placebo ‐ 1 week washout ‐ 4 weeks cross‐over) Follow‐up: daily record of pruritus severity (VAS)
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Additional outcomes: hematocrit, serum calcium, phosphate, albumin, parathyroid hormone levels
Notes	No funding source declared COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was randomised; method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data, all completed and analysed; unclear if intention‐to‐treat analysis was used
Selective reporting (reporting bias)	Unclear risk	No exclusion criteria mentioned; only means of participant groups given; poor raw data given Pruritus was scored only once a day and the scores were only subjective indications of the severity of itching; number and details of adverse events were not given.
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 25
Other bias	Low risk	No conflict of interests declared

Kuiper 2010.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 38   Number of participants evaluable: 35 Colesevelam: 17 Placebo: 18 Withdrawals/dropouts: 3 Reasons for dropout: 1 participant withdrew after randomisation but before treatment; 1 participant stopped the intake of naltrexone during the trial; 1 participant was unable to fill out the questionnaires Age (mean ± SD): Colesevelam: 50 years ± 13 Placebo: 54 years ± 13 Sex (male/female): Colesevelam: 8/9 Placebo: 5/13 Underlying disease(s): Colesevelam: PSC (n = 10), PBC (n = 4), other (n = 3) Placebo: PBC (n = 10), PSC (n = 4), other (n = 4) Participant pool: multicentre Setting: outpatient Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: symptoms present for a median period of 24 months; pruritus most severe in the evening and/or at night; scratch lesions present in 55% of cases Baseline parameters: no information
Interventions	Intervention 1: colesevelam (3 x 625 mg tablets, 2 x /d) Intervention 2: placebo (2 x /d) Additional medication: treatment with ursodeoxycholic acid was continued and participants were allowed to continue rifampicin and naltrexone at a stable dose; other antipruritic drugs were stopped 3 days prior to the study. Route of administration: oral Duration of treatment: 21 days Follow‐up: no information
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Quality of life
Notes	Funding: support by Genzyme BV (Naarden, the Netherlands). Genzyme was not involved in the statistical analysis or writing of this article. COI: Henk R. Van Buuren and Edith M. M. Kuiper received research grant support from Genzyme BV (Naarden, the Netherlands). Genzyme was not involved in the statistical analysis or writing of this article.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Participants were assigned to one of the two arms according to a standard randomization schedule (1:1) in blocks of four and were stratified by trial center."
Allocation concealment (selection bias)	Low risk	QUOTE: "Randomization was centralized with opaque serial‐numbered envelopes prepared by the trial statistician."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Both participants and investigators were blinded."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Both participants and investigators were blinded."
Incomplete outcome data (attrition bias) All outcomes	Low risk	QUOTE: "We included and randomized 38 patients, 35 of whom were analyzed because one patient withdrew from participation after randomization and before the start of treatment, one patient stopped the intake of naltrexone during the trial period, and one patient was unable to fill out the questionnaires." Per‐protocol analysis with 35 participants Modified intention‐to‐treat analysis with 36 participants (38 were included and randomised)
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 38
Other bias	Low risk	Broad information about participant characteristics; presentation of data partially unclear; assessment of compliance not stated

Kumagai 2010.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 337 Nalfurafine hydrochloride (5 µg): 114 Nalfurafine hydrochloride (2.5 µg): 112 Placebo: 111 Number of participants evaluable: 329 Nalfurafine hydrochloride (5 µg): 111 Nalfurafine hydrochloride (2.5 µg): 109 Placebo: 109 Withdrawals/dropouts: Nalfurafine hydrochloride (5 µg): 3 Nalfurafine hydrochloride (2.5 µg): 3 Placebo: 0 Reason for dropout: Nalfurafine hydrochloride (5 µg): 2 participants because of insomnia Nalfurafine hydrochloride (2.5 µg): 2 participants because of insomnia Number lost to follow‐up: Placebo: 2 Age (mean ± SD): Nalfurafine hydrochloride (5 µg): 59.6 ± 11.5 Nalfurafine hydrochloride (2.5 µg): 61 ± 11.4 Placebo: 59.6 ± 11.8 Sex (male/female): Nalfurafine hydrochloride (5 µg): 93/21 Nalfurafine hydrochloride (2.5 µg): 85/27 Placebo: 89/22 Underlying disease(s): ESRD Participant pool: multicentre (73 centres) Setting: inpatient Haemodialysis: 3 x /week Baseline pruritus assessment: yes Duration/severity of pruritus: no information on duration; pruritus resistant to currently available treatments (mean morning or evening VAS > 50 mm, daytime or night‐time VAS > 20 mm on more than 5 days during the 7‐day pre‐observation period) Baseline parameters: Pruritus score (mean VAS value 100‐mm in the pre‐observation period): (mean ± SD) Nalfurafine hydrochloride (5 µg): 65 ± 14 Nalfurafine hydrochloride (2.5 µg): 69 ± 14 Placebo: 65 ± 14
Interventions	Intervention 1: nalfurafine hydrochloride (5 µg once daily after supper) Intervention 2: nalfurafine hydrochloride (2.5 µg once daily after supper) Intervention 3: placebo (once daily after supper) Additional medication: opioids and phototherapy were prohibited; hypnotics, antidepressants, antipsychotics, antiepileptics and anxiolytics that were likely to affect itch were administered at a consistent dosage and via normal method of administration, as were the antipruritic drugs administered for basic therapy. Route of administration: oral Duration of treatment: 2 weeks (2 weeks pre‐observation ‐ 2 weeks nalfurafine 5µg/2.5µg/placebo ‐ 8 days post observation) Follow‐up: 8 days
Outcomes	Pruritus assessment: VAS 100‐mm Adverse events
Notes	No funding source declared COI: Conflict of interest statement: Hiroo Kumagai, Hidetomo Nakamoto, Taro Muramatsu and Hiromichi Suzuki occasionally worked as medical consultants in the development of anti‐itch agents at Toray Industries, Inc. Toshiya Ebata and Kenji Takamori occasionally worked as medical consultants in the field of dermatology at Toray Industries, Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: ". . . were randomized 1:1:1 to receive 5 µg, 2.5 µg nalfurafine or a placebo using a variable size permuted block design stratified by center."
Allocation concealment (selection bias)	Low risk	QUOTE: "a variable size permuted block design stratified by center"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data; intention‐to‐treat‐analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	Unclear risk	Number of participants randomised: 337 (50 to 199 participants per treatment arm)
Other bias	Low risk	Broad information about participant characteristics; power calculation

Makhlough 2010.

Study characteristics
Methods	RCT Vehicle‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 34 Group A (capsaicin ‐ vehicle): 17 Group B (vehicle ‐ capsaicin): 17 Number of participants evaluable: no information Withdrawals/dropouts: no information Reason for dropout: NA Age (mean ± SD): 57 years ± 18.6 Sex (male/female): 14/20 Underlying disease(s): hypertension (n = 14), diabetes mellitus (n = 12), glomerulonephritis (n = 1), urological problems (n = 1), unknown (n = 1) Participant pool: single‐centre Setting: inpatient Haemodialysis: mean duration of 25 months (SD 15) Baseline pruritus assessment: yes Duration/severity of pruritus: no information on duration; pruritus non‐responsive to common treatment options Baseline parameters: Pruritus score (measured by score by Duo): (mean ± SD) Capsaicin: 15.9 ± 6.3 Placebo: 15.0 ± 6.0
Interventions	Intervention 1: capsaicin (0.03%) Intervention 2: vehicle Additional medication: no information Route of administration: topical Duration of treatment: 4 weeks (2 weeks washout ‐ 4 weeks cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: score by Duo (0‐30) Adverse events Additional outcomes: parathyroid hormone, serum alkaline phosphatase level
Notes	No funding source declared COI: authors declared no conflict of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "The patients were equally divided and randomly assigned by lottery into two groups"
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear if all participants were evaluable; unclear if used intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	Number of evaluable participants not given; no raw data given
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 34
Other bias	Unclear risk	Poor additional information (e.g. dermatological, psychological evaluation); no power calculation; assessment of compliance not stated

Mayo 2007.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 12 Number of participants evaluable: 12 Withdrawals/dropouts: 0 Reason for dropout: NA Age: no information Sex (male/female): 2/10 Underlying disease(s): PBC (n = 9), PSC (n = 2), drug‐induced (postnecrotic cirrhosis) (n = 1) Participant pool: single‐centre Setting: outpatient Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: at least 3 months; no information on severity Baseline parameters: no information
Interventions	Intervention 1: sertraline (dose was previously in an open‐label dose‐escalation trial determined to be optimal for that individual, 25‐100 mg) Intervention 2: placebo Additional medication: concomitant ursodiol treatment was allowed if participants were on a stable dose; other antipruritic medications were stopped at least 2 weeks prior to the study. Route of administration: oral Duration of treatment: 6 weeks (4 weeks washout ‐ 6 weeks cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Additional outcomes: pruritus course, duration, distribution, pruritus insomnia, tolerability, depression, study drug preference, scratching lesions
Notes	Funding: NIH grants R03DK64170‐2 and M01 RR00633, and an Independent Investigator Grant from Pfizer Pharmaceuticals Group COI: Dr. Rush owns stock in Pfizer.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Part B of the study consisted of subjects randomized to double‐blind treatment with either sertraline or placebo." Method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts mentioned; unclear whether intention‐to‐treat analysis was used
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 12
Other bias	Low risk	Assessment of compliance not stated; power calculation used

Murphy 2003.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 24 Group A (ondansetron ‐ placebo): 14 Group B (placebo ‐ ondansetron): 10 Number of participants evaluable: 17 (Group A: 10, Group B: 7) Withdrawals/dropouts: 7 Reason for dropout: Group A (ondansetron ‐ placebo): transplantation (n = 1), constipation (n = 1), non‐compliance (n = 1), CVA (n = 1) Group B (placebo ‐ ondansetron): non‐compliance (n = 2), line sepsis (n = 1) Age (years, median): 59 Sex (male/female): 20/4 Underlying disease(s): no information Participant pool: multicentre Setting: inpatient Haemodialysis: no information Baseline pruritus assessment: yes Duration/severity of pruritus: duration > 8 weeks; mean VAS at least 5/10 during baseline Baseline parameters: Pruritus score (measured by VAS 10‐cm): (mean ± SD) Group A (ondansetron ‐ placebo) and Group B (placebo ‐ ondansetron): 6.1 ± 1.9
Interventions	Intervention 1: ondansetron (8 mg 3 x /d) Intervention 2: placebo (lactose) Additional medication: no information Route of administration: oral Duration of treatment: 2 weeks (7 days baseline ‐ 2 weeks ondansetron/placebo ‐ 7 days washout ‐ 2 weeks cross‐over) Follow‐up: pruritus VAS 2 x /d, collected weekly
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events
Notes	No raw data of the participants This work was supported by a grant from the Northern and Yorkshire NHS Executive. COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"On a random basis 14 patients were blindly allocated to the ondansetron‐placebo sequence and 10 to the placebo‐ondansetron sequence". Method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	". . . 14 patients were blindly allocated to the ondansetron‐placebo sequence and 10 to the placebo‐ondansetron sequence."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Dropouts and reasons for dropouts addressed, per‐protocol analysis
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 24
Other bias	Low risk	Power calculation was carried out before the study; per‐protocol analysis

Naini 2007.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 34 Number of participants evaluable: 34 Withdrawals/dropouts: 0 Reason for dropout: NA Age (mean ± SD): 62 ± 10, range 43‐81 years Sex (male/female): 16/18 Underlying disease(s): no information Participant pool: single‐centre Setting: inpatient Haemodialysis: at least twice a week for at least 3 months Baseline pruritus assessment: yes Duration/severity of pruritus: itching > 8 weeks; unresponsive to antihistamines Baseline parameters: Mean pruritus score (measured by VAS 10‐cm): (mean ± SD) Gabapentin: 7.2 ± 2.3 (range: 3‐10) Placebo: 7.2 ± 2.3 (range: 3‐10)
Interventions	Intervention 1: gabapentin (400 mg 2 x /week after HD session) Intervention 2: placebo (2 x /week after HD session) Additional medication: no information Route of administration: oral Duration of treatment: 4 weeks Follow‐up: no information
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Additional outcomes: haemoglobin, serum parathormone, serum phosphorus, liver enzymes, alkaline phosphatase, bilirubin
Notes	No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"The patients were randomly allocated to receive either gabapentin 400 mg or placebo." Method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blinding stated in the abstract
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No missing outcome data; no information whether intention‐to‐treat analysis used
Selective reporting (reporting bias)	Unclear risk	Number of side effects not stated
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 34
Other bias	Unclear risk	Number of participants of the verum and the placebo group not stated; no power calculation; assessment of compliance not stated

Nasrollahi 2007.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 16 Group A (montelukast ‐ placebo): 8 Group B (placebo ‐ montelukast): 8 Number of participants evaluable: 14 Withdrawals/dropouts: 2 Reason for dropout: Group A: 1 man faced anaemia that was diagnosed as myelodysplastic syndrome during placebo period. Group B: 1 diabetic woman with ischaemic heart disease died during placebo period of myocardial infarction. Age: range 20‐85 years (mean: 65 for male participants, 63 for female participants) Sex (male/female): 10/6 Underlying disease(s): ESRD Participant pool: multicentre Setting: outpatient Haemodialysis: 3 x /week Baseline pruritus assessment: yes Duration/severity of pruritus: persistent pruritus > 3 months; at least 1 course of unsuccessful treatment Baseline parameters: no information
Interventions	Intervention 1: montelukast (10 mg daily) Intervention 2: placebo Additional medication: Erythropoietin, other antipruritic treatment options (14 participants were receiving antihistamines, naltrexone or doxepin) were discontinued 1 week prior the study. Route of administration: oral Duration of treatment: 20 days (20 days montelukast/placebo ‐ 14 days washout ‐ 20 days cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: score by Duo (0‐45) Adverse events Additional outcomes: serum levels of calcium, phosphorus, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, urea, creatinine, parathyroid hormone, haemoglobin
Notes	No funding source declared COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"The study was designed as a randomized, single‐blind, placebo‐controlled, crossover clinical trial." Method of randomisation not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	High risk	Single‐blind; unclear who was blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Dropouts and reasons for dropout mentioned; unclear if used intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	Only score reduction in percentages; no raw data given
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 16
Other bias	Low risk	No power calculation; no raw data given; per protocol analysis; assessment of compliance stated

O'Donohue 2005.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 19 Ondansetron: 9 Placebo: 10 Number of participants evaluable: 18 Ondansetron: 8 Placebo: 10 Withdrawals/dropouts: Ondansetron:1 Placebo: 0 Reason for dropouts: participant with cholestasis due to chronic rejection; post‐orthotopic liver transplantation required rescue antipruritic treatment (oral antihistamines) Age: range 27‐80 years (mean 55) Ondansetron (mean): 55.3 years ± 15.9 Placebo (mean): 54.8 years ± 15.3 Sex (male/female): Ondansetron: 2/7 Placebo: 1/9 Underlying disease(s): primary biliary sclerosis (PBC) (n = 17), cirrhosis because of hepatitis C (n = 1), chronic rejection after orthotopic liver transplantation for hepatitis C cirrhosis (n = 1) Participant pool: single‐centre Setting: combination of inpatient and outpatient setting Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: no information on duration; resistant pruritus Baseline parameters: Pruritus score (measured by VAS 10‐cm): Ondansetron: 4.1 (range: 0.4‐7.1) Placebo: 4.7 (range: 2.7‐9.3)
Interventions	Intervention 1: ondansetron (8 mg) Intervention 2: placebo Additional medication: all antipruritic medications were withdrawn at least 3 days before entry into the study; antipruritic medication before entry into the study was comparable in both groups (cholestyramine (n = 17), ursodeoxycholic acid (n = 12), antihistamines (n = 9), tamoxifen (n = 2), cyclosporin (n = 1), rifampicin (n = 1)). Route of administration: Day 1: ondansetron 8 mg in 10 mL 0.9% saline or 10 mL saline, intravenously over 5 min; 8 hours after injection oral tablets containing either 8 mg ondansetron or placebo were given Day 2‐5: oral tablets twice daily Duration of treatment: 5 days (day 0: 24 h observation phase) Follow‐up: within 2 weeks of the last dose of study medication; adverse events documented and blood sample taken for routine hepatic and renal biochemical markers
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Additional outcomes: serum albumin, alkaline phosphatase, serum bilirubin, prothrombin time
Notes	This study was funded by a grant from GlaxoWellcome, Uxbridge, Middlesex, UK. COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Each patient was consecutively allocated an individual sequential treatment number that corresponded to one of two..."
Allocation concealment (selection bias)	Low risk	QUOTE: "Each patient was consecutively allocated an individual sequential treatment number that corresponded to one of two, identical in appearance, medication regimes. The study pharmacist held sealed envelopes containing the codes to the treatment regimes, so that the patient and all investigators were unaware which of the regimes was being administered."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "[T]he patient and all investigators were unaware which of the regimes was being administered." Participants and personnel were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	No information provided, but not likely
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropouts and reasons for dropouts provided; unclear if used intention‐to‐treat‐analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 19
Other bias	Low risk	Very transparent treatment regimen; exact instruction for pruritus rating; no carry‐over effects

Pederson 1980.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 20 Number of participants evaluable: 11 Withdrawals/dropouts: Group A (charcoal ‐ placebo): 4 Group B (placebo ‐ charcoal): 5 Reason for dropouts: Group A (charcoal ‐ placebo): non‐compliance (n = 4) Group B (placebo ‐ charcoal): transplanted (n = 1), developed bleeding (n = 1), died (n = 1), dissatisfaction (n = 2) Age (years): 34‐72 (mean 53) Sex (male/female): 16/4 Underlying disease(s): no information Participant pool: no information Setting: inpatient Haemodialysis: duration of 3.5 months to 72 months Baseline pruritus assessment: not clear if conducted Duration/severity of pruritus: 1 to 72 months; no information regarding severity Baseline parameters: no information
Interventions	Intervention 1: activated charcoal (6 g/d) Intervention 2: placebo (dextrose, 6 g/d) Additional medication: no information Route of administration: oral Duration of treatment: 8 weeks (8 weeks charcoal/placebo ‐ 8 weeks cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: questionnaire as suggested by Lowrie and Ingham Additional outcomes: Skin lesions Serum urea nitrogen, creatinine, glucose, uric acid, calcium, phosphorus, albumin, prothrombin time, alkaline phosphatase, bilirubin, triglycerides, cholesterol
Notes	No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Patients were randomly assigned. . ." Method not stated
Allocation concealment (selection bias)	Unclear risk	Treatments "administered orally in identical opaque capsules"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Dropouts and reasons for dropouts provided; no intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	Missing participant characteristics
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 20
Other bias	Unclear risk	Small sample size; high number of dropouts; no information on whether there was a washout period between the treatment periods

Podesta 1991a.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 14 Number of participants evaluable: 14 Withdrawals/dropouts: 0 Reason for dropout: NA Age: range 32‐72 years (mean 43) Sex (male/female): 1/13 Underlying disease(s): PBC stage IV (n = 5), PBC stage III (n = 4), PBC stage II (n = 3), PBC stage I (n = 2) Participant pool: multicentre Setting: outpatient Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: no information regarding duration; 9 participants were receiving cholestyramine with a poor or no response in 6 participants Baseline parameters: no information
Interventions	Intervention 1: rifampicin (300 mg 2 x /d) Intervention 2: placebo Additional medication: participants stopped treatment 15 days before the study (washout period). Route of administration: oral Duration of treatment: 7 days ‐ 7 days washout period ‐ cross‐over treatment for 7 days Follow‐up: no information
Outcomes	Pruritus assessment: VAS 100‐mm Adverse events Additional outcomes: bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, anti‐mitochondrial antibody
Notes	No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation made using a coin toss
Allocation concealment (selection bias)	Low risk	QUOTE: "Vials containing a one‐week supply of drug or placebo by an independent observer and randomization made with the toss of a coin"
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of participants used but disclosed because of treatment effects
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data; no information on intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 14
Other bias	Low risk	Assessment of compliance using pill count

Pour‐Reza‐Gholi 2007.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 24 Number of participants evaluable: 23 Withdrawals/dropouts: 1 Reason for dropout: drowsiness Age (mean ± SD): 48 ± 5.6, range: 35 to 65 Sex (male/female): 13/11 Underlying disease(s): ESRD Participant pool: single‐centre Setting: outpatient Haemodialysis: 3 x /week, Kt/V >  1.2 Baseline pruritus assessment: no information Duration/severity of pruritus: no information Baseline parameters: no information
Interventions	Intervention 1: doxepin (10 mg 2 x /d) Intervention 2: placebo Additional medication: erythropoietin weekly (n = 10); others did not receive erythropoietin regularly Route of administration: oral Duration of treatment: 1 week (1 week doxepin/placebo ‐ 1 week washout ‐ 1 week cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: subjective outcome determined by asking the participants to describe their pruritus as completely improved, relatively improved, or remained unchanged/worsened Adverse events Additional outcomes: serum calcium levels, serum phosphate levels, serum intact parathyroid hormone, serum aluminium, serum magnesium, blood haemoglobin
Notes	No scales or score for rating of pruritus; subjective outcome report of participants No funding source declared COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "They were randomly assigned. . ." Method not stated
Allocation concealment (selection bias)	Low risk	QUOTE: "Doxepin was placed in another capsule in order to provide placebo capsules similar in shape, size and colour".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "The patients and the physicians involving in their management were blind to the randomization."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "The patients and the physicians involving in their management were blind to the randomization."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropouts and reasons for dropout provided; intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 24
Other bias	Low risk	No scales or score for rating of pruritus; subjective outcome report of participants

Shayanpour 2019.

Study characteristics
Methods	RCT Placebo‐controlled
Participants	Pruritus: uremic Number of participants: 64 Omega‐3: 32 Placebo: 32 Withdrawls/dropouts: none Age (mean ± SD): Intervention group: 51.91 ± 6.586 Placebo group: 56.25 ± 8.865 Sex (male/female): Intervention group: 25/5 Placebo group: 23/9 Underlying disease(s): ESRD Setting: HD unit Haemodialysis: not specified
Interventions	Intervention 1: single dose of 2 g omega‐3 daily before lunch Intervention 2 (placebo): microcrystalline cellulose (Activel, PH 101) and lactose, similar in shape, size and taste Route of administration: oral Duration of treatment: 3 weeks Follow‐up: none
Outcomes	Pruritus assessment: 5‐D itch scale questionnaire
Notes	Funding: Supported by Ahvaz Jundishapur University of Medical Sciences. This study was extracted from M.D. Thesis of Parastoo Lakhaye Rizi. COI: Authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "patients were divided in to the control and intervention groups randomly using blocks of six for allocation concealment."
Allocation concealment (selection bias)	Low risk	QUOTE: "Using blocking for allocation concealment, someone who was unaware of the study, prescribed omega‐3 and placebo to patients."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "This study is a randomized, double‐blind, controlled clinical trial."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not mentioned
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts
Selective reporting (reporting bias)	Unclear risk	QUOTE protocol: "Registration timing: retrospective"
Size of study (possible biases confounded by small size)	High risk	< 50 patients per treatment arm.
Other bias	Low risk	The study appeared to be free of other sources of bias.

Silverberg 1977.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 10 Cholestyramine: 5 Placebo: 5 Number of participants evaluable: 10 Withdrawals/dropouts: 0 Reason for dropout: NA Age (years): no information Sex (male/female): 10/0 Underlying disease(s): no information Participant pool: no information Setting: inpatient Haemodialysis: 3 x 3‐5 h/week Baseline pruritus assessment: yes Duration/severity of pruritus: long‐lasting; no information regarding severity Baseline parameters: Pruritus score (measured by 4‐point score; 0 = none, 3 = great): Cholestyramine: 1.9, 2.2, 2.3, 1.9, 1.9 Placebo: 1.9, 0.9, 2.1, 1.2, 2.2
Interventions	Intervention 1: cholestyramine (5 g 2 x /d in juice) Intervention 2: placebo (methylcellulose) (2 x /d) Additional medication: no information Route of administration: oral Duration of treatment: 4 weeks Follow‐up: no information
Outcomes	Pruritus assessment: 4‐point score Adverse events Additional outcomes: prothrombin time, blood urea, serum creatinine, sodium, potassium, chloride, bicarbonate, calcium, phosphate, alkaline phosphatase, albumin, cholesterol, triglyceride concentration
Notes	No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "The 10 patients were randomly assigned to two treatments". Method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blinding stated in the abstract
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts
Selective reporting (reporting bias)	Unclear risk	Small number of participants; inclusion and exclusion criteria not mentioned; only means of 21 days before treatment and means of 28 days of treatment were compared.
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 10
Other bias	Unclear risk	Missing participant characteristics; assessment of compliance not stated

Somkearti 2021.

Study characteristics
Methods	RCT Placebo‐controlled
Participants	Pruritus: uremic Number of participants: 55 Oral zinc: 28 Placebo: 27 Withdrawls/dropouts: not specified Demographics: not specified Underlying disease(s): ESRD Setting: not specified Haemodialysis: Kt/V
Interventions	Intervention 1: zinc sulfate capsules 440 mg/d (220 mg/bid) Intervention 2 (placebo): identical placebo Route of adminsitration: oral Duration of treatment: 12 weeks Follow‐up: 4 weeks
Outcomes	Pruritus assessment: VAS & UP‐Dial scale (every 4 weeks) Additional outcomes: QOL (VAS) Adverse effects
Notes	Funding: not specified COI: not specified
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: " A double‐blinded, randomized controlled trial."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not specified
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not specified
Selective reporting (reporting bias)	Unclear risk	Not specified
Size of study (possible biases confounded by small size)	High risk	< 50 participants per treatment arm
Other bias	Unclear risk	Insufficient reporting (conference poster)

Turner 1994a.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 50 Flumecinol: 24 Placebo: 26 Number of participants evaluable: 50 Withdrawals/dropouts: 0 Reason for dropout: NA Age (years): no information Sex (male/female): 3/47 Underlying disease(s): primary biliary cirrhosis (n = 46), alcoholic liver disease (n = 2), autoimmune chronic active hepatitis (n = 1), cholestatic phase of hepatitis A (n = 1) Participant pool: no information Setting: outpatient Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: no information Baseline parameters: Pruritus score (measured by VAS 100‐mm), median (IQR): Flumecinol: 46 (32‐63) Placebo: 38 (17‐69) Quality of life (measured by 100‐mm scale), median (IQR): Flumecinol: 26 (16‐48) Placebo: 11 (4‐30)
Interventions	Intervention 1: flumecinol (600 mg 1x/week with evening meal) Intervention 2: placebo Additional medication: antipruritic treatment was stopped at least 1 week prior to the study; if unable to stop, they continued medication at an unchanged dose. Cholestyramine was stopped in 6 of 9 actively‐treated and 7 of 8 placebo participants. Route of administration: oral Duration of treatment: 3 weeks Follow‐up: no information
Outcomes	Pruritus assessment: VAS 100‐mm Adverse events Additional outcomes: Self‐assessment of pruritus improvement (yes or no) Liver function tests (bilirubin, albumin, alkaline phosphatase, aspartate transaminase), serum biochemical and haematological parameters at study commencement and completion
Notes	No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation not stated
Allocation concealment (selection bias)	Unclear risk	QUOTE: "[D]ouble‐blindly allocated"; not precisely stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study was double‐blind, QUOTE: "without the questioner or the patient knowing the treatment arm"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE:"without the questioner or the patient knowing the treatment arm"
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data; not reported if intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 50
Other bias	Low risk	Poor additional information; imbalance male/female 3/47; assessment of compliance not stated

Turner 1994b.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 19 Flumecinol: 10 Placebo: 9 Number of participants evaluable: 19 Withdrawals/dropouts: 0 Reason for dropout: NA Age (years): no information Sex (male/female): 0/19 Underlying disease(s): primary biliary cirrhosis (19) Participant pool: no information Setting: outpatient Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: no information Baseline parameters: Pruritus relief (measured by VAS 100‐mm), median (IQR): Flumecinol: 45 (37‐66) Placebo: 50 (35‐58) Quality of life (measured by 100‐mm scale), median (IQR): Flumecinol: 32 (20‐54) Placebo: 42 (23‐50)
Interventions	Intervention 1: flumecinol (300 mg 1x/d) Intervention 2: placebo Additional medication: antipruritic treatment was stopped at least 1 week prior to the study; if unable to stop they continued medication at an unchanged dose. Cholestyramine was stopped in 2 of 10 actively‐treated and 1 of 9 placebo participants but 1 continued using it. Route of administration: oral Duration of treatment: 3 weeks Follow‐up: no information
Outcomes	Pruritus assessment: VAS 100‐mm Adverse events Additional outcomes: Self‐assessment of pruritus improvement (yes or no) Liver function tests (bilirubin, albumin, alkaline phosphatase, aspartate transaminase and alanine transaminase), serum biochemical and haematological parameters at study commencement and completion
Notes	No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation not stated
Allocation concealment (selection bias)	Unclear risk	QUOTE: "double‐blindly allocated"; not precisely stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "without the questioner or the patient knowing the treatment arm"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE:"without the questioner or the patient knowing the treatment arm"
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data; no information on intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 19
Other bias	Low risk	Poor additional information; assessment of compliance not stated

Vessal 2010.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number total (randomised): 62 (+ 20 as negative control) Cromolyn sodium: 32 Placebo: 30 Number of participants evaluable: 40 (+19 as negative control) Cromolyn sodium: 21 Placebo: 19 Withdrawals/dropouts: 22 (+1 as negative control) Cromolyn sodium: 11 Placebo: 11 Reason for dropouts: Cromolyn sodium: 2 died, 3 transferred, 5 noncompliant, 1 transplanted Placebo: 1 died, 2 transferred, 5 noncompliant, 3 adverse events Negative control group: due to transfer Age (mean ± SD): Cromolyn sodium: 56.9 years ± 15.49 Placebo: 57.47 years ± 13.6 Sex (male/female): Cromolyn sodium: 12/9 Placebo: 8/11 Underlying disease(s): no information Participant pool: multicentre (2 centres) Setting: inpatient Haemodialysis: 4‐5 hours for 2‐3 x per week Baseline pruritus assessment: yes Duration/severity of pruritus: pruritus that did not respond to treatment for at least 6 weeks Baseline parameters: Pruritus relief (measured by VAS 10‐cm): Cromolyn sodium (mean ± SD): 8.68 ± 1.8 (range 4‐10, median 10) Placebo (mean ± SD): 8.48 ± 2.2 (range 4‐10, median 10)
Interventions	Intervention 1: cromolyn sodium (135 mg) Intervention 2: placebo (lactose powder) Additional medication: antipruritic medication was discontinued 1 week prior the study. Route of administration: oral (capsule was dissolved in a minimal amount of water and administered half an hour before each meal) Duration of treatment: 8 weeks Follow‐up: no information
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Additional outcomes: haemoglobin, calcium, phosphorus, albumin, ferritin, parathyroid hormone, white blood cells, serum tryptase, platelet, hematocrit
Notes	Funding: "This research was supported by Shiraz University of Medical Sciences (grant no. 4146)". COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Patients were randomly assigned into two groups using the stratified randomization method where the prognostic factor was the gender variable."
Allocation concealment (selection bias)	Low risk	QUOTE: "Drug packages were prepared by the principal investigator. . . Both the participants and the investigator that administered the interventions and assessed the outcomes were blinded to group assignment. Code breaking was performed at the end of data analysis."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind; participants and personnel blinded QUOTE: "Both the participants and the investigator that administered the interventions and assessed the outcomes were blinded to group assignment. Code breaking was performed at the end of data analysis."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessor blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropouts and reasons for dropouts mentioned; per‐protocol analysis "19 resp. 21 remained and data were analyzed."
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number total (randomised): 62 (less than 50 per treatment arm)
Other bias	Low risk	No indication

Villamil 2005.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 18   Lidocaine: 12 Placebo: 6 Number of participants evaluable: 16 Lidocaine: 11 Placebo: 5 Withdrawals/dropouts: 2 Lidocaine: 1 Placebo: 1 Reason for dropouts: Lidocaine: liver transplantation Placebo: incomplete records Age: (mean ± SD) Lidocaine: 45 ± 3, range 33‐54 Placebo: 48 ± 2, range 31‐67 years Sex (male/female): Lidocaine: 2/10 Placebo: 2/4 Underlying disease(s): Lidocaine: PBC (n = 9), PSC (n = 2), drug‐induced (n = 1) Placebo: PBC (n = 4), PSC (n = 2) Overall: PBC (n = 13), PSC (n = 4), drug‐induced (n = 1) Participant pool: single‐centre Setting: no information Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: at least 3 months; resistant to treatment Baseline parameters: no information
Interventions	Intervention 1: lidocaine (100 mg) Intervention 2: placebo (5 cc, saline) Additional medication: ursodeoxycholic acid Route of administration: intravenous (5 minutes) Duration of treatment: 7 days Follow‐up: no information
Outcomes	Pruritus assessment: VAS (0‐100 mm) Adverse events Additional outcomes: total serum bilirubin, alkaline phosphatase, albumin
Notes	No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "Patients were randomised (2:1) to receive. . ." Method not stated
Allocation concealment (selection bias)	Unclear risk	Not information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Drug administration was done under strict double‐blind conditions and the code was not opened until the final analysis of the results."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessor probably blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropouts and reasons for dropouts mentioned; not reported if intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	Presentation of study results inappropriate; neither baseline nor endpoint data given
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 18
Other bias	Low risk	Assessment of compliance not stated

Wikström 2005b.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: patients with ESRD on haemodialysis Number of participants randomised: 34 Group A (nalfurafine ‐ placebo): 16 Group B (placebo ‐ nalfurafine): 18 Number of participants evaluable: 31 Withdrawals/dropouts: 3 Reason for dropout: no information Age (years): no information Sex (male/female): no information Underlying disease(s): ESRD Participant pool: multicentre Setting: no information Haemodialysis: "routine" Baseline pruritus assessment: yes Duration/severity of pruritus: no information on duration; severe, uncontrolled pruritus secondary to ESRD, at least 3 "worst itching" VAS measurements during run‐in period of > 50 mm and average worst itching > 25 mm Baseline parameters: Pruritus relief (measured by VAS 100‐mm): (mean ± SD) Group A (nalfurafine ‐ placebo): 63.3 ± 10.9 Group B (placebo ‐ nalfurafine): 61.9 ± 12.6
Interventions	Intervention 1: nalfurafine (5 µg 3 x /week immediately after their haemodialysis session) Intervention 2: placebo Additional medication: before the run‐in period, all antipruritic medications, except for topical neutral agents, were discontinued for at least 7 days. Route of administration: intravenous Duration of treatment: 2 weeks (1‐week run‐in period ‐ 2 weeks nalfurafine/placebo ‐ 3 weeks washout ‐ 2 weeks cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: VAS 100‐mm Adverse events
Notes	No funding source declared COI: no author COI statements provided Results combined with results of study Wikström 2005a
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	". . . patients were randomly assigned 1:1. . .." Method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No information on withdrawals
Selective reporting (reporting bias)	Unclear risk	Combined with results of study Wikström 2005a; conflicting information concerning number of included participants
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 34
Other bias	Unclear risk	Missing participant characteristics; assessment of compliance not stated

Zylicz 2003.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: various malignancies Description: participants with the following conditions: Solid tumours (n = 17) Haematological malignancies (n = 4) Various non‐malignant or idiopathic conditions (n = 5) Drug‐induced pruritus (n = 8) Paraneoplastic pruritus (n = 7) CP (n = 3) Primary skin amyloidosis due to MEN2A syndrome (n = 1) Number of participants was higher than total number of participants due to simultaneously existing causes for pruritus. Number of participants randomised: 26 Group A (placebo ‐ paroxetine): 11 Group B (paroxetine ‐ placebo): 13 Number of participants evaluable: 24 Withdrawals/dropouts: 2 participants in group B during paroxetine treatment Reason for dropouts: severe nausea and vomiting Age (mean ± SD): Group A (placebo ‐ paroxetine): 64.4 years ± 18.3 Group B (paroxetine ‐ placebo): 64.9 years ± 11.3 Sex (male/female): Group A (placebo ‐ paroxetine): 6/5 Group B (paroxetine ‐ placebo): 7/6 Underlying disease(s): solid tumours (n = 17), haematological malignancies (n = 4), osteoporosis (n = 2), Parkinson's (n = 1), skin amyloidosis due to MEN2A (n = 1), rheumatoid arthritis (n = 1) Participant pool: multicentre (2 palliative care centres) Setting: inpatient Haemodialysis: NA Duration/severity of pruritus: Group A (placebo ‐ paroxetine): < 3 months (n = 2), > 3 months (n = 9); generalised (n = 6), local (n = 5) Group B (paroxetine ‐ placebo): < 3 months (n = 3), > 3 months (n = 10); generalised (n = 7), local (n = 6) Baseline parameters: Pruritus relief (measured by numerical analogue scale = NAS) (mean ± SD) Group A (placebo ‐ paroxetine): 6.6 ± 1.0 Group B (paroxetine ‐ placebo): 6.5 ± 1.1
Interventions	Intervention 1: paroxetine (20 mg)/d Intervention 2: placebo Additional medication: cisapride (in case of severe nausea) Route of administration: oral Duration of treatment: 1 week (1 week run‐in ‐ 1 week paroxetine/placebo ‐ 1 week cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: NAS (0‐10) Adverse events Participant satisfaction
Notes	No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "The patients were randomised when the mean NAS of pruritus. . ." Method not stated
Allocation concealment (selection bias)	Unclear risk	Allocation not stated
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Blinding and randomisation were in the hands of the same pharmacist as well."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data; planning of sample size; power calculation done, intention‐to‐treat approach for the primary endpoint done
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 26
Other bias	Low risk	Assessment of compliance not stated; no washout period but carry‐over effect evaluated

Ataei 2019.

Study characteristics
Methods	RCT Active control Parallel‐group design
Participants	Pruritus: cholestatic Description: PBC and PSC patients Number of participants randomised: 36 Group A (sertraline): 18 Group B (rifampin): 18 Withdrawals/dropouts: NA Age (mean): Group A (sertraline): 38; Group B (rifampin): 45.2 Male sex (%): Group A (sertraline): 11 (61.1) ; Group B (rifampin): 9 (50.0) Underlying disease(s): PBC/PSC Setting: inpatient Haemodialysis: no
Interventions	Intervention 1: sertraline 100 mg/day Intervention 2: rifampin 300 mg/day Route of administration: oral Duration of treatment: 4 weeks Follow‐up: no
Outcomes	Primary outcomes: mean pruritus score (VAS) Secondary outcomes: NA
Notes	Funding: grant from Hamadan University of Mcdical Sciences COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on generation of sequence
Allocation concealment (selection bias)	Unclear risk	QUOTE: "We prepared 36 pieces of paper written on half of them A, and on the rest B. patients were grouped randomly by selecting one of the papers."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Single‐blinded; no further information
Blinding of outcome assessment (detection bias) All outcomes	High risk	Single‐blinded; no further information
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or missing data reported
Selective reporting (reporting bias)	Low risk	IRCT2015062822956N1; https://en.irct.ir/trial/19687?revision=19687 All outcomes were prespecified.
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	Unclear risk	Only a small number of baseline values provided

Aubia 1980.

Study characteristics
Methods	Study design: parallel‐group RCT Time frame: 10‐month time period Duration of study/follow‐up: 4 weeks
Participants	Setting: single‐centre (outpatients) Country: Spain Inclusion criteria: HD patients with a customised pruritus score 5 and above Number: treatment group (6); control group (7) Mean age ± SD (years): not reported Sex (M/F): 8/5 Relevant comorbidities: not reported Exclusion criteria: aged < 18 years
Interventions	Treatment group Cimetidine (oral): 600 mg/day for 4 weeks Control group Placebo (oral): daily for 4 weeks
Outcomes	Pruritus: custom itch consisting of intensity, duration, and localisation score totalling 0 to 8. Only P values and t‐scores reported
Notes	No declared source of funding COI: no author COI statements provided Correspondence: Nephrology Service, Hospital Gral. M.D. Esperanca, S. Josep de la Muntanya, 12 Barcelona
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "...included in a double blind randomised study that evaluated the effects of classic antihistaminic (group AH) before the effects of a placebo (P) during 4 weeks."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "...included in a double blind randomised study that evaluated the effects of classic antihistaminic (group AH) before the effects of a placebo (P) during 4 weeks."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts post randomisation
Selective reporting (reporting bias)	High risk	Only P values and t‐scores reported; unable to meta‐analyse
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 13
Other bias	Low risk	No evidence of publication or funding bias

Begum 2004.

Study characteristics
Methods	Study design: parallel‐group RCT Time frame: 2004 Duration of study/follow‐up: 16 weeks
Participants	Setting: multicentre (3 sites) (inpatients) Country: USA Inclusion criteria: HD patients aged > 20 years with pruritis Number: treatment group 1 (12); treatment group 2 (10) Mean age ± SD (years): treatment group 1 (60.2 ± 19.4); treatment group 2 (49.2 ± 18.1) Sex (M/F): treatment group 1 (6/6); treatment group 2 (7/3) Relevant comorbidities: not reported Exclusion criteria: DM; malabsorption problems; conditions that may affect fatty acid metabolism
Interventions	Treatment group 1 Fish oil (oral): 6 g ethyl ester/day for 16 weeks Treatment group 2 Safflower oil (oral): 6 g ethyl ester/day for 16 weeks
Outcomes	Pruritus: Duo score Adverse effects
Notes	No declared funding or conflicts of interest COI: no author COI statements provided Louise Peck, PhD, RD, Department of Epidemiology, University of Washington, PO Box 353410, Seattle, WA 98195. E‐mail: lpeck@u.washington.edu
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "randomised"
Allocation concealment (selection bias)	Unclear risk	QUOTE: "randomised"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "double‐blind study for 2 treatment groups"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not enough information to judge
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts and complete reporting
Selective reporting (reporting bias)	Low risk	No dropouts and complete reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 22
Other bias	Low risk	No evidence of publication or funding bias

Bhaduri 2006.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design Time frame: 5 weeks Duration of study/follow‐up: 5 weeks
Participants	Setting: multicentre (number of sites not reported) Country: Japan Inclusion criteria: patients with pruritus aged 40 to 80 years receiving HD treatment 3 times/week for 3 months Number: treatment group 1 (26); treatment group 2 (27); control group (25) Mean age ± SD: not reported Sex M/F: not reported Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Treatment group 1 Nalfurafine: 5 µg infusion post dialysis Treatment group 2 Nalfurafine: 2.5 µg infusion post dialysis Control group Placebo
Outcomes	Cumulative decrease in VAS
Notes	Abstract‐only publication No declared source of funding COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE "randomised"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Baseline, percent change and CI reported
Size of study (possible biases confounded by small size)	Unclear risk	Number of participants randomised: 78
Other bias	Unclear risk	Abstract‐only publication

Chourdakis 2019.

Study characteristics
Methods	RCT Active control Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis or peritoneal dialysis Number of participants randomised: 20 Group 1 (desloratadine): 10 Group 2 (bilastine): 10 Withdrawals/dropouts: 10 in total Number of participants analysed: 10, 5 in each group Age (mean ± SD): Total Sample: 66.5 ± 12.9 Male sex (%): Total sample: 7 (70) Underlying disease(s): ESRD Setting: NA Haemodialysis: yes, frequency NA
Interventions	Intervention 1: desloratadine (5 mg) once daily Intervention 2: bilastine (20 mg) once daily Route of administration: oral Duration of treatment: 1 month Follow‐up: NA
Outcomes	Primary outcomes: presence of pruritus (5‐D‐Itch scale) Secondary outcomes: adverse events
Notes	Poster‐abstract publication only No declared source of funding COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Patients were randomy assigned; no further information
Allocation concealment (selection bias)	High risk	Open‐label study
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study
Incomplete outcome data (attrition bias) All outcomes	High risk	10/20 included participants refused to receive or discontinued treatment.
Selective reporting (reporting bias)	Unclear risk	No protocol available
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants
Other bias	Unclear risk	No information on other bias

Fishbane 2020a.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 378 Difelikefalin group: 189 Placebo group: 189 Withdrawals/dropouts: 1 (placebo group) Age (mean ± SD): Difelikefalin group: 58.2 ± 11.2; Placebo group: 56.8 ± 13.9 Male sex (%): Difelikefalin group: 112 (59.3) ; Placebo group: 118 (62.8) Underlying disease(s): ESRD Setting: outpatient Haemodialysis: 3 times/week
Interventions	Intervention: Difelikefalin: 0.5 μg per kilogram of body weight Control: matched placebo Route of administration: intravenous, 3 times/week as an intravenous bolus into the venous port of the dialysis circuit after each dialysis session Duration of treatment: 12 weeks Follow‐up: yes, 2 weeks after treatment
Outcomes	Primary outcomes: ≥ 3‐point improvement from baseline at wk 12 in the weekly mean score of the daily 24‐hr WI‐NRS Secondary outcomes: Quality of life: 5‐D itch scale; Skindex‐10; safety
Notes	Funded by Cara Therapeutics COI: Dr. Fishbane reports receiving grant support from Cara Therapeutics; Drs. Munera and Wen, being employed by and owning stock in Cara Therapeutics; and Dr. Menzaghi, being employed by and owning stock in Cara Therapeutics, holding a patent (U.S. 2017/0007574 A1) on peripheral kappa opioid receptor agonists for uremic pruritus in dialysis patients, licensed to Cara Therapeutics, and holding a patent (U.S. 8.236,766 B2) on uses of synthetic peptide amides, licensed to Cara Therapeutics. No other potential conflict of interest relevant to this article was reported.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on generation of sequence
Allocation concealment (selection bias)	Low risk	Randomisation was performed with the use of an interactive Web‐response system.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE Protocol: "During the double‐blind treatment period, patients, investigators, study staff, and the sponsor will be blinded to study drug assignment."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE Protocol: "During the double‐blind treatment period, patients, investigators, study staff, and the sponsor will be blinded to study drug assignment."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few dropouts that were comparable between groups; multiple imputation
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes reported in the protocol, available at https://www.nejm.org/doi/full/10.1056/NEJMoa1912770
Size of study (possible biases confounded by small size)	Unclear risk	50 to 199 participants per treatment arm
Other bias	Low risk	Well‐designed study

Fishbane 2020b.

Study characteristics
Methods	RCT Placebo‐controlled; dose‐ranging study Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 174 Difelikefalin 0.5 μg/kg: 44 Difelikefalin 1 μg/kg: 42 Difelikefalin 1.5 μg/kg: 44 Placebo: 45 Withdrawals/dropouts: Placebo: 3; Difelikefalin 0.5 μg/kg: 5; Difelikefalin 1 μg/kg: 7; Difelikefalin 1.5 μg/kg: 11 Age median (range min‐max): Placebo: 60 (27‐84); Difelikefalin 0.5 mg/kg: 57 (29‐80); Difelikefalin 1 mg/kg: 59 (26‐84); Difelikefalin 1.5 mg/kg: 56.5 (29‐74) Male sex (%) : Placebo: 28 (62.2); Difelikefalin 0.5 mg/kg: 26 (59.1); Difelikefalin 1 mg/kg: 23 (56.1); Difelikefalin 1.5 mg/kg: 28 (63.6) Underlying disease(s): ESRD Setting: NA Haemodialysis: 3 times/week
Interventions	Intervention: IV bolus of difelikefalin (0.5, 1.0, or 1.5 μg/kg) at the end of each haemodialysis session Control: IV bolus of placebo in isotonic acetate buffer (pH 4.5) at the end of each haemodialysis session Route of administration: intravenous Duration of treatment: 8 weeks Follow‐up: no
Outcomes	Primary outcomes: weekly mean of daily 24‐h Worst Itching Intensity NRS score Secondary outcomes: Quality of life: Skindex, 5‐D itch scale, Itch MOS sleep disturbance score; responder‐rate; safety
Notes	Funded by Cara Therapeutics COI: CM, RHS, and FM are employed by Cara Therapeutics, Inc. SS attended a data release meeting and received travel expenses for attending this meeting. SB, MJG, and VM received fees from Cara for serving as medical consultants and/or medical monitors during the conduct of the study. SF was chair of the Data Safety Monitoring Board.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on generation of sequence
Allocation concealment (selection bias)	Low risk	Randomised (1:1:1:1 ratio using a Web Response System)
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Patients, investigators, clinical study site staff, and sponsor staff directly involved with the study were masked to treatment assignment throughout the trial."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Patients, investigators, clinical study site staff, and sponsor staff directly involved with the study were masked to treatment assignment throughout the trial."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Only 1 dropout
Selective reporting (reporting bias)	High risk	Protocol: https://clinicaltrials.gov/ct2/show/NCT02858726; primary outcome not reported for week 12; secondary outcomes did not match the outcomes in the publication.
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	Low risk	Well‐designed study

Fouroutan  2017.

Study characteristics
Methods	RCT Active control Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 90 Pregabalin group: 46 Doxepin group: 44 Withdrawals/dropouts: 18 (doxepin group: 9; pregabalin group: 9) Age (mean ± SD): pregabalin group: 58.8 ± 17.2; doxepin group: 60.6 ± 14.5 Male sex (%) : pregabalin: 19/37, (51.4% ); doxepin: 18/35 (51.4%) Underlying disease(s): ESRD Setting: outpatient Haemodialysis: 3 times/week
Interventions	Intervention 1: 50 mg pregabalin every second day Intervention 2: 10 mg doxepin daily Note: In the cases of insufficient response, defined as less than 2 units decrease in score of visual analog scale (VAS) after one week of the therapy, the dose of pregabalin and doxepin was increased to 50 mg per day and 10 mg two times per day, respectively. Route of administration: NA Duration of treatment: 4 weeks Follow‐up: 1‐week, 2‐week and 4‐week assessment
Outcomes	Primary outcomes: Pruritus severity (VAS) Secondary outcomes: Quality of life (5‐D‐itch scale, DLQI); adverse events
Notes	Funding: Kerman University of Medical Sciences COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on generation of sequence
Allocation concealment (selection bias)	Unclear risk	No information on concealment
Blinding of participants and personnel (performance bias) All outcomes	High risk	QUOTE: "Patients were not blind to their treatment, but who evaluated the participants and who statistically analysed the results did not know the allocated medication of each patient."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Patients were not blind to their treatment, but who evaluated the participants and who statistically analysed the results did not know the allocated medication of each patient."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few dropouts that were comparable between groups
Selective reporting (reporting bias)	Unclear risk	No protocol available
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	Low risk	Study design appropriate; no differences in baseline values

Gholyaf 2020.

Study characteristics
Methods	RCT Active control Cross‐over design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 77 Group 1 (mirtazapine/gabapentin treatment sequence): 39 Group 2 (gabapentin/mirtazapine treatment sequence): 38 Withdrawals/dropouts: after first sequence: 7 (4 mirtazapine/3 gabapentin); after second sequence 9 (6 gabapentin/3 mirtazapine) Age (mean ± SD): Total sample: 58.51 ± 11.91 Male sex (%): Total sample: 35 (57.4) Underlying disease(s): CKD Setting: inpatient Haemodialysis: 3 times/week for 4 hours; bicarbonate‐based haemodialysis
Interventions	Intervention 1: Gabapentin (Neurontin, Pfizer Pharmaceutical Company) was administered at a dose of 100 per day Intervention 2: Mirtazapine (Remeron, Pfizer) at a dose of 15 mg per day at bedtime Route of administration: oral Duration of treatment: 8 weeks total (2 weeks washout‐ 2 weeks (sequence 1) – 2 weeks washout – 2 weeks (sequence 2) Follow‐up: yes
Outcomes	Primary outcomes: pruritus severity (VAS); mean change in VAS score; responder rate (= percentage of patients with VAS score < 4) Secondary outcomes: adverse events
Notes	Funding: supported by the Vice‐Chancellor of Research and Technology of Hamadan University of Medical Sciences COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Block randomisation, however, the process of selecting the blocks remained unclear (e.g. random number table; computer random number generator)
Allocation concealment (selection bias)	Unclear risk	No information on concealment, only on allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The researcher responsible for recording patients’ severity of pruritus and co‐authors responsible for data analysis were blind to patients’ study allocations.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The researcher responsible for recording patients’ severity of pruritus and co‐authors responsible for data analysis were blind to patients’ study allocations.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropouts comparable between groups; no missing data reported
Selective reporting (reporting bias)	Low risk	IRCT | Comparison of oral mirtazapine and oral gabapentin in treatment of uremic pruritus in haemodialysis patients
Size of study (possible biases confounded by small size)	Unclear risk	50 to 199 participants per treatment arm
Other bias	Low risk	No carry‐over effect

Ghorbani 2012.

Study characteristics
Methods	Study design: parallel RCT Time frame: January to April 2010 Duration of study/follow‐up: 8 weeks
Participants	Setting: single‐centre Country: Iran Health status: patients on dialysis; aged 18 to 60 years of age; minimum duration of pruritus 6 weeks Number: treatment group (30); control group (30) Mean age ± SD (years): not reported Sex: not reported Relevant comorbidities: not reported Exclusion criteria: Pregnancy and breastfeeding; hypersensitivity to pimecrolimus; any other condition except for ESKD causing pruritus; and use of antihistamines or other anti‐pruritus drugs in the previous 3 months
Interventions	Treatment group Pimecrolimus ointment (topical): 1% (amount not stated), twice/day for 8 weeks Control group Placebo (topical): twice/day for 8 weeks
Outcomes	Pruritus: patients recorded VAS daily; mean VAS reported at baseline and 8 weeks
Notes	Supported by a grant from Islamic Azad University of Gachsaran, Gachsaran Branch, Iran
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Randomization was performed by using a simple random table."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double Blind; patients given unlabelled medication as start of trial"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Patient‐recorded VAS
Incomplete outcome data (attrition bias) All outcomes	Low risk	All enrolled patients completed the trial and were analysed.
Selective reporting (reporting bias)	Low risk	Baseline and results clearly reported.
Size of study (possible biases confounded by small size)	Unclear risk	Number of participants randomised: 60
Other bias	Low risk	No evidence of publication, funding, or other confounding bias

Ghorbani Birgani 2011.

Study characteristics
Methods	Study design: parallel‐group RCT Time frame: 2010 Duration of study/follow‐up: 8 weeks
Participants	Setting: single‐centre (inpatients) Country: Iran Inclusion criteria: patients aged 18 to 60 years with ESKD on HD Number: treatment group 1 (30); treatment group 2 (30) Mean age ± SD: 56 ± 13.2 years Sex (M/F): (31/29) Relevant comorbidities: not reported Exclusion criteria: Skin, liver, and metabolic or any illness or condition other than kidney disease
Interventions	Treatment group 1 Cromolyn cream (topical): 4%, twice/day for 16 weeks Treatment group 2 Pimecrolimus cream (topical): 2%, twice/day for 8 weeks
Outcomes	Pruritis score (VAS)
Notes	In Arabic No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "randomised"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	QUOTE: "Blinded"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	QUOTE: "Blinded"
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear if any patient dropped out
Selective reporting (reporting bias)	Low risk	Full results clearly reported
Size of study (possible biases confounded by small size)	Unclear risk	Number of participants randomised: 60
Other bias	Low risk	No evidence of publication or funding bias

Gobo‐Oliveira 2018.

Study characteristics
Methods	RCT Active control Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 60 Gabapentin group: 30 Dexchlorpheniramine group: 30 Withdrawals/dropouts: 2 (gabapentin: 1; dexchlorpheniramine: 1) Age (mean ± SD): gabapentin group: 64 ± 15; dexchlorpheniramine group: 59 ± 12 Male sex (%) gabapentin group: 15 (50); dexchlorpheniramine group: 19 (63) Underlying disease(s): ESRD Setting: inpatient Haemodialysis: 3 times/week
Interventions	Intervention 1: 300 mg oral gabapentin (Gabapentina® ‐ EMS) thrice weekly after HD Intervention 2: 6 mg dexchlorpheniramine (Polaramine®) twice daily Route of administration: oral Duration of treatment: 3 weeks Follow‐up: no
Outcomes	Primary outcomes: Decrease in pruritus score (VAS) Secondary outcomes: Quality of life (DLQI)
Notes	Funding: grant by FUNADERSP (São Paulo, Brazil) COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed by an individual unrelated to the clinical follow‐up using specific software.
Allocation concealment (selection bias)	Low risk	The information was held in a sealed opaque envelope containing the name of the therapeutic agent proposed for each group.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "To maintain blinding of the study, for the GABA group, the 'Home' bottle contained a placebo identical to the gabapentin capsule, and the medication was stored in the 'Dialysis' bottle. The 'Dialysis' bottle remained in the Dialysis Unit, and the medication was administered to patients at the end of the session by the responsible technician. Participants and assessors were blinded to the treatment groups."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "To maintain blinding of the study, for the GABA group, the 'Home' bottle contained a placebo identical to the gabapentin capsule, and the medication was stored in the 'Dialysis' bottle. The 'Dialysis' bottle remained in the Dialysis Unit, and the medication was administered to patients at the end of the session by the responsible technician. Participants and assessors were blinded to the treatment groups."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Though last recorded values (LOCF) is an often criticised procedure, the risk of bias was low because only one patient discontinued the intervention.
Selective reporting (reporting bias)	Low risk	Protocol: http://www.braziliantrials.com/index/view/ensaios/1169?_language=pt‐br&keywords=4rxr2c&order=%7Eensaios.patrocinador_primario; the protocol confirmed the reported outcomes. Possibly there was a mistake in the manuscript because 21 days instead of 15 days were reported in the methods.
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	Low risk	Study design appropriate; no differences in baseline‐values

Kebar 2020.

Study characteristics
Methods	RCT Active control Cross‐over design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 32; 16 in each sequence Withdrawals/dropouts: NA Age (mean ± SD): gabapentin group: 58.24 ± 8.06; hydroxyzine group: 56.7 ± 7.63 years Male sex (%): gabapentin group: 8 (59); hydroxyzine group: 8 (50) Underlying disease(s): ESRD Setting: NA Haemodialysis: yes, frequency not described
Interventions	Intervention 1: Gabapentin GBP 100 mg/day Intervention 2: Hydroxyzine 25 mg/day Route of administration: oral Duration of treatment: 14 weeks (6 weeks sequence 1–2 weeks washout – 6 weeks sequence 2) Follow‐up: no
Outcomes	Primary outcomes: pruritus severity (VAS) Secondary outcomes: itching frequency
Notes	Supported financially by Ardabil University of Medical Sciences COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on sequence generation
Allocation concealment (selection bias)	Unclear risk	No information on concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "double blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Double blind; but no further information
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or missing data reported
Selective reporting (reporting bias)	Low risk	IRCT: Comparison of the effectiveness of gabapentin and hydroxyzine in pruritus in dialysis patients
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants
Other bias	Low risk	No baseline imbalance, no carry‐over effect

Kumada 2017.

Study characteristics
Methods	RCT Placebo‐controlled, dose‐ranging study Parallel‐group design
Participants	Pruritus: cholestatic Description: patients chronic liver disease including chronic hepatitis and primary biliary cholangitis (PBC) Number of participants randomised: 317 Placebo: 103 Nalfurafine 2.5 μg: 105 Nalfurafine 5 μg: 109 Withdrawals/dropouts: 8 by week 4: Placebo: 1; Nalfurafine 2.5 μg: 2; Nalfurafine 5 μg: 5; after week 5: Placebo: 6; Nalfurafine 2.5 μg: 5; Nalfurafine 5 μg: 5 Age (mean ± SD): Placebo: 65.3 ± 10.8; Nalfurafine 2.5 μg: 65.6 ± 10.3; Nalfurafine 5 μg: 65.7 ± 10.8 Male sex (%): Placebo: 43 (41.7); Nalfurafine 2.5 μg: 46 (43.8); Nalfurafine 5 μg: 46 (42.2) Underlying disease(s): chronic liver disease including chronic hepatitis and primary biliary cholangitis (PBC) Setting: inpatient Haemodialysis: no
Interventions	Placebo: two placebo capsules Nalfurafine 2.5 μg group: one 2.5‐μg soft capsule and one placebo capsule Nalfurafine 5 μg group: two 2.5‐μg soft capsules Route of administration: oral; once daily after evening meal Duration of treatment: 12 weeks Follow‐up: week 1, 2, 3, 4, 8 and 12 assessment
Outcomes	Primary outcomes: Pruritus severity (VAS) Secondary outcomes: adverse events
Notes	Funding support of Toray Industries COI: Naoki Ando and Takanori Oh are employees of Toray Industries, Inc.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "generated an assignment table"
Allocation concealment (selection bias)	Unclear risk	After that, treatment was designated based on the assignment table.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "double blind"; probably patients and physicians
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	QUOTE: "double blind"; unclear if person that assesses the outcome was blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Though last recorded values (LOCF) is an often criticised procedure, the risk of bias was low because only one patient discontinued the intervention.
Selective reporting (reporting bias)	Unclear risk	Protocol: https://www.clinicaltrials.jp/cti‐user/trial/Show.jsp
Size of study (possible biases confounded by small size)	Unclear risk	50 to 199 participants per treatment arm
Other bias	Low risk	Study design appropriate; no differences in baseline‐values

Lahiji 2018.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: uremic Description: UP participants treated with ambulatory peritoneal dialysis (CAPD) Number of participants randomised: 40 Withdrawals/dropouts: 3 patients (but pre‐randomisation) Age (mean ± SD): Omega 3: 62.1 ± 11.6; Placebo: 61.9 ± 10.8 Male sex (%): Omega 3: (45%); Control: (50%) Underlying disease(s): ESRD Setting: outpatient Haemodialysis: yes, frequency NA
Interventions	Intervention: 3 omega‐3 capsules (each 1 g capsule of omega‐3 contained 180 mg EPA and 120 mg DHA) Placebo: 3 placebo capsules identical in shape, size, odour, taste, and color of liquid paraffin Route of administration: oral, once daily Duration of treatment: 4 weeks–6 weeks washout & crossover – 4 weeks Follow‐up: baseline, 2 and 4 weeks post intervention in each study period
Outcomes	Primary outcomes: Pruritus intensity (VAS ranging from 1 to 10) Secondary outcomes: NA
Notes	In cross‐over trials, patient characteristics have to be reported according to sequences not study drugs; however, study reported age differences; see Participants (Age). No funding source declared COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on generation of sequence
Allocation concealment (selection bias)	Unclear risk	No information on concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "double‐blinded"; both patients and investigators were blinded to the study protocol.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	QUOTE: "double‐blind"; unclear if person that assessed the outcome was blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Forty of 43 enrolled subjects completed both periods of the study.
Selective reporting (reporting bias)	Low risk	https://www.irct.ir/trial/2037
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	High risk	Results were adequately reported in this cross‐over trial; differences in baseline values for VAS score may have biased the analysis and magnitude of the effect.

Mahmudpour 2017.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 80 Intervention: 40 Placebo: 40 Withdrawals/dropouts: 7 (4 in the intervention; 3 in control group) Age (mean ± SD): total sample: 53.3 ± 15.8 ; per group: NA Male sex (%) : NA Underlying disease(s): ESRD Setting: NA Haemodialysis: yes, frequency not described
Interventions	Intervention: 10 mg (1 tablet) of montelukast daily Placebo: 10 mg (1 tablet) placebo Route of administration: oral Duration of treatment: 30 days Follow‐up: no follow‐up
Outcomes	Primary outcomes: pruritus severity (VAS) and combined score: severity and distribution of pruritus and sleep disturbance (Detailed Pruritus Scale Score) Secondary outcomes: NA
Notes	No funding source declared COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on generation of sequence
Allocation concealment (selection bias)	Unclear risk	No information on concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "All medication and placebo tablets were similar in size, shape, weight, color, and package. Clinical investigators, laboratory personnel, and patients were all masked to the treatment assignment and code breaking was done at the end of study."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "All medication and placebo tablets were similar in size, shape, weight, color, and package. Clinical investigators, laboratory personnel, and patients were all masked to the treatment assignment and code breaking was done at the end of study."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few dropouts that were comparable between groups
Selective reporting (reporting bias)	High risk	Protocol: https://clinicaltrials.gov/ct2/show/NCT02559388 Manuscript contained some outcomes that were not listed in the protocol; the Detailed Pruritus Scale was not specified as a primary outcome in the manuscript but was in the protocol.
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	Unclear risk	Baseline imbalance for the Detailed Pruritus Scale

Marin 2013.

Study characteristics
Methods	Study design: parallel‐group RCT Time frame: not reported Duration of study/follow‐up: 12 weeks
Participants	Setting: single‐centre Country: Mexico Inclusion criteria: aged 18 to 70 years on APD and having pruritus without alternative cause for more than 3 months Number: treatment group 1 (18); treatment group 2 (18) Mean age ± SD (years): treatment group 1 (56.7 ± 12.4); treatment group 2 (48.5 ± 14.6) Sex (M/F): treatment group 1 (22/8); treatment group 2 (21/9) Exclusion criteria: pre‐existing skin or liver disease, or requiring treatment of gabapentin for alternative reasons such as diabetic neuropathy
Interventions	Treatment group 1 Gabapentin (oral): 300 mg every 24 hours for 12 weeks Treatment group 2 Loratadine (oral): 10 mg every 24 hours for 12 weeks
Outcomes	Pruritus: VAS Adverse effects
Notes	Abstract‐only publication Funding: "government" COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE:"A simple randomization will be carried out by computer using the medcalc software".
Allocation concealment (selection bias)	High risk	QUOTE:"open, comparative clinical trial"
Blinding of participants and personnel (performance bias) All outcomes	High risk	QUOTE:"open, comparative clinical trial"
Blinding of outcome assessment (detection bias) All outcomes	High risk	QUOTE:"open, comparative clinical trial"
Incomplete outcome data (attrition bias) All outcomes	Low risk	5% attrition rate (2 dropouts in the gabapentin group and none in the loratidine group)
Selective reporting (reporting bias)	Low risk	All results fully and clearly reported
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 36
Other bias	Low risk	QUOTE:"The study is financed by the Hospital de Concentración ISSEMyM Satélite". No evidence of publication or funding bias

Mathur 2017.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 373 Group 1: Nalbuphine 120 mg: 120 Group 2: Nalbuphine 60 mg: 128 Group 3: Placebo: 125 Withdrawals/dropouts: 4 (Group 2: 22; Group 3: 2) Age (mean ± SD): Nalbuphine 120 mg: 55 (12); Nalbuphine 60 mg: 55 (12) Placebo: 57 (13) Male sex (%): Nalbuphine 120 mg: 58; Nalbuphine 60 mg: 54; Placebo: 59 Underlying disease(s): ESRD Setting: NA Haemodialysis: 3 times/week
Interventions	Intervention 1: nalbuphine ER tablets to a target dose of 120 mg (BID) Intervention 2: nalbuphine ER tablets to a target dose of 60 mg (BID) Placebo: matching placebo Route of administration: oral, twice daily Duration of treatment: 8 weeks Follow‐up: week 2, 3, 4, 5, 6, 7 assessment
Outcomes	Primary outcomes: Pruritus severity on NRS Secondary outcomes: itching‐related quality of life (Skindex‐10), hospital anxiety and depression score, adverse events
Notes	Funding: Trevi Therapeutics COI: V.S.M. and H.H. are consultants to Trevi Therapeutics, J.K. and P.W.C. received research grants from Trevi Therapeutics, and T.S.is an employee of Trevi Therapeutics.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE Supplement: "The randomization allocation sequence was generated by a contract research organization by personnel not otherwise connected with the trial conduct using a proprietary SAS program (SAS Institute, Cary NC) and validated SAS macros."
Allocation concealment (selection bias)	Low risk	QUOTE Supplement: "The allocation sequence was therefore inaccessible to investigative sites, study subjects, and all blinded parties within the trial." "corresponding treatment assignment was automatically assigned by the system".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Sponsor, study site personnel, and all contract research organisation personnel involved in the conduct of the trial were blinded to treatment assignment.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Sponsor, study site personnel, and all contract research organisation personnel involved in the conduct of the trial were blinded to treatment assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few dropouts
Selective reporting (reporting bias)	Unclear risk	Protocol: https://clinicaltrials.gov/ct2/show/NCT02143648 Results of the Patient Assessed Disease Severity Scale (PADS) not reported
Size of study (possible biases confounded by small size)	Unclear risk	50 to 199 participants per treatment arm
Other bias	Low risk	Study design appropriate; no differences in baseline values

Mayo 2019.

Study characteristics
Methods	RCT Placebo‐controlled; dose‐ranging study Parallel‐group design
Participants	Pruritus: cholestatic Description: PBC patients Number of participants randomised: 66 Group 1: Maralixibat 10 mg: 21 Group 2: Maralixibat 20 mg: 21 Group 3: Placebo: 24 Withdrawals/dropouts: 5 (Maralixibat 10 mg group: 3; placebo group: 2) Age (mean ± SD): Maralixibat 10 mg group: 54.7 ± 12.74; Maralixibat 20 mg group: 53.5 ± 10.53; Placebo group: 52.0 ± 9.32 Female sex (%): Maralixibat 10 mg group: 20 (95.2); Maralixibat 20 mg group: 17 (81.0); Placebo group: 23 (95.8) Underlying disease(s): Primary biliary cholangitis (PBC) Setting: NA Haemodialysis: no
Interventions	Intervention 1: once daily maralixibat 10 mg Intervention 2: once daily maralixibat 20 mg Placebo: matching placebo Route of administration: oral Duration of treatment: 13 weeks treatment period Follow‐up: assessment at week 4, 8, 13; 4‐week safety follow‐up
Outcomes	Primary outcomes: change from baseline to study endpoint (week 13/ET) in pruritus, measured by the Adult ItchRO™ weekly sum score Secondary outcomes: 5‐D‐Itch Score, quality of life, adverse events
Notes	Funding: Lumena Pharmaceuticals COI: extensive COI statement in the article (too long to display here)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on generation of sequence
Allocation concealment (selection bias)	Low risk	Patients were randomised 2:1 using an interactive web response system to receive once‐daily oral maralixibat or matching placebo
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All patients, monitors, study centre personnel, and the sponsor were blinded to treatment throughout the study.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All patients, monitors, study centre personnel, and the sponsor were blinded to treatment throughout the study.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few non‐completers; all randomised patients received at least one dose of the study drug and had at least one post baseline; ITT population
Selective reporting (reporting bias)	Low risk	https://clinicaltrials.gov/ct2/show/NCT01904058?cond=NCT01904058&draw=2&rank=1
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	Unclear risk	Only a small number of baseline values provided

Mirnezami 2013.

Study characteristics
Methods	Study design: parallel‐group RCT Time frame: 2 weeks Duration of study/follow‐up: 2 weeks
Participants	Setting: single‐centre Country: Iran Inclusion criteria: patients with CKD undergoing HD; minimum age 18 years. Number: 70 Mean age ± SD: not reported Sex: not reported Relevant comorbidities not reported Exclusion criteria: Patients with a history of skin or metabolic disease causing itching; patients who received antipruritic medications two weeks before; pregnant women
Interventions	Treatment group 1 Ondansetron (oral): 8 mg 3 times/day Treatment group 2 Loratidine (oral): 10 mg twice/day
Outcomes	Change in 10‐cm VAS scores after treatment with ondansetron and loratadine
Notes	No declared source of funding
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "randomised"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double blinded"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Change in pruritus and baseline pruritus reported
Size of study (possible biases confounded by small size)	Unclear risk	Number of participants randomised: 70
Other bias	Unclear risk	Abstract only

Mohamed 2012.

Study characteristics
Methods	Study design: parallel‐group RCT Time frame: not reported Duration of study/follow‐up: 6 months
Participants	Setting: single‐centre (inpatients) Country: Egypt Inclusion criteria: ESRD on HD; "Those who were complaining of severe pruritus as scored using the Dermatological Life Quality Index (DLQI)" Number: treatment group (25); control group (20) Mean age ± SD (years): not reported Sex: not reported Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Treatment group Sodium thiosulfate (IV): 12.5 mg, once/dialysis session for 6 months Control group Placebo (IV): once/dialysis session for 6 months
Outcomes	Severe pruritus: VAS daily at baseline and study completion
Notes	Abstract‐only publication No declared source of funding Walid Mohamed Alexandria; University Student Hospital, Elshatby, Alexandria, Egypt COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "Randomly assigned"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	High risk	No numeric results
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 45
Other bias	Unclear risk	Abstract‐only publication; poorly explained inclusion/exclusion criteria

Mortazavi  2017.

Study characteristics
Methods	Study design: cross‐over RCT Time frame: not reported Duration of study/follow‐up: 4 weeks + "washout" + 4 weeks
Participants	Setting: single‐centre (inpatients) Country: Iran Inclusion criteria: ESRD on HD with uraemic pruritus Number: 20 Mean age ± SD (years): not reported Sex: not reported Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Treatment group Fish oil (oral): 1 g, 3 times/day for 4 weeks Control group Placebo (oral): 3 times/day for 4 weeks
Outcomes	Aggregate "Pruritus score" change
Notes	Abstract‐only publication No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "randomised"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear dropout rate
Selective reporting (reporting bias)	High risk	Only group means and a nonspecific P value reported
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 20
Other bias	Unclear risk	Abstract‐only publication; insufficient information to permit judgement

Naghibi 2007.

Study characteristics
Methods	Study design: cross‐over RCT Time frame: not reported Duration of study/follow‐up: 9 weeks (1 week washout + 4‐week trial for each ordering)
Participants	Setting: single‐centre (inpatients) Country: Iran Inclusion criteria: ESKD on HD with uraemic pruritus Number: 20 Mean age ± SD (years): not reported Sex (M/F): not reported Relevant comorbidities: not reported "Gabapentin therapeutic response was not affected by age, sex, dialysis duration, cause of ESRD and pruritus duration". Exclusion criteria: referenced, but not explicitly stated
Interventions	Treatment group Gabapentin (oral): 4 weeks (dose and frequency not reported) Control group Placebo (oral): 4 weeks (dose and frequency not reported)
Outcomes	The mean difference of pruritus score (VAS) before and after treatment Adverse effects with incomplete reporting ("well tolerated")
Notes	Abstract‐only publication No funding source declared Correspondence: Dr Massih Naghibi, Department of Internal Medicine, Imam‐Reza Hospital, Mashad University of Medical Sciences (MUMS), Mashhad, Khorasan, Iran
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "On a random and blinded basis"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "On a random and blinded basis"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	QUOTE: "All of the patients completed the study".
Selective reporting (reporting bias)	Low risk	The mean difference of pruritus score (VAS) before and after treatment was fully reported. One week washout in between all interventions and controls. Carry‐ over effects unlikely
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 20
Other bias	Unclear risk	Abstract‐only publication; group level data without patient level comparisons provided; correlation may inflate SE

Najmeh 2019.

Study characteristics
Methods	RCT Active control Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: Total: 30 Withdrawals/dropouts: NA Age (mean ± SD): NA Male sex (%): NA Underlying disease(s): ESRD Setting: NA Haemodialysis: yes, frequency NA
Interventions	Intervention 1: Pregabalin 50 mg 3 x /day Intervention 2: Ketotifen 2 x /day; amount NA Route of administration: NA Duration of treatment: 4 weeks Follow‐up: NA
Outcomes	Primary outcomes: treatment efficacy (VAS) Secondary outcomes: quality of life (Itchy QoL)
Notes	Abstract‐only publication No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomisation; no further information
Allocation concealment (selection bias)	Unclear risk	No information on concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information on blinding of outcome assessment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No information on dropouts or missing data (only abstract available)
Selective reporting (reporting bias)	Unclear risk	No protocol available
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants
Other bias	Unclear risk	No information on other bias

Nofal 2016.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 54 Group 1 (Gabapentin) 27 Group 2 (Placebo): 27 Withdrawals/dropouts: no withdrawals described Age (mean ± SD): Gabapentin group: 51.5 ± 9.96; Placebo group: 52.15 ± 9.94 Male sex (%): Gabapentin group: 23 (85.2%); Placebo group: 18 (66.7%) Underlying disease(s): ESRD Setting: inpatient Haemodialysis: 3 times/week
Interventions	Intervention: gabapentin (starting with 100 mg; in cases with no significant improvement, the dose was gradually titrated up to a maximum of 300 mg after each HD session) Placebo: emptied gabapentin capsules filled with starch after each HD session Route of administration: oral Duration of treatment: 1 month Follow‐up: 1 week after end of study
Outcomes	Primary outcomes: pruritus severity (VAS, 5‐D pruritus scale) Secondary outcomes: adverse events
Notes	No funding source declared COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was done by random number list.
Allocation concealment (selection bias)	Unclear risk	No information on concealment
Blinding of participants and personnel (performance bias) All outcomes	High risk	Single‐blinded; no further information
Blinding of outcome assessment (detection bias) All outcomes	High risk	Single‐blinded; no further information
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts or missing data reported
Selective reporting (reporting bias)	Unclear risk	No protocol available
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	Unclear risk	Slight baseline imbalances for VAS without adjusting for baseline values in statistical analyses

Noshad 2011.

Study characteristics
Methods	Study design: parallel‐group RCT Time frame: 12‐month period Duration of study/follow‐up: 4 weeks
Participants	Setting: single‐centre (inpatients) Country: Iran Inclusion criteria: patients with ESKD on HD with uraemic pruritus Number: treatment group (20); control group (20) Mean age ± SD (years): treatment group (46.2 ± 12.4); control group (45.6 ± 12.4) Sex (M/F): treatment group (11/9); control group (9/11) Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Treatment group Gabapentin (oral): 100 to 200 mg/day for 4 weeks Control group Hydroxyzine (oral): 10 mg/day for 4 weeks
Outcomes	Pruritus: mean VAS at baseline and after the intervention Adverse effects
Notes	Abstract‐only publication No funding source declared COI: no author COI statements provided Correspondence: Dr Hamid Noshad, Assistant Professor of Nephrology, hamidnoshad1@yahoo.com Translated from Farsi
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "...randomised in two groups..."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind", "Patients and investigators were not aware of the medications prescribed."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Double‐blind", "Patients and investigators were not aware of the medications prescribed."
Incomplete outcome data (attrition bias) All outcomes	Low risk	All enrolled patients randomised and analysed at trial completion. No dropouts
Selective reporting (reporting bias)	Low risk	Mean and SE of VAS at baseline and after the intervention reported in full for both placebo and Gabapentin groups
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 40
Other bias	Unclear risk	Abstract‐only publication; insufficient information to permit judgement

Pakfetrat 2018.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 50 Group 1 (Sertraline) 25 Group 2 (Placebo): 25 Withdrawals/dropouts: 4 (control group) Age (mean ± SD): Sertraline group: 44.0 ± 15.5; Placebo group: 44.2 ± 17.1 Male sex (%): Sertraline group: 18 (72.0); Placebo: 16 (76.2) Underlying disease(s): ESRD Setting: inpatient Haemodialysis: 3 times/week
Interventions	Intervention: 50 mg sertraline twice daily Placebo: placebo (starch, magnesium, lactose, and talcum powder) twice daily Route of administration: oral Duration of treatment: 8 weeks Follow‐up: assessment week 2, 4, 6, 8
Outcomes	Primary outcomes: pruritus severity (VAS, DUO‐Score) Secondary outcomes: NA
Notes	Funding: The Vice‐Chancellery of Research and Technology of Shiraz COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on generation of sequence
Allocation concealment (selection bias)	Unclear risk	No information on concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "double blind"; probably patients and physicians
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	QUOTE: "double blind"; unclear if person that assessed the outcome was blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Data based on 50 patients were reported in the beginning of the results but only 46 were reported in the results tables.
Selective reporting (reporting bias)	Low risk	Protocol: https://en.irct.ir/trial/16894 Primary outcome of the protocol was reported in the publication. However, the expression primary outcome was not used in the publication.
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	Low risk	No relevant baseline imbalances

Ravindran 2020.

Study characteristics
Methods	RCT Active control Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 50 Group A (Gabapentin): 25 Group B (Pregabalin): 25 Withdrawals/dropouts: 8 (4 in each group) Age (mean ± SD): Gabapentin group: 55.29 ± 14.58; Pregabalin group: 58.1 ± 11.09 Male sex (%): Gabapentin group: 14 (66.6); Pregabalin group: 17 (80.9) Underlying disease(s): ESRD Setting: NA Haemodialysis: yes, frequency NA
Interventions	Intervention 1: Gabapentin 100 mg Intervention 2: Pregabalin 25 mg Route of administration: NA Duration of treatment: 6 weeks Follow‐up: no
Outcomes	Primary outcomes: pruritus severity (VAS, 5‐D‐Itch scale) Secondary outcomes: NA
Notes	No funding source declared COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on generation of sequence
Allocation concealment (selection bias)	Unclear risk	No information on allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	High risk	Single‐blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Single‐blinded; no further information
Incomplete outcome data (attrition bias) All outcomes	Low risk	Few dropouts that were comparable between groups, n = 4 per group
Selective reporting (reporting bias)	Unclear risk	No protocol available
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	High risk	Baseline charcteristics were not checked for between‐group differences

Rivory 1984.

Study characteristics
Methods	Study design: cross‐over RCT Time frame: 20 days Duration of study/follow‐up: 20 days
Participants	Setting: multicentre (3 sites) (outpatients) Country: France Inclusion criteria: chronic HD patients for > 1 year, suffering from pruritus evolving for more than a month Number: 13 Mean age ± SD (years): not reported Sex (M/F):7/6 Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Treatment group Nicergoline (oral): 30 mg/day Nicergoline 5 mg as a continuous IV infusion Control group Oral and IV placebo
Outcomes	VAS
Notes	No funding COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE " in a random order"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE "in double blind manner"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts reported
Selective reporting (reporting bias)	High risk	Only nonspecific, interpreted results reported
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 13
Other bias	Unclear risk	Abstract‐only publication

Rossi 2019.

Study characteristics
Methods	RCT Placebo‐controlled, dose‐ranging study Parallel‐group design
Participants	Pruritus: uremic Description: UP participants treated with haemodialysis Number of participants randomised: 21 Group 1 (Gabapentin 100): 8 Group 2 (Gabapentin 300): 5 Group 3 (Placebo): 8 Withdrawals/dropouts: 2 (gabapentin 300 mg; treatment allocation was unmasked and enrolment in this treatment arm no longer continued) Age median (range): Gabapentin 100: 60 (31–79); Gabapentin 300: 74 (50–80); Placebo: 70 (26–76) Male sex (%): Gabapentin 100: 5 (62.5); Gabapentin 300: 2 (40); Placebo: 2 (25) Underlying disease(s): ESRD Setting: NA Haemodialysis: 3 times/week
Interventions	Intervention 1: Gabapentin 100 mg; after dialysis (3 x /week) Intervention 2: Gabapentin 300 mg; after dialysis (3 x /week) Placebo: matching placebo after dialysis (3 x /week) Route of administration: oral Duration of treatment: 2 weeks Follow‐up: assessment week 0, 2, 3
Outcomes	Primary outcomes: pruritus severity (VAS) Secondary outcomes: adverse events
Notes	Funding: "This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors". COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation code
Allocation concealment (selection bias)	Unclear risk	No precise information on concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	QUOTE: "Double blind; Gabapentin 100 mg, 300 mg, and placebo tablets were blinded to patients, physicians and nurses, and were administered after each DS for 2 weeks. The treatment allocation of these two patients was then unmasked for safety concerns: both of them were in the 300 mg arm. Enrolment in this arm was no longer continued. 300 mg pills were unmasked and discarded by the designated pharmacist. Blinding was maintained thereafter, the patients being randomized only to gabapentin 100 mg or placebo."
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	QUOTE: "Double blind; Gabapentin 100 mg, 300 mg, and placebo tablets were blinded to patients, physicians and nurses, and were administered after each DS for 2 weeks. The treatment allocation of these two patients was then unmasked for safety concerns: both of them were in the 300 mg arm. Enrolment in this arm was no longer continued. 300 mg pills were unmasked and discarded by the designated pharmacist. Blinding was maintained thereafter, the patients being randomized only to gabapentin 100 mg or placebo."
Incomplete outcome data (attrition bias) All outcomes	High risk	QUOTE: "Four patients were excluded as they refused taking the drug after randomization." These patients were not evaluated in the sense of an intention‐to‐treat‐analysis. Four out of 25 patients resulted in 16%; in addition, two patients with AEs switched doses from 300 mg to 100 mg due to adverse events.
Selective reporting (reporting bias)	Unclear risk	No primary or secondary outcomes stated in the protocol: https://www.clinicaltrialsregister.eu/ctr‐search/trial/2009‐010437‐50/IT
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	High risk	Baseline imbalance for the VAS without adjustment for baseline values in the statistical analysis

Sja'bani 1997.

Study characteristics
Methods	Study design: parallel‐group RCT Time frame: not reported Duration of study/follow‐up: 5 weeks
Participants	Setting: single‐centre (inpatients) Country: Indonesia Inclusion criteria: aged 18 to 65 years on HD with pruritis Number: treatment group (15); control group (14) Mean age ± SD (years): treatment group (52.3 ± 14.7); control group (46.3 ± 9.0) Sex: not reported Relevant comorbidities: "No significant difference in sex, age, weight, height, or blood pressure" Exclusion criteria: non‐HD‐related skin or allergic pathology
Interventions	Treatment group rHuEPO (SC): 2000 UI, twice/week for 4 weeks Control group Placebo (oral): twice/week for 4 weeks
Outcomes	Pruritus score: mean VAS score at end of treatment period
Notes	Abstract‐only publications No funding source declared COI: no author COI statements provided Correspondence: Gadjah Mada University, Yogyakarta, Indonesia
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "randomised double blind study design"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Three dropouts (2 placebo, 1 rHuEPO); reasons not reported
Selective reporting (reporting bias)	Unclear risk	Baseline VAS scores not reported
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 29
Other bias	Unclear risk	Insufficient information to permit judgement

Solak 2012.

Study characteristics
Methods	RCT Active control Cross‐over design
Participants	Pruritus: uremic Description: UP or neuropathy patients on haemodialysis Number of participants randomised: 50 Group 1 (gabapentin): 25 Group 2 (pregabalin): 25 Withdrawals/dropouts: 10 (5 patients per group) Number of participants analysed: 40 Number of participants with pruritus: 29 Number of participants without pruritus: 11 Age (mean ± SD): Total sample: 58.2 ± 13.7; patients with pruritus: 57.9 ± 14.9; patients without pruritus: 59.1 ± 10.6 Male sex (%): Total sample: 12 (30); patients with pruritus: 8 (28); patients without pruritus: 4 (36) Underlying disease(s): ESRD Setting: NA Haemodialysis: 3 times/week
Interventions	Intervention 1: gabapentin: 300 mg after each haemodialysis session (thrice weekly) Intervention 2: pregabalin at a dose of 75 mg per day Route of administration: NA Duration of treatment: 6 weeks Follow‐up: no
Outcomes	Primary outcomes: pruritus severity (VAS) Secondary outcomes: pain (Short Form of McGill Pain Questionnaire SF‐MPQ)
Notes	Funding: ERA‐EDTA COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Using computer‐generated random numbers
Allocation concealment (selection bias)	Unclear risk	No information on concealment
Blinding of participants and personnel (performance bias) All outcomes	High risk	QUOTE: "This is a 14 week long, open‐label, prospective, randomized crossover study that was conducted at a private haemodialysis centre".
Blinding of outcome assessment (detection bias) All outcomes	High risk	QUOTE: "This is a 14 week long, open‐label, prospective, randomized crossover study that was conducted at a private haemodialysis centre".
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	20% dropouts in both groups; probabaly a per‐protocol analysis of a subsample of 29 patients for efficacy outcomes
Selective reporting (reporting bias)	Unclear risk	No protocol available
Size of study (possible biases confounded by small size)	High risk	Fewer than 50 participants per treatment arm
Other bias	High risk	Test of carry‐over effects not evaluated or reported appropriately but this is a critical point in cross‐over trials.

Spencer 2015.

Study characteristics
Methods	Study design: parallel RCT Time frame: not reported Duration of study/follow‐up: 15 days
Participants	Setting: multicentre (number of sites not reported) Country: USA Inclusion criteria: HD patients with persistent moderate‐to‐severe daily pruritus for 6 weeks prior Number: treatment group (33); control group (32) Mean age ± SD (years): treatment group (60 ± 12); control group (60.1 ± 16) Sex (M/F): treatment group (16/17); control group (15/17) Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Treatment group CR845 (IV) (difelikefalin): 1 µg/kg every dialysis session for 15 days Control group Placebo (IV): every dialysis session for 15 days
Outcomes	Change in itch from baseline to days 12 to 15 using VAS
Notes	Additional data obtained from poster presented at the ASN Kidney Week 2015 Annual Meeting; November 5‐8, 2015; San Diego, CA Fully supported by Cara Therapeutics, Inc. The authors received medical writing assistance from Edward Weselcouch, PhD, of PharmaWrite (Princeton, NJ), which was funded by Cara Therapeutics, Inc. RHS, JWS, and FM are employees of Cara Therapeutics, Inc. COI: no author COI statements provided Correspondence: Frédérique Menzaghi, PhD fmenzaghi@caratherapeutics.com
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "Multi‐center (21 US sites), randomised (1:1), double‐blind, placebo‐ controlled, parallel‐group Phase 2 study"
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "double‐blind, placebo‐controlled, parallel‐group Phase 2 study"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	QUOTE: "double‐blind, placebo‐controlled, parallel‐group Phase 2 study" Insufficient information to permit judgement
Incomplete outcome data (attrition bias) All outcomes	Low risk	One dropout in the placebo group, unlikely to affect outcomes
Selective reporting (reporting bias)	Low risk	Mean and SD of changes and baseline VAS score reported for both CR845 and placebo
Size of study (possible biases confounded by small size)	Unclear risk	Number of participants randomised: 65
Other bias	High risk	The present study was fully supported by Cara Therapeutics, Inc. The authors received medical writing assistance from Edward Weselcouch, PhD, of PharmaWrite (Princeton, NJ), which was funded by Cara Therapeutics, Inc. RHS, JWS, and FM are employees of Cara Therapeutics, Inc.

Subach 2001.

Study characteristics
Methods	Study design: three‐way cross‐over RCT Time frame: not reported Duration of study/follow‐up: not reported
Participants	Setting: not reported Country: USA Inclusion criteria: HD‐related itch Number: 23 participants Mean age ± SD (years): not reported Sex M/F: not reported Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Quote: "23 patient with HDI were to receive 3 doses of ondansetron 8 mg, diphenhydramine 25 mg, or matching placebo during 9 separate occasions of HDI".
Outcomes	VAS 10‐cm at 30, 60, and 120 min after administration Itch relief defined as 50% reduction in baseline. 3‐way ANOVA used for analysis
Notes	Abstract‐only publication No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "in a randomised..."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "double blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Dropouts not reported
Selective reporting (reporting bias)	Unclear risk	Unclear reporting. Assumed to be results from 120 min, but not clear. No results of the ANOVA reported
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 23
Other bias	Unclear risk	Abstract only; no declaration relating to conflicts of interest

Suwanpidokkul 2007.

Study characteristics
Methods	Study design: cross‐over RCT Time frame: 10 weeks Duration of study/follow‐up: 10 weeks
Participants	Setting: not reported Country: Thailand Inclusion criteria: HD patients with pruritus (VAS > 50 mm) Number: 19 patients (subgroups not reported) Mean age: 56.9 years Sex M/F: not reported Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Treatment group 1 Gabapentin first: 100 mg/day for 4 weeks, washout 2 weeks, then loratadine 10 mg/day for 4 weeks Treatment group 2 Loratadine first: 10 mg/day for 4 weeks, washout 2 weeks, then gabapentin 100 mg/day for 4 weeks Route not specified but implied oral
Outcomes	Itch: VAS, difference in mean change between treatment groups Adverse effects: occur during treatment of either loratadine or gabapentin
Notes	Abstract‐only publications Additional data obtained from poster presentation presented at Kidney Week 2017; New Orleans, LA; Oct 31 – Nov 5 Funded by Cara Therapeutics COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "Patients were randomised assigned".
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "double‐blinded"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Partial reporting on 5 dropouts
Selective reporting (reporting bias)	Low risk	Within‐ and between‐group changes clearly reported
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 19
Other bias	Low risk	Abstract only; no declaration relating to conflicts of interest

Tapia 1977.

Study characteristics
Methods	Study design: parallel RCT Time frame: not reported Duration of study/follow‐up: 1 week
Participants	Setting: single centre (inpatients) Country: USA Inclusion criteria: pruritis during HD, aged 16 to 65 years Number: treatment group (10); control group (10) Mean age: 39 years Sex (M/F): 13/7 Relevant comorbidities: not reported Exclusion criteria: not reported
Interventions	Treatment group Lidocaine (IV): 200 mg infused over 15 min during HD and additional 3 times if no effect Control group Placebo (IV): infused over 15 min during HD and additional 3 times if no effect
Outcomes	Itch relief or no relief (binary) after treatment vs. baseline itch status (all patients reporting itch). Unclear definition of relief Adverse effects
Notes	Supported by NIH grant COI: no author COI statements provided Correspondence: Dr Tapia Rogosin Kidney Center, New York Hospital‐Cornell Medical Center, 525 E68th St New York, NY 10021
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Table of random numbers"
Allocation concealment (selection bias)	Low risk	QUOTE: "Vial arranged in order and patient enters study area with unlabelled vials".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double Blind", "Identical vials"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "investigator unaware of vial order"
Incomplete outcome data (attrition bias) All outcomes	High risk	Four placebo patients unaccounted for in analysis
Selective reporting (reporting bias)	High risk	Simple binary response fully reported, only 6 placebo patients reported on with no explanation
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 20
Other bias	Low risk	No evidence of publication or funding bias

Tol 2010.

Study characteristics
Methods	Study design: cross‐over RCT Time frame: not reported Duration of study/follow‐up: 9 weeks (2 x 4‐week treatment periods, 1 week washout
Participants	Setting: single centre (inpatients) Country: Slovakia Inclusion criteria: CKD‐related pruritus for at least 8 weeks Number: 14 Mean age ± SD: 59.7 ± 17.2 years Sex (M/F): 7/7 Relevant comorbidities: not reported Exclusion criteria: aged < 18 years; concomitant dermatological, liver, or metabolic diseases; pregnant or lactating women
Interventions	Treatment group Gabapentin (oral): 300 mg every HD session for 4 weeks Control group Placebo (oral): every HD session for 4 weeks
Outcomes	Mean VAS Post‐sleep Inventory Mental scale Depression scale at baseline and end of treatment periods
Notes	No funding source declared COI: no author COI statements provided Correspondence: Dr Huseyin Atalay Tel: 0332‐223 72 06; Email: hatalay1971@yahoo.com
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "On a random basis..."
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Blinded"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Patient recorded VAS independent of assessors.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients enrolled completed the trial.
Selective reporting (reporting bias)	High risk	Placebo results not reported. Intervention level data without patient level comparisons provided. Carry‐over effects unlikely due to washout periods
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 14
Other bias	Low risk	No evidence of publication or funding bias

Amirkhanlou 2016.

Study characteristics
Methods	RCT Comparative trial Parallel‐group design
Participants	Pruritus: UP Description: UP participants treated with haemodialysis Number of participants randomised: 52 Number of participants evaluable: 52 Gabapentin (group G): 26 Ketotifen (group K): 26 Withdrawals/dropouts: 0 Reason for dropout: NA Age (mean ± SD): gabapentin (group G): 60.2 years ± 7.4, ketotifen (group K): 57.6 years ± 6.2 Sex (male/female): gabapentin: 12 (46.2%)/14 (53.8%); ketotifen: 13 (50%)/13 (50%) Underlying disease(s): ESRD Participant pool: single‐centre Setting: inpatient Haemodialysis: similar in frequency and method (maximum duration and frequency of haemodialysis) Baseline pruritus assessment: no Duration/severity of pruritus: NA Baseline parameters: NA
Interventions	Intervention 1: gabapentin capsule (Iran Daroo Pharmaceutical Co., Tehran, Iran) 100 mg daily for 2 weeks Intervention 2: ketotifen (Abidi Pharmaceutical Co., Tehran, Iran) 1 mg twice daily for 2 weeks Additional medication: NA Route of administration: oral Duration of treatment: 2 weeks Follow‐up: no information
Outcomes	Clinical response: complete response (no itching or minimal itching after treatment), partial response (mild or moderate severity of itching after treatment) and no response (severe pruritus after treatment) Adverse events Pruritus severity: Clinical response to treatment: (1) Complete response, (2) Partial response and (3) No response
Notes	Not reported: before and at the end of study, authors determined pruritus severity based on Shiratori's severity scores (0 = no itching, 1 = minimal, 2 = mild, 3 = moderate and 4 = severe itching) Funding: grant from Golestan University of Medical Sciences COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "Patients were randomly assigned".
Allocation concealment (selection bias)	Low risk	QUOTE: "The patients and drug distributors were not aware of the prescribed medications".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "The patients and drug distributors were not aware of the prescribed medications".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information
Incomplete outcome data (attrition bias) All outcomes	Low risk	No attrition
Selective reporting (reporting bias)	High risk	Pruritus severity was determined based on Shiratori's severity scores but not determined.
Size of study (possible biases confounded by small size)	Unclear risk	Number of participants randomised: 52
Other bias	Unclear risk	Trial was not registered.

Feily 2012.

Study characteristics
Methods	RCT Vehicle‐controlled Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD who were treated with haemodialysis Number of participants randomised: 60 Number of participants evaluable: 60 CS 4% group: 30 Placebo group: 30 Withdrawals/dropouts: 0 Reason for dropout: NA Age (mean ± SD): 53 years ± 11.4 Sex (male/female): 38 (63%)/22 (37%) Underlying disease(s): ESRD Participant pool: single‐centre Setting: inpatient Haemodialysis: 3 times per week Baseline pruritus assessment: yes Duration/severity of pruritus: for at least 6 weeks without any systemic or topical treatment for the pruritus Baseline parameters: mean VAS ± SD: Cromolyn sodium (CS 4%): 2.5 ± 1.1 Vehicle group: 2.7 ± 1.3
Interventions	Intervention 1: topical CS 4% 2 times a day starting immediately after dialysis Intervention 2: vehicle 2 times a day immediately after dialysis Additional medication: all other anti‐pruritus treatments were prohibited during the study; other routine medications were allowed. Route of administration: topical Duration of treatment: 4 weeks Follow‐up: no information
Outcomes	Pruritus assessment: VAS (0‐5, 0: no pruritus and 5: the worst pruritus) Adverse events
Notes	Results in abstract and full text (e.g. Table 13) are conflicting; we worked with the results stated in the abstract. No declared source of funding COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "[S]imple random table"
Allocation concealment (selection bias)	Unclear risk	QUOTE: "[P]atients were randomly allocated to one of the two arms of the study".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "The medications used were not revealed to their physicians". QUOTE: "A similar tube was used to store CS 4% to make both creams to look physically identical".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "The placebo was formulated by a pharmacist to have a similar base with the drug but not containing the active ingredient and stored in a tube without any labelling. A similar tube was used to store CS 4% to make both creams to look physically identical".
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts; unclear if intention‐to‐treat analysis was used
Selective reporting (reporting bias)	Unclear risk	No protocol or registration number
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 60 (30 per treatment arm)
Other bias	High risk	Results in abstract and full text (e.g. Table 13) are conflicting.

Ghanei 2012.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD who were under intermittent haemodialysis Number of participants randomised: 22 Number of participants evaluable: 22 Withdrawals/dropouts: 0 Reason for dropout: NA Age (mean ± SD): omega‐3‐placebo: 59.90 years ± 14.82, placebo‐omega‐3: 53.09 ±13.08 Sex (male/female): omega‐3‐placebo: 72%/28%, placebo‐omega‐3: 54%/46% Underlying disease(s): ESRD Participant pool: multicentre Setting: inpatient Haemodialysis (mean ± SD): omega‐3‐placebo: 3.81 ± 2.04, placebo‐omega‐3: 5.09 ± 4.88 Baseline pruritus assessment: yes Duration/severity of pruritus: for over 3 months with no response to antipruritic drugs Baseline parameters: mean (95% CI): Omega‐3: 20.3 (16.7 to 23) Placebo: 17.0 (12.4 to 21.6)
Interventions	Intervention 1: 1 g omega‐3 capsule every eight hours (1 g omega ‐ contained 180 mg of Eicosapentaenoic Acid (EPA) and 120 mg of Docosahexaenoic Acid (DHA) Intervention 2: 1 g capsule placebo every 8 hours Additional medication: All other anti‐pruritus treatments were discontinued 1 week before the study. Route of administration: oral Duration of treatment: 20 days (20 days omega‐3/placebo ‐ 14 days washout ‐ 20 days cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: Duo Pruritus Score (0‐45) Adverse events Additional outcomes: KT/V index, blood pressure, cholesterol, triglyceride, haemoglobin
Notes	No protocol or registration number No declared source of funding COI: authors declared no conflict of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	"Patients were divided into two groups randomly by alternation method".
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Fish oil and placebo capsules with the same shape and volume"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	QUOTE: "The pruritus assessment was carried out throughout the study by the same person at the start, during, and at the end of the study."
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts; unclear if intention‐to‐treat analysis was used
Selective reporting (reporting bias)	Unclear risk	No protocol or registration number
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 22
Other bias	Low risk	Small sample size

Legroux‐Crespel 2004.

Study characteristics
Methods	RCT Comparative trial Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 52 Naltrexone: 26 Loratadine: 26 Number of participants evaluable: approximately 42, number not clearly stated Withdrawals/dropouts: approximately 10/15, number not clearly stated Reason for dropout: adverse events Age: no information Sex (male/female): no information Underlying disease(s): no information Participant pool: multicentre Setting: inpatient Haemodialysis: 3 x /week in sessions of 4.2 h; mean duration of 82 months Baseline pruritus assessment: yes Duration/severity of pruritus: at least 1 month; substantial pruritus Baseline parameters: Pruritus score (measured by VAS 10‐cm): Naltrexone: 4.85 (results)/6.04 (discussion) Loratadine: 4.85 Sleep parameters (measured by VAS 10‐cm): Naltrexone: 1.44
Interventions	Intervention 1: naltrexone (50 mg/d) Intervention 2: loratadine (10 mg/d) Additional medication: no information Route of administration: oral Duration of treatment: 2 weeks Follow‐up: day 0‐7‐14
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Additional outcomes: blood urea, creatinine, creatinine clearance, calcium, phosphate, parathyroid hormone, ASTA, ALAT, alkaline phosphatases, bilirubin, haemoglobin
Notes	Compliance assessed by collecting drug boxes at the end of the study No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "This was a randomized study (drawing of lots) . . ."
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not reported; likely not blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Likely not blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Missing endpoint data for some participants
Selective reporting (reporting bias)	High risk	Missing raw data; conflicting data
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 52 (less than 50 per treatment arm)
Other bias	High risk	Conflicting data given Only 2 measurements of pruritus over the study period; most results for day 7 instead of day 14; number of participants and of withdrawals confusing; missing endpoint data

Mapar 2015.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD who were treated with haemodialysis Number of participants randomised: 40 Number of participants evaluable: 36 Zinc sulphate group: 18 Placebo group: 18 Withdrawals/dropouts: 4 Reason for dropout: zinc group, expired because of congestive heart failure (n = 1) and decreased blood sugar (n = 1); placebo: vomiting (n = 1), "did not continue the study for the itching improvement" (n = 1) Age (range): 23‐79 years Sex (men/women): 27 (67.5%)/13 (32.5%) Underlying disease(s): ESRD Participant pool: single‐centre Setting: inpatient Haemodialysis: average of 3 years; frequency: 2‐3 per week Baseline pruritus assessment: yes Duration/severity of pruritus: pruritus for more than 6 weeks Baseline parameters: Modified Duo Score (mean ± SD): Zinc sulphate group: 15.9 ± 6.3 Placebo group: 15 ± 6.0
Interventions	Intervention 1: single daily dose of 220 mg zinc sulphate Intervention 2: placebo Additional medication: no steroids or opiate analgesics; discontinuation if antipruritic agents Route of administration: oral Duration of treatment: 4 weeks Follow‐up: no information
Outcomes	Pruritus assessment: Modified Duo Score from 0 to 45, with higher scores indicating more severe symptoms; (based on severity, distribution and sleep disturbance of pruritus) Adverse events
Notes	Conclusion: "decrease and discontinuation of pruritus in hemodialytic patients" Intention‐to‐treat analysis Funding: support was provided by Ahvaz Jundishapur University of Medical Sciences COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Triple blind"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Triple blind"
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 dropouts per group
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	20 patients per group
Other bias	Unclear risk	No information about study registration

Najafabadi 2012.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: UP Description: ESRD participants under haemodialysis Number of participants randomised: 40 Number of participants evaluable: 40 Withdrawals/dropouts: 0 Reason for dropout: NA Age (mean ± SD): zinc sulphate group: 53.35 years ± 14.5, placebo group: 57.55 years ± 16.1 Sex (male/female): zinc sulphate group: 15 (75%)/5 (25%), placebo group: 14 (70%)/6 (30%) Underlying disease(s): ESRD (the cause of ESRD was determined to be: diabetes in 37.5%; hypertension in 17.5%; congenital kidney disease in 10%; glomerulonephritis in 7.5%; and other causes in 27.5%) Participant pool: multicentre Setting: no information Haemodialysis (months ± SD): Zinc sulphate group: 45.95 ± 28.8, placebo group: 52.9 ± 33.1; at least 1 month Baseline pruritus assessment: yes Duration/severity of pruritus: pruritus complaints for more than 8 weeks, not taking other oral or local anti‐pruritic drugs Baseline parameters: mean ± SD: (0 = no itching; 10 = worst pruritis) Zinc sulphate group: 7.3 ± 1.92 Placebo group: 6.3 ± 1.62
Interventions	Intervention 1: Zinc sulphate 220 mg by mouth twice daily Intervention 2: similarly shaped and coloured capsule (placebo) Additional medication: To reduce confounding variables, participants with comorbidities were advised on how to take the medications as to not interfere with the effects of zinc. Route of administration: oral Duration of treatment: 8 weeks Follow‐up: at week 12
Outcomes	Pruritus assessment: VAS (0‐10) Adverse events Additional outcomes: demographic data of patients, haemodialysis duration, cause of renal failure, pruritus score, skin examinations, possible side effects and extra‐laboratory tests
Notes	Authors' conclusion questionable: baseline differences; no group differences at all time points Authors declared no financial support from pharmaceutical companies for the present study. COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"The patients were then randomly assigned into treatment and placebo groups."
Allocation concealment (selection bias)	Unclear risk	"The patients were then randomly assigned into treatment and placebo groups."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	". . . while the other group received a similar shaped and colored capsule which was a placebo" "Neither the patients nor the physicians had any knowledge of the group to which patients were assigned."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"The patients were assigned codes, and at the end of the study the drug and placebo groups were determined by decoding."
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts; unclear if intention‐to‐treat analysis was used
Selective reporting (reporting bias)	Unclear risk	No protocol or registration number
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 40
Other bias	Unclear risk	Small baseline differences; primary outcome not stated

Nakhaee 2015.

Study characteristics
Methods	RCT Comparative trial three‐armed trial Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD who were treated with haemodialysis Number of participants randomised: 25 Number of participants evaluable: 23 Avena sativa group: 8 Vinegar solution group: 7 Hydroxyzine group: 8 Withdrawals/dropouts: 2 (vinegar solution group) Reason for dropouts: 2 kidney transplantations Age (mean ± SD): 57.04 years ± 12.20 Sex (male/female): 17 (73.9%)/6 (26.1%) Underlying disease(s): ESRD Participant pool: single‐centre Setting: inpatient Haemodialysis (mean ± SD): duration: 3.55 ± 2.78; frequency (per week): 2.57 ± 0.51 Baseline pruritus assessment: yes Duration/severity of pruritus (mean ± SD): 5.19 years ± 4.85 Baseline parameters: Intensity (mean ± SD): vinegar: 5.19 ± 1.88, avena sativa: 5.21 ± 1.69, hydroxyzine: 5.21 ± 1.82 Frequency (mean ± SD): vinegar: 1.95 ± 1.06, avena sativa: 2.30 ± 1.18, hydroxyzine: 2.04 ± 0.92 Surface % (mean ± SD): vinegar: 33.86 ± 24.11, avena sativa: 29.30 ± 23.28, hydroxyzine: 29.83 ± 22.32
Interventions	Intervention 1: avena sativa lotion (Spain), twice daily Intervention 2: vinegar solution (30 mL synthetic white vinegar 5% in 500 mL of water), twice daily Intervention 3: hydroxyzine tablet, 10 mg tablet every night Additional medication: NA Route of administration: intervention 1 and 2: topical; intervention 3: oral Duration of treatment: 2 weeks Follow‐up: no information
Outcomes	Clinical response to treatment: complete response, partial response and no response VAS: a 10‐cm long line on which 0 referred to no pruritus and 10 showed the most severe pruritus the patient could imagine Adverse events Additional outcomes: frequency, surface percentage of total body surface, verbal descriptor, consequences
Notes	Washout: 72 hours "All the patients performed the interventions completely", Financial support was received from the Research Council of Birjand University of Medical Sciences. COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Patients were assigned by random numbers to 3 groups.
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not possible due to type of interventions
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding not possible due to type of interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	2 kidney transplantations
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 23
Other bias	Low risk	The study protocol was registered in the Iranian Registry of Clinical Trials (IRCT2013021912525N1); http://www.irct.ir/searchresult.php?id=12525&number=1

Omidian 2013.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: UP Description: ESRD participants under haemodialysis Number of participants randomised: 50 Number of participants evaluable: 49 Withdrawals/dropouts: 1 Reason for dropout: no information Age (mean ± SD): 49.6 ± 12.7 years (range 18‐60) Sex (male/female): no information Underlying disease(s): ESRD Participant pool: single‐centre Setting: outpatient Haemodialysis: average dialysis time before treatment: 44 months; 3 times per week Baseline pruritus assessment: yes Duration/severity of pruritus: pruritus complaints for more than 8 weeks, not taking other oral or local anti‐pruritic drugs Baseline parameters: Nicotinamide group (mean ± SD): 2.96 ± 0.45 Placebo group (mean ± SD): 2.72 ± 0.37
Interventions	Intervention 1: oral nicotinamide (500 mg) twice a day Intervention 2: placebo; similar base with the drug but not containing the active ingredient Additional medication: All other antipruritus treatments were prohibited during the study; other routine medications were allowed. Duration of treatment: 4 weeks Follow‐up: no information
Outcomes	Pruritus assessment: VAS (0‐5) [0: no pruritus and 5: the worst pruritus] Adverse events
Notes	Results and conclusion in abstract (e.g. Table 13) conflict with the full text, i.e. different SDs, and nicotinamide and placebo seem to be interchanged No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "[S]imple random table and the study patients were randomly allocated to one of the two arms of the study".
Allocation concealment (selection bias)	Unclear risk	QUOTE: "[S]imple random table and the study patients were randomly allocated to one of the two arms of the study".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "The placebo was formulated by a pharmacist to have similar base with the drug but not containing the active ingredient". "The used medications were not revealed to the treating physicians".
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "The used medications were not revealed to the treating physicians".
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	1 patient dropped out but a reason was not given.
Selective reporting (reporting bias)	Unclear risk	No protocol or registration number
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 50
Other bias	High risk	Results and conclusion in abstract (e.g. Table 13) conflict with the full text, i.e. different SDs, and nicotinamide and placebo seem to be interchanged

Özaykan 2001.

Study characteristics
Methods	RCT Comparative trial Parallel‐group design
Participants	Pruritus: UP Description: participants on haemodialysis Number of participants randomised: 20 Group A (ondansetron): 10 Group B (cyproheptadine): 10 Number of participants evaluable: 20 (group A: 10, group B: 10) Withdrawals/dropouts: 0 Reason for dropout: NA Age: Group A (ondansetron): range 23‐63 years (median 42.90, IQR 28.57‐57.23) Group B (cyproheptadine): range 20‐58 years (median 39.50, IQR 27.90‐51.10) Sex (male/female): Group A (ondansetron): 4/6 Group B (cyproheptadine): 3/7 Underlying disease(s): no information Participant pool: single‐centre Setting: no information Haemodialysis: no information Baseline pruritus assessment: yes Duration/severity of pruritus: > 8 weeks Baseline parameters: Pruritus scoring system proposed by Duo and modified by Mettang (mean ± SD) Group A (ondansetron): 28 ± 7 Group B (cyproheptadine): 24 ± 7
Interventions	Intervention 1: ondansetron (4 mg 2 x /d) Intervention 2: cyproheptadine (2 mg/5mL 2 x /d) Additional medication: antipruritic medication was discontinued 2 weeks prior the study. Route of administration: oral Duration of treatment: 30 days
Outcomes	Pruritus assessment: Duo scale modified by Mettang 1990 (0‐48) Adverse events
Notes	Article in Turkish No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised; method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	No missing outcome data; not reported if intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	Only data for the treatment groups given; no data on single participants
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 20
Other bias	Low risk	No indication

Pauli‐Magnus 2000.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis HD (n = 18) and peritoneal dialysis (PD) (n = 5) Number of participants randomised: 23 Number of participants evaluable: 16 Withdrawals/dropouts: 7 Reason for dropouts: During naltrexone period: major gastrointestinal side effects (n = 3), lower limb amputation (n = 1); During placebo period: major gastrointestinal side effects (n = 1), cerebral ischaemia (n = 1) Period unspecified: renal transplantation (n = 1) Age (range): 20‐85 years Sex (male/female): no information Underlying disease(s): no information Participant pool: multicentre Setting: inpatient Haemodialysis: 3 x 4‐5 h/week, Kt/V > 1.2, dialysis Peritoneal dialysis: weekly, Kt/V > 2, Hb > 10 g/L Baseline pruritus assessment: yes Duration/severity of pruritus: duration > 6 months; substantial pruritus: persistent, treatment‐resistant, impairing sleep/daytime activities Baseline parameters: Pruritus score (measured by VAS 10‐cm and Duo detailed score, range 0‐45; higher values = more pruritus): Group A (naltrexone ‐ placebo): VAS 5.5, Duo detailed score 17.7 Group B (placebo ‐ naltrexone): VAS 6.5, Duo detailed score 16.8
Interventions	Intervention 1: naltrexone hydrochloride (50 mg/d single morning dose) Intervention 2: placebo Additional medication: no information Route of administration: oral Duration of treatment: 4 weeks (4 weeks naltrexone/placebo ‐ 1 week washout ‐ 4 weeks cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: VAS (10‐cm) and modified Duo score (comprising severity and distribution of pruritus and sleep disturbance) Adverse events Additional outcomes: plasma haemoglobin concentrations, serum concentrations of creatinine, urea, calcium, phosphate, alkaline phosphatase, bilirubin, transaminase, parathyroid hormone
Notes	Funding: This work was supported by the Robert Bosch Foundation and the Khalil Foundation. COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was randomised; method not stated
Allocation concealment (selection bias)	Unclear risk	Not information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis and per‐protocol analysis performed
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 23
Other bias	Low risk	Missing participant characteristics; sex and underlying disease not stated; no raw data given Assessment of compliance by collecting drug boxes at the end of each study period and taking blood samples for naltrexone measurement at randomly chosen time

Peer 1996.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 15 Group A (naltrexone‐placebo): 8 Group B (placebo‐naltrexone): 7 Number of participants evaluable: 15 Withdrawals/dropouts: 0 Reason for dropout: NA Age (years): no information Sex (male/female): no information Underlying disease(s): no information Participant pool: no information Setting: inpatient Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: persistent, treatment‐resistant pruritus Baseline parameters: Pruritus score (measured by VAS 10‐cm): Group A (naltrexone‐placebo): 9.9 Group B (placebo‐naltrexone): 9.9 Biochemical parameters: Histamine: 2.32 ß‐endorphin: 8.90
Interventions	Intervention 1: naltrexone (50 mg/d) Intervention 2: placebo (50 mg/d) Additional medication: all antipruritic therapy was stopped 1 week before the study; erythropoietin for at least 3 months before the study Route of administration: oral Duration of treatment: 7 days (7 days naltrexone/placebo ‐ 7 days cross‐over) Follow‐up: 5 participants continued treatment with the same dose of drug for 10 weeks with no pruritus. The other participants discontinued because of the high cost of naltrexone.
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Additional outcomes: plasma, endorphin, histamine
Notes	Funding: The study was supported by Travenol Laboratories, Israel. Naltrexone was given by Du Pont Pharmaceutical, USA. COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was randomised; method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data; no information on intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	No indication
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 15
Other bias	Low risk	No indication

Shirazian 2013.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: UP Description: participants with UP on haemodialysis Number of participants randomised: 50 Number of participants evaluable: 44 Withdrawals/dropouts: 6 Reason for dropouts: ergocalciferol group: 1 relocated out of town, 1 renal transplantation, 2 withdrew consent; placebo group: 1 death, 1 withdrew consent Age (mean ± SD): ergocalciferol group: 66.1 years ± 14.7, placebo group: 66.2 years ± 13.7 Sex (male/female): ergocalciferol group: 15/10 (60%/40%), placebo group: 14/11 (56%/44%) Underlying disease(s): ESRD; comorbidities in ergocalciferol and placebo groups, respectively: diabetes (n = 11, 44%;, n = 11, 44%); hypertension (n = 20, 80%; n = 23, 92%); coronary artery disease (n = 10, 40%; n = 8, 32%); congestive heart failure (n = 6, 24%; n = 5, 20%; skin condition (n = 6, 24%; n = 4, 20%) Participant pool: single‐centre Setting: outpatient Haemodialysis (mean ± SD): ergocalciferol group: 27.3 months ± 19.6, placebo group: 43.6 months ± 27.5; at least 3 months Baseline pruritus assessment: yes Duration/severity of pruritus: no information/excessive pruritus Baseline parameters: ergocalciferol group: not stated in text; read from figure: mean about 10.9 placebo group: not stated in text; read from figure: 9
Interventions	Intervention 1: ergocalciferol 50.000 IU capsule, 1 pill/week Intervention 2: placebo pills, 1 pill/week Additional medication: no information Route of administration: oral Duration of treatment: 12 weeks Follow‐up: no information
Outcomes	Pruritus assessment: Pruritus Severity Questionnaire (0‐21): "Active itching received 5 points whereas itching affecting sleep or other activities in the past few days received 4 points. Itching that was perceived as mild received 1 point, moderate received 3 points, and severe received 4 points. Localised itching received 1 point, itching in most of the body received 2 points, and itching in all of the body received 3 points. Use of medications for itching received 5 points. A maximum pruritus score on the survey was 21 points." Adverse events Additional outcomes: calcium, phosphorus, PTH, and vitamin D levels
Notes	"From the 50 patients that were dispensed study medication, 6 patients (4 in the ergocalciferol group and 2 in the control group) did not complete all study visits. These patients were included in all analyses by intention to treat." "[A]cceptable compliance was present in 41 of 50 patients, or 82%". Absolute values were only shown in figure and numbers were not stated. Funding: "This study was supported by a research grant from the Council of Renal Nutrition of the National Kidney Foundation." COI: authors declared no financial conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "[U]sing simple randomization procedures (computer‐generated random numbers)"
Allocation concealment (selection bias)	Low risk	QUOTE: "Study subjects and investigators administering study surveys to the patient were blinded to randomization assignment".
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "A research pharmacist prepackaged ergocalciferol and placebo tablets into opaque bottles."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "A research nurse, who did not participate in consent, pruritus surveys, or study analysis assigned patients to the appropriate pill bottle. The research nurse also dispensed the medication to the patient".
Incomplete outcome data (attrition bias) All outcomes	Low risk	QUOTE: "These patients were included in all analyses by intention to treat".
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting; NCT01114672 ‐ however, number not stated in the publication
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 50
Other bias	Low risk	No indication; "acceptable compliance was present in 41 of 50 patients, or 82%".

Silva 1994.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 29 Group A (thalidomide ‐ placebo): 14 Group B (placebo ‐ thalidomide): 15 Division into 3 subgroups: according to baseline scoring/proportion of responders analysed Number of participants evaluable: 18 Group A (thalidomide ‐ placebo): 11 Group B (placebo ‐ thalidomide): 7 Withdrawals/dropouts: 11 Group A (thalidomide ‐ placebo): 3 Group B (placebo ‐ thalidomide): 8 Reason for dropouts: Group A (thalidomide ‐ placebo): inadequate completion of the form (n = 3) Group B (placebo ‐ thalidomide): low pruritus score at baseline (n = 3), non‐adherence to treatment (n = 1), inadequate completion of the form (n = 4) Age (mean ± SD): Group A (thalidomide ‐ placebo): 57.5 years ± 7.3 Group B (placebo ‐ thalidomide): 50.5 years ± 11.2 Sex (male/female): Group A (thalidomide ‐ placebo): 12/2 Group B (placebo ‐ thalidomide): 5/10 Underlying disease(s): malignant nephrosclerosis (n = 11), chronic glomerulonephritis (n = 5), polycystic disease (n = 3), others (n = 10) Participant pool: no information Setting: inpatient Haemodialysis: 3 x /week for over 6 months Baseline pruritus assessment: yes Duration/severity of pruritus: no information on duration; > 25% of the maximum score during baseline Baseline parameters: Pruritus score as percent of maximum score (measured by 4‐point score; 0 = absence of itching, 1 = not interfering with usual tasks, 2 = perturbing but not interrupting usual tasks, 3 = causing interruptions of usual tasks/sleep): (mean ± SE) Group A (thalidomide ‐ placebo): 58.7% ± 6.5% Group B (placebo ‐ thalidomide): 59.0% ± 8.2%
Interventions	Intervention 1: thalidomide (100 mg 1 x /d in the evening) Intervention 2: placebo Additional medication: phosphate binders (n = 17), vitamins (n = 12), antihypertensives (n = 10), calcitriol (n = 10), iron (n = 6), H2‐blockers (n = 3), EPO (n = 2) Route of administration: oral Duration of treatment: 1 week (1 week baseline ‐ 1 week thalidomide/placebo ‐ 1 week washout ‐ 1 week cross‐over) Follow‐up: pruritus score 3 x /d; blood samples at beginning/end of each study period
Outcomes	Pruritus assessment: 4‐point score Adverse events Additional outcomes: complete blood count, plasma levels of calcium, phosphorus, magnesium, alkaline phosphatase, blood urea nitrogen
Notes	Response rate higher in participants with low baseline pruritus score; differentiation between responders and non‐responders No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "they were randomly assigned". Method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "in a double‐blind fashion"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropouts and reasons for dropouts provided; not reported if intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 29
Other bias	Low risk	Residual effect identified and participants therefore excluded from cross‐over

Smith 1997a.

Study characteristics
Methods	RCT Comparative trial Parallel‐group
Participants	Pruritus: HIV Description: participants with HIV‐1 Number of participants randomised: 40 Hydroxyzine HCl: 10 Pentoxifylline: 10 Indomethacin: 10 Triamcinolone: 10 Number of participants evaluable: 33 Hydroxyzine HCl: 8 Pentoxifylline: 9 Indomethacin: 8 Triamcinolone: 8 Withdrawals/dropouts: 7 Hydroxyzine HCl: 2 Pentoxifylline: 1 Indomethacin: 2 Triamcinolone: 2 Reason for dropouts: Hydroxyzine HCl: side effects (n = 2) Pentoxifylline: non‐compliance (n = 1) Indomethacin: non‐compliance (n = 1), side effects (n = 1) Triamcinolone: non‐compliance (n = 2) Age (years): no information Sex (male/female): no information Underlying disease(s): HIV‐1 Participant pool: no information Setting: no information Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: no information Baseline parameters: Pruritus score (Baseline: measured by 4‐point score; 1 = periodic at night only, 4 = interferes with daily activities and sleep at night): Hydroxyzine HCl: median 3 (median for compliant participants 3) Pentoxifylline: median 3 Indomethacin: median 3 Triamcinolone: median 3
Interventions	Intervention 1: hydroxyzine HCl with or without doxepin HCl at night (25 mg 3 x /d, 25 mg at bedtime) Intervention 2: pentoxifylline (400 mg, 3 x /d) Intervention 3: indomethacin (25 mg, 3 x /d) Intervention 4: triamcinolone (0.025% lotion, 120 mL/week) Additional medication: no information Route of administration: oral, oral, oral, topical Duration of treatment: 4‐6 weeks Follow‐up: no information Number lost to follow‐up: Pentoxifylline: 1 Indomethacin: 1 Triamcinolone: 2
Outcomes	Pruritus assessment: 4‐point score (1 = periodic at night only, 4 = interferes with daily activities and sleep at night) Adverse events Additional outcomes: skin lesions
Notes	No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "[W]e randomly placed patients of four different forms of therapy for their pruritus".
Allocation concealment (selection bias)	Unclear risk	QUOTE: "Patients were assigned to one of three treatment groups and a control group based on entry into the study".
Blinding of participants and personnel (performance bias) All outcomes	High risk	No information
Blinding of outcome assessment (detection bias) All outcomes	High risk	No information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Reasons for dropouts not clearly stated; per‐protocol analysis
Selective reporting (reporting bias)	Unclear risk	Inclusion and exclusion criteria inadequately described
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 40
Other bias	High risk	Duration of treatment not clearly stated (overall changes in pruritus after 4‐6 weeks of treatment were graded) Missing participant characteristics; poor additional information; study design comparing 4 treatments to placebo is problematic; assessment of compliance by asking the participants the number of pills they had left and if they had received any refills if follow‐up was longer than 4 weeks

Tarng 1996.

Study characteristics
Methods	RCT Vehicle‐controlled Cross‐over design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 19 Group A (capsaicin ‐ vehicle): 12 Group B (vehicle ‐ capsaicin): 7 Number of participants evaluable: 17 Withdrawals/dropouts: Group A (capsaicin ‐ vehicle): 2 Group B (vehicle ‐ capsaicin): 0 Reason for dropout: Group A (capsaicin ‐ vehicle): insufficient improvement (1), participant died because of myocardial infarction (1) Group B (vehicle ‐ capsaicin): NA Age (range): 27‐85 years Sex (male/female): 13/6 Underlying disease(s): no information Participant pool: single‐centre Setting: inpatient Haemodialysis: mean duration of 71.4 months (range 4‐219); 3 x 4−4.5 h/week Baseline pruritus assessment: yes Duration/severity of pruritus (mean ± SD): 33.1 ± 39.3 months; 5 had moderate, 12 had severe pruritus Baseline parameters: Pruritus score (measured by a 4‐point score, 1 = no itching, 4 = severe itching disturbing daily life and/or sleep): Capsaicin: moderate (n = 8), severe (n = 9)
Interventions	Intervention 1: capsaicin (0.025% 4x/d) Intervention 2: vehicle Additional medication: all topical agents other than moisturisers were discontinued at least 2 weeks prior the study; any ongoing medications were continued. Route of administration: topical Duration of treatment: 4 weeks (4 weeks capsaicin/placebo ‐ 2 weeks washout ‐ 4 weeks cross‐over) Follow‐up: 8 weeks (without treatment)
Outcomes	Pruritus assessment: 4‐point score (self‐assessment): 1 = no itching, 4 = severe itching disturbing daily life and/or sleep Adverse events Additional outcomes: Degrees of cutaneous burning and/or stinging sensations, dryness of skin, and erythaema over the treated area Serum albumin, calcium, inorganic phosphorus, alkaline phosphatase and intact parathyroid hormone (PTH)
Notes	Carry‐over effect up to 8 weeks after end of treatment No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Treatment order is block‐randomized with the use of computer‐generated random numbers."
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind; QUOTE: "to which both observers and patients were blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	Dropouts and reasons for dropout provided; no intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	No separate data for phase 1 reported
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 19
Other bias	Unclear risk	Poor additional information; not clear whether significant difference in itch improvement is within‐ or between‐group; assessment of compliance not stated

Terg 2002.

Study characteristics
Methods	RCT Placebo‐controlled Cross‐over design
Participants	Pruritus: CP Description: participants with cholestasis Number of participants randomised: 20 Group A (naltrexone‐placebo): 11 Group B (placebo‐naltrexone): 9 Number of participants evaluable: 18 Withdrawals/dropouts: 2 Reason for dropout: 1 because of clinical impairment due to progression of prior hepatocarcinoma, 1 because of nausea and vomiting Age: (mean ± SD) Group A: 55 ± 10, range 36‐70 years Group B: 55 ± 9, range 42‐69 years Sex (male/female): Group A: 3/8 Group B: 0/9 Underlying disease(s): PBC (n = 15), chronic hepatitis C (n = 2), PSC (n = 1), overlap syndrome (n = 1), cryptogenic cirrhosis (n = 1) Participant pool: 2 centres Setting: inpatient Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: lasting 6 to 11 months; no information on severity Baseline parameter: Pruritus score (VAS 10‐cm): (mean ± SD) Group A: 6.27 ± 1.61 (daytime), 6.52 ± 2.42 (night‐time) Group B: 6.32 ± 3.12 (daytime), 5.03 ± 2.48 (night‐time)
Interventions	Intervention 1: naltrexone (25 mg/d) 2x (9:00 h and 14:00 h) Intervention 2: placebo (25 mg/d) 2x (9:00 h and 14:00 h) Additional medication: All participants were instructed to continue with their previous medication throughout the study. Route of administration: oral Duration of treatment: 2 weeks (2 weeks naltrexone/placebo ‐ 1 week washout ‐ 2 weeks cross‐over) Follow‐up: no information
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Additional outcomes: serum bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, prothrombin time, serum albumin, platelets, red and white cell count, serum urea, creatinine, sodium, potassium, γ‐glutamyltransferase
Notes	Additional open trial: 2 additional months naltrexone for participants with at least 50% pruritus decrease (9 participants included) Funding: grant by FUNDHIG (Fundacio´n Argentina para el Estudio del Hı´gado). Laboratorios Souberian Chobet, Buenos Aires, provided naltrexone COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Randomization was generated by tables with two random numbers for each patient. These were the numbers of the bottles containing medication or placebo".
Allocation concealment (selection bias)	Low risk	QUOTE: "Information was placed in sealed, opaque, and numbered envelopes."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "This study was double‐blind".
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data; no information on intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 20
Other bias	Low risk	Assessment of pruritus by counting the pills remaining in the box

Wikström 2005a.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 51 Nalfurafine: 26 Placebo: 25 Number of participants evaluable: 48 Withdrawals/dropouts: Nalfurafine: 2 Placebo: 1 Reason for dropouts: Nalfurafine: moderate nausea and vomiting (n = 1), reason for second participant not provided Placebo: reason not provided Age (years): no information Sex (male/female): no information Underlying disease(s): ESRD Participant pool: multicentre Setting: no information Haemodialysis: no information Baseline pruritus assessment: yes Duration/severity of pruritus: severe, uncontrolled pruritus secondary to ESRD; at least 3 "worst itching" VAS measurements during run‐in period of > 50 mm and average worst itching > 25 mm Baseline parameters: Pruritus relief (measured by VAS 100‐mm): (mean ± SD) Nalfurafine: 65.3 (± 15.2) Placebo: 65.3 (± 15.0)
Interventions	Intervention 1: nalfurafine (5 µg 3 x /week immediately after their haemodialysis session) Intervention 2: placebo Additional medication: before the run‐in period, all antipruritic medications, except for topical neutral agents, were discontinued for at least 7 days. Route of administration: intravenous Duration of treatment: 4 weeks (1‐week run‐in period ‐ 4 weeks nalfurafine/placebo) Follow‐up: 2 weeks after the administration of the final dose
Outcomes	Pruritus assessment: VAS 100‐mm Adverse events
Notes	Not clear who conducted the study; not clear if and where study was published; 17 (65%) of 26 participants had adverse drug events in the nalfurafine group, but only 15 were described. No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method not stated "Seventy‐nine patients were randomly assigned in this study."
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	QUOTE: "double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Substantial missing outcome data; number of participants included unclear
Selective reporting (reporting bias)	Unclear risk	Conflicting data (number of participants included); combined results from study Wikström 2005b
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 51 (less than 50 participants per treatment arm)
Other bias	Unclear risk	Missing participant characteristics; Bergstrom effect; assessment of compliance not stated

Wolfhagen 1997.

Study characteristics
Methods	RCT Placebo‐controlled Parallel‐group design
Participants	Pruritus: CP Description: participants with cholangitis Number of participants randomised: 16 Naltrexone: 8 Placebo: 8 Number of participants evaluable: 16 Withdrawals/dropouts: 0 Reason for dropouts: NA Age: Naltrexone: range 37‐72 years (mean: 58) Placebo: range 43‐74 years (mean: 46) Sex (male/female): Naltrexone: 1/7 Placebo: 3/5 Underlying disease(s): Naltrexone: PBC (n = 8) Placebo: PBC (n = 5), PSC (n = 2), unclassified (n = 1) Participant pool: single‐centre Setting: inpatient for one day, then outpatient Haemodialysis: NA Baseline pruritus assessment: yes Duration/severity of pruritus: no information Baseline parameters: Pruritus relief (measured by VAS 100‐mm): Naltrexone: mean 65 (range: 52‐93) in the daytime; mean 59 (range: 8‐92) in the night‐time Placebo: mean 48 (range:18‐80) in the daytime; mean 47 (range: 7‐80) in the night‐time
Interventions	Intervention 1: naltrexone (50 mg) Intervention 2: placebo Additional medication: UDCA (n = 8), anion binders (n = 7), antihistamines (n = 3), rifampicin (n = 3), light therapy (n = 2), plasmapheresis (n = 1) Route of administration: oral Duration of treatment: 4 weeks Follow‐up: twice before randomisation ‐ after 2 weeks ‐ after 4 weeks
Outcomes	Pruritus assessment: VAS 100‐mm Adverse events Additional outcomes: Withdrawal‐like symptoms, blood pressure, heart rate, liver function (bilirubin, transaminase, alkaline phosphatase), serum creatine, albumin, total bile salt, prothrombin time Scratch lesions
Notes	Study described participants as responders and non‐responders. No funding source declared COI: no author COI statements provided
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Patients were randomly assigned (using opaque envelopes)."
Allocation concealment (selection bias)	Low risk	Opaque envelopes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Low risk	No dropouts; not reported if intention‐to‐treat analysis
Selective reporting (reporting bias)	Low risk	Study free of selective outcome reporting
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 16
Other bias	Low risk	"Treatment compliance, assessed by pill counts, was 100%".

Young 2009.

Study characteristics
Methods	RCT Vehicle‐controlled Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD on haemodialysis Number of participants randomised: 28 1% pramoxine HCl lotion: 14 Cetaphil lotion: 14 Number of participants evaluable: 27 1% pramoxine HCl lotion: 13 Cetaphil lotion: 14 Withdrawals/dropouts: 1 Reason for dropout: unrelated subject death Age (range): 18‐70 years Sex (male/female): 14/14 Underlying disease(s): ESRD Participant pool: single‐centre Setting: inpatient Haemodialysis: at least 3 months Baseline pruritus assessment: yes Duration/severity of pruritus: symptoms of itch in a regular pattern over 6 months; at least 2 episodes of itch > 2 minutes within 2 weeks Baseline parameters: (mean ± SD) Pruritus relief (measured by VAS 10‐cm): 5.5 (no SD) Quality of life (measured by Investigator Global Assessment, 0‐6, higher values = worse): 4.11 ± 1.13 Burning/stinging (measured by scale 1‐3): 0.14 ± 0.45
Interventions	Intervention 1: pramoxine HCl (1%) Intervention 2: moisturising lotion (Cetaphil) Additional medication: no information Route of administration: topical to all affected areas of pruritus/2 x daily Duration of treatment: 4 weeks Follow‐up: baseline ‐ week 1‐week 4
Outcomes	Pruritus assessment: VAS 10‐cm Adverse events Additional outcomes: Erythaema, xerosis, and lichenification (assessed by a 3‐point Likert scale with '0' indicating no symptoms and with '3' representing severe) Individual pruritus history and assessment questionnaire Investigator Global Assessment (IGA) of response to treatment Skin hydration measurements using the MoistureMeter pico
Notes	Funding obtained from Stiefel Laboratories Dr. Fleischer has the following potential conflicts covering the past 5 years: Advisory Board ‐Amgen, Astellas, Galderma, Stiefel; Consultant ‐ Astellas, Combe, Galderma, Gerson, Lehrman, Intendis, Kikaku America International, Merz; Investigator ‐ 3M, Abbott, Amgen, Biogen, Dow, Coria, Galderma, GSK, Genentech, Healthpoint, lntendis, Medicis, Novartis, Ortho‐Neutrogena, Pfizer, Steifel; Speaker Bureau Amgen, Astellas, Connetics, Coria, Ferndale, Galderma, Intendis, Medicis, Novartis; Stockholder ‐None. Tte other authors had no conficts of interest to disclose.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomised; method not stated
Allocation concealment (selection bias)	Unclear risk	No information provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No information provided
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	One participant lost because of unrelated subject death; not reported if intention‐to‐treat analysis
Selective reporting (reporting bias)	Unclear risk	Inclusion and exclusion criteria inadequately described; insufficient data on pruritus VAS (no confidence interval, only graphical illustration)
Size of study (possible biases confounded by small size)	High risk	Number of participants randomised: 28
Other bias	Unclear risk	Assessment of compliance not stated; possible carry‐over effect not mentioned

Yue 2015.

Study characteristics
Methods	RCT Placebo‐controlled three‐armed trial Parallel‐group design
Participants	Pruritus: UP Description: participants with ESRD who were treated with haemodialysis Number of participants randomised: 188 Number of participants evaluable: 179 Pregabalin group: 62 Ondansetron group: 60 Placebo group: 57 Withdrawals/dropouts: 9 Reason for dropouts: pregabalin: somnolence: 3; dizziness: 1; loss of balance: 1; ondansetron: nausea and vomiting: 2; kidney transplantation: 2 Age (mean ± SD): pregabalin: 57.7 ± 16.9, ondansetron: 56.5 ± 12.7, placebo: 57.2 ± 10.8 Sex (% male sex): pregabalin: 62.9%, ondansetron: 60.0%, placebo: 57.9% Underlying disease(s): ESRD Participant pool: single‐centre Setting: inpatient Haemodialysis (mean ± SD): pregabalin: 56.5 months ± 12.2, ondansetron: 57.6 months ± 16.2, placebo: 54.9 months ± 10.7 Duration/severity of pruritus: all patients suffered from persistent pruritus. Baseline parameters: VAS (0‐10) (mean ± SD): pregabalin: 8.0 ± 2.2, ondansetron: 7.9 ± 1.8, placebo: 7.7 ± 1.5 Modified Duo's VAG Scale (mean ± SD): pregabalin: 31.2 ± 8.9, ondansetron: 29.4 ± 7.5, placebo: 28.9 ± 9.2 Quality of life (SF‐12 MCS) (mean ± SD): pregabalin: 41.2 ± 13.4, ondansetron: 39.6 ± 10.1, placebo: 40.5 ± 12.9
Interventions	Intervention 1: pregabalin: 75 mg twice‐weekly Intervention 2: ondansetron: 8 mg/d Intervention 3: placebo Additional medication: the use of concomitant pruritus medications was not allowed. Route of administration: oral Duration of treatment: 12 weeks Follow‐up: no information
Outcomes	Pruritus assessment: VAS: 10‐cm horizontal line marked from 0 (no pruritus) to 10 (worst possible imaginable pruritus) Modified Duo's VAG: scale ranges from 0 to 40, with higher scores indicating more severe symptoms (based on criteria such as scratching, severity, frequency, distribution of pruritus, number of sleeping hours, and frequency of waking‐up during the night for scratching) Adverse events Additional outcomes: Health‐related quality of life: Mental Component Summary scale (MCS) from the 12‐item short‐form (SF‐12; version 2); SF‐12 was scored from 0 to 100, with higher scores indicating better HRQoL
Notes	Imprecise: the primary end point of the study was to compare the effects between pregabalin and ondansetron on UP in dialysis patients. No funding source declared COI: authors declared no conflict of interest.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "Patients were randomly assigned".
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not stated
Incomplete outcome data (attrition bias) All outcomes	Low risk	Reason for dropouts: pregabalin: somnolence: 3; dizziness: 1; loss of balance: 1; ondansetron: nausea and vomiting: 2; kidney transplantation: 2
Selective reporting (reporting bias)	Low risk	Primary outcomes stated; no information about registration of the study
Size of study (possible biases confounded by small size)	Unclear risk	QUOTE: "The 179 patients included 62 cases from the pregabalin group, 60 from the ondansetron group, and 57 from the placebo group".
Other bias	Unclear risk	No information about registration of the study

ALAT: glutamate‐pyruvat‐transaminase; ANOVA: analysis of variance; APD: ambulatory peritoneal dialysis;  ASTA: glutamate‐oxalacetat‐transaminase; BID:  twice a day; CI: confidence interval; CAPD: continious ambulatory peritoneal dialysis;  CKD: chronic kidney disease; COI: conflict of interest; CP: cholestatic pruritus; CR845: difelikefalin;  CS: cromolyn sodium; CVA: cerebrovascular accident;  DHA: docosahexaenoic acid; DLQI: dermatology life quality index;  DM: diabetes melitus; DS: dialysis; EDTA: ethylenediaminetetraacetic acid  EPA:  eicosapentaenoic acid; EPO: erythropoietin; ER: extended release; ERA: European Renal Association; ESKD: end stage renal kidney disease;    ESRD: end‐stage renal disease; ET: early termination; F: female; Hb: hemoglobin; HCI: hydrochloride; HD: haemodialysis; HDI: hemodialysis; HIV: human immunodeficiency virus; HRQoL: health related quality of life;  HSA: hourly scratching activity; IGA: investigator globasl assessment; IQR: interquartile range; ITT: intention to treat; IV: intravenous; KT/V: number used to quantify hemodialysis treatment adequacy;  LOCF: last observer carried forward; M: male; MEN2A: multiple endocrine neoplasia type 2A; MOS: medical outcome study; NA: not applicable/available; NAS: numerical analogue scale; NRS: numeric rating scale;  PADS: patient assessed disease severity scale;  PBC: primary biliary cholangitis; PD: peritoneal dialysis; PP: per protocol; PSC: primary sclerosing cholangitis; iPTH: intact parathyroid hormone; QoL: quality of life;  RCT: randomised controlled trial; SC: subcuntanous;  SD: standard deviation; SE: standard error;  SF‐12 MCS: Short Form 12 Health Survey, mental health composite score; SF‐MPQ: short form McGill pain questionaire;  UDCA: ursodeoxycholic acid; UP: uraemic pruritus; VAS: visual analogue scale; WII: worst itch intensity;  WI‐NRS: worst itch numeric rating scale 

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Afrasiabifar 2016	Complementary therapy: sweet almond oil
Almasio 2000	Study intervention targeted on the treatment of underlying disease
Anggraini 2020	Participants did not meet inclusion criteria
Aperis 2010	Not an RCT
Aramwit 2012	Complementary therapy: sericin cream
Aymard 1980	Not an RCT
Balaskas 1998	Not an RCT
Bergasa 1991	Not an RCT
Bergasa 1992	Not an RCT
Bergasa 1995	Did not meet inclusion criteria concerning palliative care patients
Bergasa 1999	Did not meet inclusion criteria concerning palliative care patients
Berman 1998	Not an RCT
Bigliardi 2007	Did not meet inclusion criteria concerning palliative care patients
Bousquet 1989	Not an RCT
Breneman 1992b	Not an RCT
Castello 2011	Not an RCT
Chen 2006	Not a pharmacological intervention as defined in inclusion criteria, will be included in an additional review
Datta 1966	Not an RCT
Davis 2003	Not an RCT
Easton 1978	Not an RCT
Fjellner 1979	Not an RCT
Giovanetti 1995	Not an RCT
Goicoechea 1999	Not an RCT
Goncalves 2010	Not an RCT
Hegade 2017	Pruritus not primary endpoint
Hellier 1963	Not an RCT
Jones 2005	Not an RCT
Jones 2007	Did not meet inclusion criteria concerning palliative care patients
Juby 1994	Not an RCT
Kato 2001	Not an RCT
Korfitis 2008	Not an RCT
Kuypers 2004	Not an RCT
Lysy 2003	Did not meet inclusion criteria concerning palliative care patients
Mansour‐Ghanaei 2006	Not an RCT
Marquez 2012	Not an RCT
Metze 1999a	Not an RCT
Montero 2006	Not an RCT
Müller 1998a	Did not meet inclusion criteria concerning palliative care patients
Müller 1998b	Did not meet inclusion criteria concerning palliative care patients
Pakfetrat 2014	Complementary medicine: turmeric
Podesta 1991b	Not an RCT
Price 1998	Not an RCT
Prieto 2004	Not an RCT
Razeghi 2009	Not an RCT
Rehman 2018	Pruritus not primary endpoint
Reig 2018	Pruritus not primary endoint
Rifai 2006	Not an RCT
Sadeghnejad 2021	Complementary intervention: ostrich oil
Shavit 2013	Not RCT
Ständer 2009	Did not meet inclusion criteria concerning palliative care patients
Szepietowski 2005	Not an RCT
Tan 1990	Complementary: sana lotion
Tokgöz 2005	Not an RCT
Woolf 1990	Pruritus not primary endpoint
Yoshimoto‐Furuie 1999	Complementary therapy: primose oil

RCT: randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

NCT01852318.

Study name	A multicenter, double‐blind, randomized, placebo and active‐controlled study of pregabalin for the treatment of uremic pruritus
Methods	Multicentre, randomised, double‐blind, placebo‐controlled, parallel assignment, phase 4
Participants	210 haemodialysis patients
Interventions	Group 1: pregabalin 75mg; drug: fexofenadine 60 mg Group 2: placebo
Outcomes	Changes in pruritus symptoms assessed by VAS; changes in pruritus score (PS), Skindex‐10, brief itching inventory and itch medical outcomes study
Starting date	April 2014
Contact information	Hsien‐Yi Chiu, MD (extra.owl0430@yahoo.com.tw); Tsen‐Fang Tsai, MD (tftsai@yahoo.com)
Notes	The recruitment status of this study is unknown because the information has not been verified recently (since 2014).

NCT02032537.

Study name	Efficacy of calmmax cream in the management of chronic uremic pruritus
Methods	Prospective, double‐blind, placebo‐controlled, randomised trial, single group assessment
Participants	28 participants with UP
Interventions	Group 1: callmax cream application over affected skin Group 2: placebo
Outcomes	Improvement of UP measured by reduction of VAS by more than 50 percent from baseline score; quality of life assessed by questionnaire
Starting date	November 2014
Contact information	Dr. Linda Shavit (lshavit@szmc.org.il)
Notes	The recruitment status of this study is unknown because the information has not been verified recently (since 2014).

NCT02229929.

Study name
Methods	RCT
Participants	Prospective, double‐blind, placebo‐controlled, randomised trial,
Interventions	The primary purpose of this study is to: Evaluate the safety and pharmacokinetic profile of repeated doses iv CR845 over one week in patients who are undergoing hemodialysis. (part A) This study is also investigating whether repeated doses of iv CR845 over two weeks is safe and effective in reducing the intensity of itching in hemodialysis patients with uremic pruritus (part B).   Drug: part A: Placebo Drug: part A: CR845 0.5 mcg/kg Drug: part A: CR845 1.0 mcg/kg Drug: part A: CR845 2.5 mcg/kg Drug: part B: Placebo Drug: part B: CR845 1.0 mcg/kg
Outcomes	part A: determine the pharmacokinetics of repeated doses of CR845 in hemodialysis patients (half‐life, Cmax, Tmax, AUC, Vd) [time frame: 1 week ]. To evaluate the pharmacokinetics of repeated doses of CR845 in hemodialysis patients over a one‐week treatment period.   part B: change in worst Itching intensity using a 100‐mm visual analog scale [time frame: 2 weeks ]. Change from baseline to the average of week 2 worst itching (daytime and nighttime) VAS where 0 mm represents "no Itch" and 100 mm represents the "worst Itch you can imagine"
Starting date
Contact information
Notes	completed

NCT02696499.

Study name
Methods	Randomised, double blind, placebo‐controlled, parallel‐arm, multicentre, phase 2, proof‐of‐concept efficacy and safety study
Participants	Patients with end‐stage renal disease requiring haemodialysis
Interventions	Group 1: 40 mg PA101B administered via inhalation twice daily for 7 weeks; Group 2: matching placebo administered via inhalation twice daily for 7 weeks
Outcomes	Primary outcome: itching intensity (numerical rating scale) Secondary outcomes: pruritus‐specific quality of life (Skindex‐10), pruritus‐specific sleep quality (itch MOS), assessment of depression (Beck Depression Inventory‐II), patient global impression of change
Starting date
Contact information
Notes	This study is ongoing, but not recruiting participants. First received: 25 February 2016

NCT02701166.

Study name	The effect of bezafibrate on cholestatic itch (FITCH)
Methods	Randomised, double blind, placebo‐controlled, parallel‐arm, multi‐centre efficacy study
Participants	Primary biliary cholangitis or primary/secondary sclerosing cholangitis
Interventions	Group 1: bezafibrate 400 mg per day Group 2: placebo 400 mg per day
Outcomes	Proportion of patients with a reduction in itch intensity of 50% or more
Starting date	First received 8 March 2016
Contact information	Ulrich Beuers, Prof. Dr. +31205662422 u.h.beuers@amc.uva.nl
Notes	This study was recruiting participants at the time of writing, but was not updated since 2016

NCT02811783.

Study name	A double blind randomized vehicle controlled crossover study to evaluate the safety and efficacy of topical naloxone hydrochloride lotion 0.5% for the relief of pruritus in patients with the MF or SS forms of cutaneous T‐Cell lymphoma
Methods	Multicentre, double‐blind, vehicle‐controlled, randomised cross‐over design study
Participants	160
Interventions	Active comparator: naloxone hydrochloride lotion, 0.5% naloxone hydrochloride Placebo comparator: placebo lotion
Outcomes	Primary outcome measures : Numeric rating ccale (NRS) for pruritus [time frame: baseline and 2 weeks]. Change from baseline to day 14 in average NRS for pruritus for each treatment period Secondary outcome measures : Responder analysis ‐ the difference in the proportion of subjects with a meaningful clinically significant improvement at the end of the two periods. [time frame: baseline and 2 weeks]. The difference in the proportion of subjects with a meaningful clinically significant improvement at the end of the two periods. A clinically significant improvement is defined as an improvement of at least one category on the 4‐point (none, mild, moderate, severe) Likert Scale verbal rating scale (VRS) and at least two points on the 11‐point NRS for pruritus. The NRS for pruritus scores will be converted to VRS scores as follows for the analysis: 0 = none, 1‐3 = mild, 4‐6 = moderate, and 7‐10 = severe. Numeric Rating Scale for sleep [time frame: baseline and 1 and 2 weeks]. The change from baseline at each week of the NRS for sleep average score for each treatment period. Numeric Rating Scale for pruritus [time frame: baseline and 1 week]. The change from baseline at week 1 of the NRS for pruritus average score for each treatment period. Categorical Rating Scale (CRS) for skin integrity [time frame: baseline and 2 weeks]. The change from baseline at week 2 of the CRS for skin integrity for each treatment period. Pruritus Quality of Life Score (PQOL) [time frame: baseline and day 14 of each treatment period]. The change from baseline in the final categorisation of the PQOL at day 14 of each treatment period
Starting date	2017
Contact information	Contact 1: Scott B Phillips 8473628200 scott@eloracpharma.com Contact 2: Heidi Fezatte 8473628200 hfezatte@eloracpharma.com
Notes

NCT03905330.

Study name	MRX‐502: Randomized double‐blind placebo‐controlled phase 3 study to evaluate the efficacy and safety of maralixibat in the treatment of subjects with progressive familial intrahepatic cholestasis (PFIC) ‐ MARCH‐PFIC
Methods	Randomised, double‐blind, placebo‐controlled, parallel assignment, phase 3
Participants	30
Interventions	Maralixibat: participants will be randomised to Maralixibat oral solution (up to 600 microgram per kilogram [mcg/kg]) orally twice daily for 26 weeks. Placebo comparator: placebo participants will receive placebo matched to maralixibat oral solution twice daily for 26 weeks.
Outcomes	Primary outcome measures : Treatment response as measured by the mean change in pruritus severity as assessed by the Observer‐rated Itch Reported Outcome (ItchRO [Obs]) [time frame: between baseline and week 15 through 26]. Compare the average before midday (AM) Observer Itch Reported Outcome (ItchRO[Obs]) pruritus severity score between participants on active treatment versus placebo Secondary outcome measures : Treatment response as measured by the mean change in pruritus frequency as assessed by the Observer‐rated Itch Reported Outcome (ItchRO [Obs]) [time frame: between baseline and week 15 through 26]. Compare the average before midday (AM) Observer Itch Reported Outcome (ItchRO[Obs]) pruritus frequency score between participants on active treatment versus placebo Mean change in total serum bile acids [time frame: between baseline and week 26]. Compare normalisation or reduction in total serum bile acids between participants on active treatment versus placebo
Starting date	2019
Contact information	Clinical Trials Mirum +16506674085 clinicaltrials@mirumpharma.com
Notes

NCT03995212.

Study name	Study to evaluate the safety and efficacy of oral CR845 (Difelikefalin) in patients with primary biliary cholangitis (PBC) and moderate‐to‐severe pruritus
Methods	A multicentre, double‐blind, randomised, placebo‐controlled Study
Participants	60
Interventions	Drug: CR845 1.0 mg Placebo
Outcomes	Primary outcome measures: Change from baseline to week 16 with respect to the weekly mean of the daily 24‐hour worst itching intensity numeric rating scale (WI‐NRS) score. [time frame: baseline, week 16]. Intensity of itch will be measured using an NRS used to indicate the intensity of the worst itching over the past 24 hours using a 0 to 10 numeric rating scale, where "0" represents "no itching" and "10" represents "worst itching imaginable".
Starting date	2019
Contact information	clinicaltrials.gov@caratherapeutics.com
Notes

NCT04470154.

Study name	A multi‐center, randomized, double‐blind, placebo‐controlled phase II clinical trial evaluating the safety, pharmacokinetics, and efficacy of HSK21542 injection in subjects undergoing hemodialysis
Methods	Multicentre, randomised, double‐blind, placebo‐controlled, parallel assignment, phase 2
Participants	120
Interventions	Drug: HSK21542 0.05 μg/kg, 0.15 μg/kg, 0.30 μg/kg, 0.80 μg/kg. Following the principle of dose escalation and starting from the low dose of 0.05 μg/kg to the high dose 0.80 μg/kg Drug: placebo 0.05 μg/kg, 0.15 μg/kg, 0.30 μg/kg, 0.80 μg/kg. Following the principle of dose escalation and starting from the low dose of 0.05 μg/kg to the high dose 0.80 μg/kg Drug: HSK21542 0.3 μg/kg, 0.6 μg/kg HSK21542 dose 0.3 μg/kg or 0.6 μg/kg Drug: placebo 0.3 μg/kg,0.6 μg/kg. Placebo dose 0.3 μg/kg or 0.6 μg/kg
Outcomes	Primary outcome easures : Adverse events (AEs) and serious adverse events (SAEs) [time frame: from screening up to 24 weeks ] Vital signs: Systolic and diastolic blood pressure [time frame: from screening up to 24 weeks]. Vital signs (systolic and diastolic blood pressure) will be collected in subjects. At week 12, the change in weekly average of daily Worst Itch NRS (WI‐NRS) from baseline in subjects undergoing haemodialysis [time frame: from screening up to 12 weeks] Secondary outcome measures : Peak concentration (Cmax) [time frame: first dose of study drug on day 1] Terminal half‐life (t1/2) [time frame: first dose of study drug on day 1] Time to peak concentration (Tmax) [time frame: first dose of study drug on day 1] Clearance (CL) [time frame: first dose of study drug on day 1] At week 12, the proportion of subjects undergoing haemodialysis whose change in weekly average of daily Worst Itch NRS (WI‐NRS) improved by ≥ 3 from baseline [time frame: from screening up to 12 weeks]
Starting date	2021
Contact information	Liu xiao 15921176768 liux1@haisco.com
Notes

NCT04660773.

Study name	Narrow band UVB phototherapy versus pregabalin in treatment of refractory pruritus in ESRD
Methods	Randomised, parallel assignment, open‐label
Participants	40
Interventions	Active comparator: NB UVB phototherapy (20 patients): they will receive NB UVB phototherapy 3 sessions per week for 2 months. Active comparator: pregabalin (20 patients); they will receive pregabalin oral therapy (50 mg after each dialysis session) for 2 months.
Outcomes	Primary outcome measures : 5 D‐itching scale [time frame: two months]: assessment of degree, duration, direction, disability and distribution of itching
Starting date	2021
Contact information	marwa eldeeb 01200029774 marwa.eldeeb16@alexmed.edu.eg
Notes

NCT04663308.

Study name	A randomized double‐blind placebo‐controlled study to evaluate the efficacy and safety of volixibat in the treatment of cholestatic pruritus in patients with primary sclerosing cholangitis
Methods	Randomised, double‐blind, placebo‐controlled, parallel assignment, phase 2
Participants	200
Interventions	Volixibat 20 mg: participants randomised to this arm will receive volixibat 20 mg twice daily. Experimental: volixibat 80 mg: Participants randomised to this arm will receive volixibat 80 mg twice daily. Placebo comparator: placebo participants in this arm will receive capsules matched to the study drug minus the active volixibat substance, twice daily.
Outcomes	Primary outcome measures : Mean change in the daily itch scores using the adult itch reported outcome (Adult ItchRO) questionnaire [time frame: baseline through to week 28]. The adult ItchRO is an 11‐point NRS measurement of itch severity ranging from 0 = no itch to 10 = worst possible itch.
Starting date	2020
Contact information	Clinical Trials Mirum +16506674085 clinicaltrials@mirumpharma.com
Notes

NCT04728984.

Study name	A multi‐site bridging study of nalfurafine hydrochloride orally disintegrating tablet
Methods	A randomized, double‐blind, placebo‐controlled, multisite bridging clinical study
Participants	135
Interventions	Nalfurafine hydrochloride 2.5 μg * 2 Nalfurafine hydrochloride 2.5 μg + a placebo pill Two placebo pills
Outcomes	Primary outcome measures : Variation in VAS of nalfurafine hydrochloride versus placebo [time frame: up to 38 (+1) days]. The variation = the mean of the daily maximum VAS value during the observation period before administration(D8‐14) ‐ the mean of the daily maximum VAS value during the administration period (D25‐31). Only the days on which the VAS values were recorded during the day and night were evaluated.
Starting date	2021
Contact information	chenjianghua@zju.edu.cn
Notes

NCT04950127.

Study name	Global linerixibat itch study of efficacy and safety in primary biliary cholangitis (PBC) (GLISTEN)
Methods	Randomized, placebo controlled, double blind, multicenter, phase 3 Study
Participants	230
Interventions	Drug: linerixibat Drug: placebo
Outcomes	Primary Outcome Measures : Change from baseline in monthly itch scores over 24 weeks using Numerical Rating Scale (NRS) [time frame: baseline and up to 24 weeks]. Monthly itch score will be assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching.
Starting date	2021
Contact information	GSKClinicalSupportHD@gsk.com
Notes

NCT04999787.

Study name	A clinical trial evaluating the efficacy, safety, and pharmacokinetics of HSK21542 injection in liver disease subjects with pruritus
Methods	A multi‐center, randomized, double‐blind, placebo‐controlled phase II clinical trial
Participants	90
Interventions	HSK21542‐0.3 μg/kg HSK21542‐0.6 μg/kg Placebo
Outcomes	Primary outcome measures : Changes in daily worst itching intensity numerical rating scale (WI‐NRS) scores from baseline during the administration period [time frame: day 1 to day 28]. In the NRS score, 0‐10 represents different degrees of itching, the larger the number, the more severe the itching.
Starting date	2021
Contact information
Notes

NCT05075408.

Study name	To evaluate the efficacy and safety of nemolizumab for 12 weeks in participants with chronic kidney disease with associated severe pruritus (Nemo CKDaP)
Methods	A multicenter, double‐blind, randomized, placebo‐controlled study
Participants	252
Interventions	Three arms: Nemolizumab for 4 weeks Nemolizumab for 12 weeks Placebo
Outcomes	Primary outcome measures : Proportion of participants with an improvement of >= 4 from baseline in worst itch numeric rating scale (WI NRS) at week 12 [time frame: baseline, week 12]. The WI NRS is a scale that will be used by the participants to report the intensity of their worst pruritus (itch) during the last 24 hours. For maximum itch intensity: the scores are provided on a scale of 0 to 10, with 0 being 'no itch' and 10 being 'worst itch imaginable'. Higher scores indicate worse outcome.
Starting date	2021
Contact information	clinical.studies@galderma.com
Notes

NCT05180968.

Study name	Dialysis symptom control‐pruritus outcome trial (DISCO‐POT)
Methods	A randomized blinded placebo controlled cross‐over trial
Participants	12
Interventions	Nabilone 0.5 mg Placebo
Outcomes	Primary outcome measures : Change from baseline in worst uremic pruritis severity rating between treatment arms relative to MID [time frame: Measured at study baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ]. Measured using visual analogue scale (VAS)
Starting date	2022
Contact information	mpinder2@sogh.mb.ca
Notes

NCT05341843.

Study name	Sertraline effect in uremic pruritis
Methods	A double‐blinded study
Participants	50
Interventions	Group A: 25 patients will receive sertraline at the intended dose of 50 mg twice daily for 8 weeks. Group B: 25 patients will receive a placebo.
Outcomes	Primary outcome measures : Change in uremic pruritis intensity [time frame: 8 weeks]. Assessment of pruritis will be done before and after the course of treatment (8 weeks) through the following scores: Visual analogue scale (VAS II) 5D‐itch scale
Starting date	2022
Contact information	dr_mohamedmamdouh87@yahoo.com
Notes

NCT05342623.

Study name	A study to evaluate the safety and efficacy of difelikefalin in advanced chronic kidney disease patients with moderate‐to‐severe pruritus and not on dialysis
Methods	A multicentre, randomised, double‐blind, placebo‐controlled 12‐week study
Participants	400
Interventions	Difelikefalin 1 mg oral tablet Placebo
Outcomes	Primary 0utcome measures : Efficacy assessment phase (treatment period 1): Proportion of subjects achieving at least a 4‐point improvement from baseline with respect to the weekly mean of the daily 24‐hour WI‐NRS score at week 12 of treatment period 1 [time frame: Week 12 of treatment period 1]. Intensity of itch will be measured using an NRS used to indicate the intensity of the worst itching over the past 24 hours using a 0 to 10 numeric rating scale, where "0" represents "no itching" and "10" represents "worst itching imaginable".
Starting date	2022
Contact information	clinicaltrials.gov@caratherapeutics.com
Notes

ESRD: end‐stage renal disease; IV: intravenous; MOS: medical outcomes scale; NA: not available/applicable; UP; uraemic pruritus; VAS: visual analogue scale.

Differences between protocol and review

Differences protocol to review (Xander 2013):

• Only randomised controlled trials were included. We did not include controlled trials or observational studies.

• Primary outcome was slightly rephrased/specified in comparison to the protocol. This had no impact on the included studies or on the results.

• Improvements in the 'background' and concerning the Cochrane Review Management Program.

  • Review Manager 5 with an updated version of the Risk of bias tool was implemented (Higgins 2011).

Differences review (Xander 2013) to update (Siemens 2016):

• 'Size of study' as new risk of bias domain was added.

• Satisfaction analysis of 'paroxetine versus placebo' was deleted (only one study included).

Differences first update (Siemens 2016) to this update:

• No main comparison specified (original review: naltrexone, first update: paroxetine) in order to avoid misleading conclusions.

• Random‐effects model instead of fixed‐effects model was used in all meta‐analyses because the random‐effects model might be more appropriate in most biomedical research.

• Risk of bias key domains for the subjective outcome pruritus were specified: sequence generation, concealment of allocation sequence, blinding of participants and personnel, and blinding of outcome assessment.

Contributions of authors

CB: screened and extracted the new included studies, conducted meta‐analyses, updated and revised the manuscript

LJ: supported the whole update process, extracted and screened data from the new included papers

BC: conducted meta‐analyses, updated and revised the manuscript

CaB: supported the whole update process, resolved any disagreements

JM: supported the whole update process, provided guidance in developing the summary of findings tables

SB: engaged in updating the methods and revising the search strategies for CENTRAL, MEDLINE and Embase

GS: provided methodological and statistical expertise, supervised meta‐analyses

DH: provided information on studies from Hercz 2020

GB, CaB: supported the whole update process, resolved any disagreements

All review authors critically reviewed the manuscript and gave suggestions for refining the final draft.

Sources of support

Internal sources

• German Cochrane Centre, Freiburg, Germany

  https://www.cochrane.de/de/willkommen

External sources

• German Ministry for Education and Research (BMBF), Germany

  Grant No. 01KG0819

• National Institute for Health Research (NIHR), UK

  Cochrane Infrastructure funding to the Cochrane Pain, Palliative and Supportive Care Review Group (PaPaS)

Declarations of interest

CB: none known. CB is an attending physician at University Hospital Basel.

LJ: none known

BC: none known

CaB: none known

JM: none known

SB: none known

GS: received personal consulting fees for ‘External statistical consultant of Roche Pharma AG, Grenzach‐Wyhlen, Germany‘

DH: none known

GB: none known. GB is a Medical Director, Department of Palliative Care, University of Freiburg.

This review does not comply with Cochrane’s Conflict of Interest Policy. Waldemar Siemens, who is listed in the Acknowledgements, was a member of the author team for the original review and the first update, before taking on a role at Roche. Following this, he checked the draft updated review text for factual errors and approved the submitted version. The review will therefore be updated again within 12 months of publication of this version with an author team that complies with the CoI Policy for Cochrane Library content 2020.

New search for studies and content updated (no change to conclusions)