Pathogenesis and Therapeutics for Chronic Pruritus of Unknown Origin: A Systematic Review

ABSTRACT

Chronic pruritus of unknown origin (CPUO) is a distressing condition characterized by persistent itch lasting over 6 weeks without an identifiable cause. The underlying mechanisms remain poorly understood, complicating diagnosis and treatment. This systematic review examines the diagnostic work‐up and therapeutic approaches for CPUO, evaluating the quality of treatment studies using the Strength of Recommendation Taxonomy (SORT) algorithm. Our paper also uniquely integrates a review of potential pathogenic mechanisms. A comprehensive literature search was conducted in PubMed, EMBASE, Ovid MEDLINE, and Cochrane databases through September 2025 using terms including “CPUO,” “chronic idiopathic pruritus,” and “pruritus of unknown origin.” Studies discussing pathogenesis, diagnostic strategies, or treatment were included. Treatment interventions were assessed based on the SORT algorithm. Of 228 identified records, 52 met inclusion criteria: 18 addressing pathogenesis, 5 discussing competing etiological hypotheses, 3 focusing on diagnostic work‐up, 23 on treatment, and 3 on non‐pharmacological therapies. CPUO pathogenesis appears multifactorial, involving Th2 dysregulation, neurogenic factors (JAK1, GRPR, TRPV4), metabolic alterations, and aging‐related immune changes. Current diagnostic approaches emphasize exclusion of systemic, dermatologic, and neurologic causes. Treatment options include topical agents (calcineurin inhibitors, capsaicin), systemic immunomodulators (JAK inhibitors, dupilumab, nemolizumab), neuromodulators (gabapentin, pregabalin), and phototherapy. However, available treatment studies are of low quality, with few randomized controlled trials (RCTs). CPUO remains a challenging condition with unclear pathophysiology and limited high‐quality therapeutic evidence. Further research, particularly RCTs, is needed to establish evidence‐based management strategies.

Key Points

• Chronic pruritus of unknown origin (CPUO) is a persistent and distressing condition without an identifiable cause, significantly impairing quality of life, particularly in older adults.

• This systematic review highlights potential underlying mechanisms of CPUO—including Th2‐predominant immune dysregulation (e.g., IL‐4, IL‐13, IL‐31, IgE), neural sensitization (e.g., GRPR, TRPV4), metabolic factors, and aging‐related alterations—through both narrative synthesis and newly developed visual models.

• Current treatments, including topical agents, systemic immunomodulators, neuromodulators, and phototherapy, show promise but are largely supported by low‐quality evidence, and there are no FDA‐approved therapies specifically indicated for CPUO.

• This review provides a preliminary treatment algorithm stratified by clinical endotype, distinguishing inflammatory (Th2‐driven) and non‐inflammatory (neuropathic) phenotypes.

• The literature remains limited by the absence of randomized controlled trials, heterogeneous outcome reporting, and potential publication bias, underscoring the need for high‐quality, standardized research.

1. Introduction

Chronic pruritus of unknown origin (CPUO), also known as chronic idiopathic pruritus or generalized pruritus of unknown origin, is defined as an itch lasting for over 6 weeks without a known cause. Diagnosis of CPUO is made based on exclusion, only after other potential causes of chronic itch have been evaluated and ruled out [1]. These include a variety of dermatological diseases as well as systemic, neurogenic, and psychiatric causes [2]. Notably, the terminology and diagnostic boundaries of CPUO remain an area of active debate [3]. Recent international initiatives are currently revising the conceptual and diagnostic framework for chronic pruritus, with CPUO representing one of the most controversial and evolving categories [4]. CPUO frequently overlaps with age‐associated pruritic conditions such as pruritus of the elderly and Willan's itch, and many patients are coded under broad ICD‐10 categories such as “chronic pruritus, unspecified.” [5] This lack of a distinct ICD code directly affects epidemiologic estimates, contributes to misclassification in large datasets, and complicates efforts to quantify disease burden. As a result, reported prevalence figures (e.g., > 30% in older adults) likely capture a mixture of CPUO and other chronic itch phenotypes [6]. These ongoing definitional and coding challenges underscore the need for improved diagnostic criteria and standardized terminology.

Additionally, the chronic itch associated with CPUO has been shown to present a significant cost burden as well as reduced quality of life for patients [5]. CPUO is highly prevalent, reportedly affecting over 30% of elderly populations globally [6]. Regardless, the United States Food and Drug Administration (FDA) has yet to approve a single medication for CPUO treatment [7]. Given both the difficulty of diagnosis and the impact of CPUO, a more comprehensive characterization of what is currently known about CPUO and its treatments is warranted. While prior systematic reviews exist, our paper uniquely provides an in‐depth analysis of potential underlying CPUO mechanisms, supported by newly developed visual models, and an updated synthesis of recent literature pertaining to CPUO work‐up and treatment.

2. Methods

2.1. Protocol

This review was conducted in accordance with PRISMA 2020 guidelines for systematic reviews without quantitative synthesis [8]. A protocol was not registered on PROSPERO or OSF because registration is primarily recommended for interventional systematic reviews or meta‐analyses, and our review did not involve pooled statistical estimates or comparative trial synthesis [8]. Nonetheless, all methodological procedures, including search strategy, predefined eligibility criteria, reviewer workflow, and evidence grading, were established prior to conducting the review to enhance transparency and reproducibility.

2.2. Eligibility Criteria

Studies were eligible for inclusion if they met all of the following criteria: (1) Included human participants with CPUO or chronic idiopathic pruritus; (2) Reported outcomes related to pathogenesis, diagnostic work‐up, or treatment; (3) Presented original data from randomized trials, observational studies, case series (≥ 3 patients), open‐label studies, or mechanistic analyses relevant to CPUO; (4) Were published as full‐text articles in English. Studies were excluded if they were: (1) Single‐patient case reports; (2) Conference abstracts without full manuscripts; (3) Studies where pruritus could be attributed to a definitive systemic, dermatologic, neurologic, or psychiatric condition, rather than CPUO.

2.3. Search Strategy

A comprehensive literature search was performed in PubMed, EMBASE, Ovid MEDLINE, and the Cochrane Library from their inception through September 2025. Search terms included “chronic pruritus of unknown origin,” “CPUO,” “itch,” “pruritus,” “chronic idiopathic pruritus” and “pruritus of unknown origin”.

2.4. Study Selection

All retrieved studies were exported to a shared review database, where three independent reviewers (I.G., R.A., Y.M.A.) screened titles and abstracts using predefined criteria, followed by full‐text review to confirm eligibility. Disagreements were resolved through discussion, and when necessary, adjudication by a senior author (S.G.K.). The study selection process is depicted in the PRISMA flow diagram (Figure 1).

FIGURE 1.

PRISMA flow diagram illustrating the identification, screening, and inclusion process for studies on chronic idiopathic pruritus. A total of 228 records were identified from databases, with 114 unique reports screened for eligibility. After assessment, 52 studies were included in the final review.

2.5. Assessment of Methodological Quality

Given the heterogeneity of the CPUO literature, which is dominated by small case series, uncontrolled cohorts, early‐phase trials, and mechanistic studies, formal risk‐of‐bias instruments were not applicable. Consistent with recommendations for evaluating mixed‐design evidence, the Strength of Recommendation Taxonomy (SORT) framework was used to assess the level and quality of evidence for therapeutic interventions [9]. SORT levels (1–3) and strength of recommendations (A–C) are reported in Tables 2 and 3. For mechanistic and pathogenesis studies, methodological limitations were qualitatively described but not formally graded due to the absence of validated tools suitable for these designs.

TABLE 2.

Systemic and non‐pharmacological treatments.

Study	Intervention	Study design	SORT evidence level	Pruritus scale	N	Dosage	Outcomes
Yesudian & Wilson, 2005	Gabapentin	Case series	3	None	2	300 mg QD titrated up to 1800 mg QD over 3–4 weeks	Complete resolution of symptoms in both patients
Agha et al., 2023	Gabapentin	Case report	3	None	1	1000 mg Gabapentin titrated down to 500 mg. Unknown if these doses were administered daily, Unknown duration	Complete resolution of symptoms
Kouwenhoven et al., 2023	Gabapentin	Prospective cohort	2	Median average pruritus NRS Median peak pruritus NRS DLQI	25	Initiated at 300 mg/d then increased to 900–1800 mg/d, median duration 2 years	After 4 weeks: 2.5‐point reduction in median average pruritus NRS 1.0‐point reduction in median peak pruritus NRS 7.0‐point reduction in DLQI
Lee et al., 2020	Pregabalin	Unknown	2	0–10 VAS, current perception threshold (CPT)	61 (41 CPUO; 20 HC)	150 mg QD for 2 weeks	Decrease in 5 Hz‐CPT values for antihistamine‐refractory patients with CPUO between week 2 (28.4) and week 4 (16.3) (p < 0.05)
Kouwenhoven et al., 2023	Paroxetine	Prospective cohort	2	Median average pruritus NRS Median peak pruritus NRS DLQI	5	Initiated at 10 mg/day, increased up to 50 mg/day maximum. Treatment duration for 10 weeks (range 3–18 weeks)	Treatment discontinued in all five patients due to inefficacy (n = 3) or side effects (n = 2)
Clark et al., 2020	Apremilast	Phase 2a, open‐label, single arm	2	NRS itch score, DLQI	10	30 mg tablet BID for 16 weeks	No significant decrease observed in either NRS itch score or DLQI. Only 3/10 patients completed the study
Kwatra, et al., 2024	Abrocitinib	Open label clinical trial	2	PP‐NRS itch score, DLQI	10	200 mg/day for 12 weeks	53.7% reduction in NES scores at 12 weeks 60% of pts had at least 4 point improvement. −49.0% DLQI scores
Wang et al., 2019	Tofacitinib	Case series	3	NRS itch score	5 (all weeks/concomitant rheumatoid arthritis)	5 mg PO BID for mean duration of 7.8 months	Complete reduction in NRS scores pre‐ and post‐treatment (p = 0.008)
Buttgerei et al., 2021	Baricitinib	Case report	3	NRS itch score DLQI Itchy QoL	1	2 mg/day for 2 weeks	Complete reduction in NRS scores
Jeon et al., 2021	Dupilumab	Retrospective case series	3	NRS itch score	15	Single 600 mg subcutaneous injection, followed by one 300 mg injections every 2 weeks for varying periods of time	Reduction in median NRS itch score from baseline (8) to final score (1) (p < 0.001)
Edmonds et al., 2021	Dupilumab	Retrospective case series	3	None	6	Single 600 mg subcutaneous injection, followed by one 300 mg injections every 2 weeks for varying periods of time	Complete resolution of rash and pruritus in all patients
Dasilva et al., 2025	Nemolizumab	Retrospective case series	3	NRS itch score	12 (3 weeks/CPUO)	Single 60 mg subcutaneous injection, followed by one 30 mg injection every 4 weeks for varying periods of time	After 4 weeks: Complete resolution of pruritus in two patients; 5‐point reduction in pruritus in one patient
Metze et al., 1999	Naltrexone	Open‐label clinical trial	2	0–10 VAS	50 (5 weeks/CPUO)	50 mg QD for under 4 weeks (N = 13) or from 5 weeks to 2 months (N = 37)	70% decrease in pruritus in one CPUO patient, 50% decrease in another (followed by tachyphylaxis to 0%), no effect in the last three
Lim et al., 2023	Isotretinoin Acitretin	Retrospective cohort	2	NRS itch score	56 Patients with CPUO (9 treated with acitretin only; 19 isotretinoin only, 28 treated with acitretin and isotretinoin)	Unknown dose, Mean duration 671.9 days with a standard deviation of 397.6 days	Mean 2.38 point reduction in itch at 3 months (p < 0.0001)
Manway et al., 2019	Acupuncture	Pilot	3	Pre‐ and post‐treatment surveys	10	Weekly treatments sessions of 1 h (10 sessions total)	7/10 patients reported subjective decrease in pruritus (no p‐scores given)
Ziv et al., 2022	Narrowband ultraviolet B (NB‐UVB)	Retrospective cohort	2	Pruritus Visual Analog Scale (P‐VAS)	67	Mean number of treatments 30.1 (SD, 8.3) Mean NB‐UVB dose 23.5 J/cm2	49/67 (73%) patients achieved complete response Mean P‐VAS declined 4.4 points
Bertold et al., 2024	Hypnotherapy	Prospective cohort	3	NRS score	11	5 sessions over 56 days	Signfiicant decrease in the pruritus NRS score at day 84 and day 140

TABLE 3.

Adverse events of treatment.

Therapy	Recommended dosage/treatment schedule	Adverse effects	References
Gabapentin	300 mg QD titrated up to 1800 mg QD over 3–4 weeks	None observed	Yesudian & Wilson, 2005
Gabapentin	1000 mg titrated down to 500 mg; unknown frequency and duration	None observed	Agha et al., 2023
Gabapentin	300 mg QD titrated up to 900–1800 mg QD; median duration 2 years	Vertigo (n = 7), fatigue (4), headache (3), nausea (2), GI pain (2), weight gain (2)	Kouwenhoven et al., 2023
Pregabalin	150 mg QD for 2 weeks	Somnolence and dizziness	Lee et al., 2020
Paroxetine	10 mg QD titrated up to maximum of 50 mg QD	Fatigue (n = 1), drowsiness (1), headache (1), sexual dysfunction (1), agitation (1), nausea (1), diarrhea (1), GI pain (1)	Kouwenhoven et al., 2023
Serlopitant	0.25, 1, 5 mg, or placebo QD for 6 weeks, ±mid potency steroids/emollients	Unspecified	McEwen et al., 2018
Apremilast	30 mg BID for 16 weeks	Nausea, diarrhea, decreased appetite, headaches, fatigue, presyncope	Clark et al., 2020
Tofacitinib	5 mg BID	None observed	Wang et al., 2019
Baricitinib	2 mg QD for 2 weeks	None reported	Buttgerei et al., 2021
Abrocitinib	200 mg QD for 12 weeks	Acneiform eruptions (n = 2), headache, nausea, folliculitis, herpes labialis	Kwatra et al., 2024
Dupilumab	600 mg SC, then 300 mg SC every 2 weeks	Blurry vision (n = 1), eye dryness (1), headache (1), mild injection site reaction (1)	Jeon et al., 2021; Edmonds et al., 2021
Nemolizumab	60 mg SC, then 30 mg SC every 4 weeks	None reported	Dasilva et al., 2025
Naltrexone	50 mg QD for 2 months	Nausea, fatigue, dizziness, heartburn, diarrhea	Metze et al., 1999
Acitretin	Unknown dose for mean of 672.9 days	Dryness (n = 2), worse itch (1)	Lim et al., 2023
Isotretinoin	Unknown dose for a mean of 672.9 days	Dryness (n = 3), abdominal pain (1), mood swings (1)	Lim et al., 2023
Acupuncture	1 h/week, total 10 sessions	Not mentioned	Manway et al., 2019
Narrowband ultraviolet B	Mean 30.1 sessions (SD 8.3); mean 23.5 J/cm2	No serious adverse events were observed	Ziv et al., 2022
Hypnotherapy	5 treatments over 56 days	Not mentioned	Bertold et al., 2024

2.6. Ethics Statement

No study authors were contacted. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Therefore, ethical approval was not required.

3. Results

Our search yielded 228 records containing the relevant keywords and phrases, with 109 unique articles after removing duplicates (Figure 1). Only primary sources addressing chronic idiopathic pruritus were included. After eligibility assessment, 52 studies met inclusion criteria. These included 18 studies on pathogenesis, 5 addressing competing etiological hypotheses, 3 on diagnostic work‐up, 23 on treatment, and 3 on non‐pharmacological therapies, reflecting the multifaceted nature of CPUO research.

3.1. Pathogenesis (Table 1, Figure 2)

TABLE 1.

Pathophysiological aspects of CPUO.

Pathophysiology	Relevant treatments
Immunologic
Th2 dysregulation: elevated pro‐inflammatory cytokines and gata3, shift to type 2 response, aging‐related immunosenescence [14, 15, 16, 17, 18, 19, 21, 22] Eosinophils and IgE: elevated in Th2‐predominant CPUO [20]	Corticosteroids [87], Dapsone [87], UVA irradiation [87], Omalizumab [88], Dupilumab [79], ±antihistamines (more effective in acute vs. chronic urticaria) [89, 90]
MRGPRX2: drives nonhistaminergic itch
JAK1: selectively expressed in itch‐neurons, drives chronic itch [18]	JAK1 inhibitors (Tofacitinib, Abrocitinib) [74, 76]
Neuromodulator and sensory itch transmission
BNP
GRPR: mediates itch in the dorsal spinal cord [12, 25]	Gabapentin [91], Capsaicin cream [92], Lidocaine [93], Menthol [92], Electroacupuncture [94], Xanthotoxol (murine models) [95]
TRPV4: elevated expression [26]	Capsaicin [96], ±antihistamines (more effective in acute vs. chronic urticaria) [89, 90], Calcineurin inhibitors [63, 97], Vitexin (murine models) [98]
Barrier and structural dysfunction
Aging‐associated skin barrier dysfunction and xerosis: increased skin pH, PAR2 activation, reduced sweat and sebaceous gland activity, lipid matrix loss, decreased estrogen [23]	Moisturizers with lipids like those in the skin (ex. ceramides) [23], Emollients [23]
Competing etiological hypotheses
Subclinical cholestasis: elevated TSBAs in patients with CPUO [31]	Cholestyramine (current 1st line) [99], Rifampin [99], Opioid antagonists [99]
Diabetic neuropathy: higher prevalence of truncal CPUO among diabetics [33]	Urea‐based emollients [100], Polidocanol [100], Camphor [100], Menthol [100], Tannin preparations [100]
Lactase deficiency: symptom improvement in CPUO after lactose‐free diet [34]	Lactose‐free diet [34], Exogenous lactase [101]
Underlying systemic disease [12, 35]	Treat underlying cause as appropriate

FIGURE 2.

Pathogenesis of CPUO. This figure illustrates the factors potentially involved in mediating CPUO pathogenesis: Age, proteinase activated receptor 2 (PAR2), transient receptor potential vanilloid 4 (TRPV4), gastrin‐releasing peptide receptor (GRPR), Janus kinase 1 (JAK1), Mas‐related G‐protein coupled receptor member X2 (MRGPRX2), T‐helper type 2 cells (Th2), Non‐Th2 mediated neural sensitization, metabolites. In Th2 mediated immunosenescence, elevated levels of T‐helper type 2 (Th2) cells, which are governed by transcription factor GATA3, in comparison to T‐helper type 1 (Th1) cells, governed by T‐bet, can lead to the release of cytokines such as interleukin (IL)‐4, IL‐13, and IL‐31. These cytokines alongside eosinophils can act on sensory neurons to promote itch. In TRPV4 mediation, TRPV4 expression on keratinocyte and macrophages can lead to the release of serotonin which binds to 5‐hydroxytryptamine receptor (Htr) 2a and Htr7 receptors to promote itch. Created with BioRender.com.

3.1.1. Immunologic Dysregulation and Inflammatory Mediators

3.1.1.1. Th2 Dysregulation

Dysregulation of T‐helper type 2 (Th2) cells has been hypothesized as one possible pathogenic factor in CPUO, particularly in the elderly, with IL‐4, IL‐13, and IL‐31 acting on sensory neurons and eosinophils to drive itch [10, 11, 12]. Immunosenescence, a proinflammatory state with excess Th2 response, is common in aging patients with CPUO [11, 12]. IL‐31 levels have also been shown to be significantly elevated in CPUO and correlate with disease presence [13]. Likewise, CPUO was found to be an independent predictor of IL‐31 [13].

Skin biopsies in another study reveal increased GATA3 expression, indicating a Th2‐dominant immune profile [14, 15]. Additionally, IL‐33, released from damaged epithelial cells, was hypothesized to contribute to chronic itch and pain, with higher levels found in patients with CPUO [16, 17].

3.1.1.2. Eosinophils as a Biomarker

CPUO may be classified into two phenotypes based on levels of circulating eosinophils: Th2‐predominant, which is characterized by high levels of eosinophils, and non‐Th2, which lacks high levels of eosinophils. Th2‐predominant CPUO, discussed above, is mediated by the inflammatory cytokines IL‐4, IL‐13, and IL‐31, while non‐Th2 CPUO is mediated by neural sensitization, as evidenced by patients in this group being more likely to have spinal comorbidities. In terms of treatment, patients with increased circulating eosinophils are more likely to benefit from immunomodulators, while patients without increased circulating eosinophils are more likely to benefit from gabapentin [18].

3.1.1.3. IgE as a Biomarker

Beyond eosinophils, circulating IgE has also been identified as a potential biomarker to delineate CPUO patients with a Th2‐predominant endotype. Patients with elevated baseline IgE levels were more likely to respond to immunomodulatory therapies, further supporting the role of Th2‐driven inflammation in a subset of CPUO patients [19].

3.1.1.4. Mas‐Related G Protein‐Coupled Receptor X2 (MRGPRX2)

MRGPRX2 is an IgE‐independent mast cell receptor increasingly recognized for its role in nonhistaminergic itch. In a study of patients with CPUO (n = 44), MRGPRX2 expression was significantly elevated compared with both atopic dermatitis and healthy controls (p < 0.0001) [20]. MRGPRX2 levels also positively correlated with stem cell factor and eotaxin, implicating mast cell activation and eosinophil‐mast cell crosstalk as potential contributors to disease pathogenesis [20].

3.1.1.5. JAK1

Another important pathogenic factor in CPUO is the tyrosine kinase protein Janus kinase 1 (JAK1). JAK1 is selectively expressed in itch‐sensory neurons [21]. It has also been shown that JAK1 signaling in sensory neurons drives chronic itch, irrespective of inflammation in skin [22]. Interaction of IL‐31 with the JAK/STAT pathway is also relevant to CPUO pathogenesis [21].

3.1.2. Neuromodulator and Sensory Itch Transmission

3.1.2.1. BNP

B‐type natriuretic peptide is a neuropeptide which is correlated with itch severity, as measured by NRS. In a study including patients with CPUO (n = 27), plasma BNP levels were significantly correlated with age (p < 0.0001) and itch severity (p = 0.02) [23]. In another study of patients with varying chronic pruritus (n = 77, n = 33), plasma BNP (r = 0.30, p = 0.008) and N‐ Terminal Pro BNP (r = 0.62, p = 0.0001) were also elevated. Mice given an intravenous BNP injection also began to persistently scratch flank, face, hind quarters, and abdomen after 10 min, subsiding after 1 h [24].

3.1.2.2. Gastrin‐Releasing Peptide Receptor (GRPR)

GRPR has been shown to mediate itch sensation in the dorsal spinal cord via neurons at the dorsal root ganglion [10]. In one study, GRPR‐mutant mice showed no decline in pain but did show a decline in scratching behavior in response to pruritogenic stimuli. A similar decline in scratching behavior was observed with direct spinal CSF inoculation of a GRPR antagonist [25].

3.1.2.3. TRPV4

The transient receptor potential vanilloid 4 (TRPV4) is also implicated in the pathogenesis of CPUO. This receptor has been found in mice to be selectively expressed by dermal macrophages and epidermal keratinocytes, and mice with genetic deletions of TRPV4 show reduced amounts of chronic itch. Notably, TRPV4 expression has been shown to be elevated in patients with CPUO compared to healthy controls [26].

3.1.3. Barrier and Structural Dysfunction

3.1.3.1. Aging

CPUO disproportionately affects the elderly [15]. Pathogenesis of CPUO in the elderly is thought to be a result of keratinocyte/skin barrier dysfunction, non‐histaminergic sensory neuropathy, and/or immune dysregulation (Figure 3) [27]. Skin barrier dysfunction primarily presents as xerosis. Xerosis is due to a variety of factors such as increased skin alkalinity with age, which ultimately affects enzymatic activity, increases activation of PAR2 receptors that induce itch, reduces activity of sebaceous and sweat glands, decreases intercellular lipid matrix at the stratum corneum, and decreases estrogen levels [26]. There is also sensory neuropathy in aging, which results from central or peripheral nerve damage acquired during the aging process [27]. Immune dysregulation of aging may present as lymphopenia, eosinophilia, or hypo‐gammaglobulinemia [27]. Additionally, as mentioned previously, aging is associated with the process of immunosenescence, whereby immune cells in the skin show a heightened Th2 response along with a concurrent reduction in type 1 immunity [14, 15].

FIGURE 3.

Effects of aging on CPUO pathogenesis. This figure details age‐related factors which could mediate CPUO pathogenesis. These factors include skin barrier dysfunction, decreased estrogen, reduced sebaceous and sweat gland activity, increased alkalinity, immune dysregulation, decreased lipids in the stratum corneum, Th2‐mediated immunosenescence, sensory neuropathy, and increased proteinase activated receptor 2 (PAR2) receptors. Created with BioRender.com.

3.1.3.2. Sweat Duct Obstruction

In vivo imaging found 95% (19/20) of patients with CPUO had keratinaceous sweat duct obstruction and increased dermcidin deposition, implicating sweat leakage in pruritus pathogenesis. Retinoids, which reduce sweat gland hyperkeratosis, may be a therapeutic target [28]. Metabolomic profiling shows > 100‐fold reductions in amino acids and derivatives in patients with CPUO (n = 11) versus healthy controls (n = 11), suggesting metabolic dysregulation [29].

3.1.4. Metabolic Pathway

3.1.4.1. Metabolites

Several plasma metabolites were decreased > 100 fold in patients with CPUO (n = 11) compared to matched healthy controls (n = 11). These metabolites include nine amino acids (isoleucine, L‐tyrosine, threonine, DL‐tryptophan, L‐valine, methionine, glycine, lysine, and L‐phenylalanine), four amino acid derivatives (creatinine, DL‐carnitine, acetyl‐L‐carnitine, and indole‐3‐acrylic acid), and two aromatic and fatty acid derivatives (2‐hydroxycinnamic acid and oleamide). These findings suggest that metabolic reprogramming may provide therapeutic benefits for patients with CPUO [29]. Additionally, patients with obesity were noted to have an increased risk of chronic pruritus, with patients with grade III obesity reporting chronic pruritus more frequently compared to grade I patients with obesity (40.35% vs. 22.86%, p = 0.009) [30].

3.1.5. Competing Etiological Hypothesis

3.1.5.1. Subclinical Cholestasis

As pruritus is commonly observed in cholestasis, one study proposed that CPUO may represent subclinical cholestasis or a related hepatobiliary disorder [10, 31, 32]. This hypothesis is supported by a study showing that total serum bile acid (TSBA) levels were elevated in the majority of patients with CPUO compared to controls [31].

3.1.5.2. Diabetic Neuropathy

A study found truncal CPUO significantly more prevalent in diabetics than in age‐matched nondiabetics [32]. Independent risk factors included toe/sole numbness, Achilles tendon areflexia, and longer diabetes duration. Another study linked truncal CPUO to impaired blood pressure response in a head‐up tilt test, suggesting diabetic polyneuropathy involvement [33]. While neuropathy is an important mechanism contributing to chronic pruritus, a confirmed diagnosis of diabetic neuropathy would suggest a secondary pruritus classification rather than CPUO. However, in cases where neuropathic features are suspected but no objective findings are present, CPUO remains a reasonable working diagnosis.

3.1.5.3. Lactase Deficiency

A 4‐week lactose‐free diet improved pruritus in 38% of lactase‐deficient patients with CPUO, with up to 65% of severe cases responding [34]. Median NRS pruritus scores dropped from 9 to 1 (p < 0.001) in responders.

3.1.5.4. Underlying Systemic Disease

CPUO may signal systemic disease, with one study reporting 7 of 50 patients had conditions such as hypothyroidism, malignancies, hepatitis C, and HIV [35]. Other studies estimate 10%–50% of dermatologic CPUO cases stem from undiagnosed systemic disease, emphasizing the need for a broad systemic evaluation [10].

4. Work‐Up

As CPUO is a diagnosis of exclusion, a thorough work‐up is essential to determine the cause of pruritus. Physicians should obtain a detailed patient history, including pruritus frequency, duration, location, medication history, comorbidities, and environmental factors (e.g., contact dermatitis and scabies risk) [36]. Morphological assessment may help guide initial evaluation, but its utility is limited: non‐inflamed or minimally inflamed skin does not reliably exclude dermatologic causes, and inflamed lesions may reflect secondary changes from scratching rather than a primary disease process [37].

CPUO typically presents with non‐inflamed or only minimally inflamed skin, with cutaneous findings largely limited to secondary excoriations, prurigo‐like nodules, or lichenification resulting from chronic scratching rather than primary inflammatory lesions [38]. Importantly, CPUO should only be diagnosed after all dermatologic, systemic, neurologic, and psychiatric causes of chronic itch have been thoroughly evaluated and excluded, consistent with International Forum for the Study of Itch (IFSI) guidelines [39]. Given the “negative” nature of this definition, misclassification, particularly in older adults, remains a concern and underscores the need for a structured, mechanism‐informed work‐up.

Thus, in the workup of pruritus, a full skin examination and laboratory tests are recommended, including complete blood count (CBC) with differential, liver, renal, and thyroid function tests [8, 37]. Additional tests, such as ferritin, total serum bile acid (TBSA), CMP, ESR, HIV screen, chest X‐ray, and urine drug screen, may be warranted based on clinical suspicion [31, 32, 37, 40]. Skin biopsy is optional but useful when pruritic dermatosis is suspected [36]. Once all malignant, neurologic, and systemic causes are ruled out, a CPUO diagnosis can be confirmed [36].

Hematologic conditions, such as iron‐deficiency anemia, polycythemia vera, and Hodgkin lymphoma, represent established disorders causing pruritus that must be carefully considered in the diagnostic work‐up of CPUO [14]. However, such conditions may not be clinically apparent at initial presentation, and definitive diagnoses may emerge months or even years later. As such, repeated evaluation—including blood tests and malignancy screening—is warranted in persistent or treatment‐refractory cases. Elderly patients may need more frequent reassessment, given the higher risk for chronic kidney disease, cholestatic disease, hematologic disorders, and malignancy.

5. Treatment With SORT Evidence Levels

CPUO treatment should be approached using a stepwise, needs‐based method. Because many available therapies are supported by observational studies with small cohorts, the overall certainty of evidence is limited and reported benefits should be interpreted cautiously.

5.1. Topical Therapies (Table S1)

Topical treatments offer targeted symptom relief and are best understood when categorized by their underlying mechanisms—ranging from immune modulation and neural desensitization to skin barrier restoration and receptor‐specific inhibition.

5.1.1. Skin Barrier Restoration

5.1.1.1. Moisturizers

Moisturizers (humectant, occlusive, and emollient) can reinforce and repair skin barriers, thereby reducing xerosis and pruritus [41]. These products can replenish depleted compounds, such as lipids, in pruritic areas of the skin and restore a hydrated, healthy epidermis [42].

5.1.2. Neuroactive and Receptor‐Targeted Anti‐Pruritics

5.1.2.1. Antihistamines

5.1.2.1.1. SORT 1

The binding of histamine to its H1 and H4 receptors on histaminergic nerves activates transient receptor potential vanilloid 1 (TRPV1) via the phospholipase A2 and lipoxygenase pathway [43, 44]. This activation leads to neuropeptide release, triggering mast cell degranulation, plasma extravasation, and acute itch [45]. Doxepin, a potent antihistamine, has shown efficacy in pruritus management. A randomized controlled trial (n = 24) demonstrated complete pruritus resolution in 58.3% of patients treated with doxepin, compared to 8.3% in the placebo group (p < 0.001) [46]. Another study found that doxepin significantly reduced histamine‐induced cutaneous responses in atopic patients (p < 0.05) [47].

5.1.2.2. Cannabinoids

5.1.2.2.1. SORT 1

Cannabinoids, derived from Cannabis sativa , modulate synaptic neurotransmission through multiple mechanisms. One pathway involves binding to cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R), where CB1R inhibits glutamate and GABA release from presynaptic terminals [48]. Since cannabinoid receptors are present on unmyelinated C fibers, which mediate itch, their activation can inhibit C‐fiber function and attenuate pruritus [48]. A literature review found that cannabinoids effectively reduce pruritus in various dermatologic and systemic diseases, suggesting their potential as an adjuvant therapy [49].

5.1.2.3. Capsaicin

5.1.2.3.1. SORT 1

Capsaicin, a compound derived from chili peppers, is another agent which can alleviate pruritus through TRPV1 binding. The prolonged activation of TRPV1 by capsaicin desensitizes neurons, leading to the depletion of neuropeptides such as substance P [50]. This can inhibit the neuronal transmission of pruritus [42]. While a systematic review of six randomized controlled trials revealed insufficient evidence regarding the efficacy of capsaicin in pruritus treatment, multiple additional studies have demonstrated its effectiveness [48, 50, 51, 52, 53].

5.1.2.4. Anesthetics

5.1.2.4.1. SORT 2

Topical anesthetics can inhibit unmyelinated C‐nerve fibers which are responsible for transmitting pruritic sensations [49, 51, 54, 55, 56]. Pramoxine, lidocaine, prilocaine, polidocanol, ketamine, amitriptyline, and lidocaine are topical anesthetics that have been used to treat pruirtus [51]. Notably, 1% pramoxine lotion reduced pruritus by 61% in patients with uremic pruritus after 4 weeks of twice daily application in affected areas (n = 14) [57]. In another trial including 1611 patients with pruritic diagnosis, a 3% polidocanol and 5% urea preparation markedly reduced pruritus, resulting in 48.9% of patients completely itch‐free at the conclusion of a 2‐week observation period [58].

5.1.2.5. Cooling Agents

5.1.2.5.1. SORT 2

Cooling the skin reduces histaminergic and non‐histaminergic itch pathways in both chronic and acute pruritus [59]. Therefore, cooling agents such as cold compresses, calamine lotion, topical camphor, and topical menthol can reduce pruritus. Topical menthol has neuromodulator properties, such as activation of the cold receptor TRPM8, that can alleviate pruritic symptoms [32, 60]. Notably, camphor poisoning has been reported in children [55].

5.1.3. Immunomodulator and Anti‐Inflammatory Agents

5.1.3.1. Aspirin

5.1.3.1.1. SORT 1

Prostaglandins can sensitize C nerve fibers, which transmit itch and pain; aspirin inhibits this effect [61]. Topical aspirin was found to have a significant antipruritic effect in histamine‐induced and lichen simplex chronicus itch [61, 62].

5.1.3.2. PDE4 Inhibitor (Crisaborole)

5.1.3.2.1. SORT 1

Crisaborole is a PDE4 inhibitor used exclusively for atopic dermatitis. It functions by inhibiting PDE4, leading to an increase in intracellular cAMP concentrations, which then causes inhibition of pruritogenic cytokine production by T cells. Typical dosage is application of 2% crisaborole twice daily for 4 weeks [6].

5.1.3.3. Calcineurin Inhibitors

5.1.3.3.1. SORT 2

Topical calcineurin inhibitors (TCIs), such as tacrolimus and pimecrolimus cream, suppress mast cell degranulation and the synthesis of pro‐inflammatory cytokines, thereby reducing pruirtus [63]. While some studies have proposed that TCIs may reduce itch by binding to TRPV1, direct evidence supporting this hypothesis is lacking [64]. A systematic review found TCIs improved pruritus in 15/16 studies with no reports of serious infection or malignancy [65]. Transient burning after application is a common adverse effect [65]. These topicals can be applied twice daily.

5.1.3.4. Topical Corticosteroids

5.1.3.4.1. SORT 2

According to the British Association of Dermatologists, first‐line topical treatment of CPUO is doxepin 10% cream for 8 days, with use restricted to < 10% of total body surface area (TBSA) [32]. Topical clobetasone butyrate has also been recommended as an alternative treatment option [32].

5.2. Systemic Therapies (Tables 2 and 3)

When topical treatments prove ineffective or impractical, systemic treatments can potentially offer relief. When topical therapies prove insufficient or impractical, systemic treatments can provide broader or more targeted relief depending on the underlying pathophysiologic driver. These agents span immune modulation, neural desensitization, receptor antagonism, and metabolic correction, and are best understood when grouped by their mechanism of action rather than route of administration. However, the certainty of evidence supporting these therapies remains low, largely derived from small case series and open‐label studies and therefore should be interpreted with appropriate caution.

5.2.1. Neuroactive Agents

5.2.1.1. Gabapentin

5.2.1.1.1. SORT 2

Gabapentin is an anti‐seizure medication with some support for antipruritic use in CPUO [32]. Its proposed mechanisms of action vary. It has been shown to inhibit cell membrane protein a2d1, a protein that regulates voltage‐gated calcium channels, and in doing so affect the C‐fiber transmission responsible for pruritus sensation [6]. Additionally, it has been shown to inhibit excitatory neurotransmitter release (DA, 5HT, NE), increase the threshold of neuronal excitation, and stabilize synapses of the afferent itch pathway (C‐fiber, A‐d fibers, mechanoreceptors) via a decreased calcium influx, leading to inhibited presynaptic glutamate release/transmission [60]. Three case studies and a prospective cohort study, using doses of 300–1800 mg/day, showed improvement in patients' refractory CPUO [66, 67, 68].

5.2.1.2. Pregabalin

5.2.1.2.1. SORT 2

Pregabalin is an antipruritic drug, which is similar to gabapentin but with a superior potency and absorbance. It exerts its antipruritic effect by lowering the threshold of C‐fiber activation [32, 69]. In one 2020 Nature scientific report study, patients with CPUO refractory to second‐generation antihistamines improved with pregabalin at 150 mg/day for 2 weeks [69].

5.2.1.3. SSRI (Paroxetine)

5.2.1.3.1. SORT 2

In one study, 5 patients with CPUO were treated with paroxetine 10–50 mg daily. All patients discontinued treatment at the follow up appointment (median 10 weeks, range 3–18 weeks), due to side effects (n = 2) or inefficacy (n = 3). Only one patient experienced a decrease in itch symptoms, as measured by NRS, with a 4‐point decrease after 12 weeks of treatment [68].

5.2.1.4. Anti‐NK1 (Aprepitant, Serlopitant)

5.2.1.4.1. Indeterminate SORT

Presently, there is very limited evidence supporting the use of anti‐NK1 therapeutics specifically for CPUO. However, they may still be beneficial, as these agents have demonstrated effectiveness in treating chronic pruritus of various etiologies. Aprepitant is a drug that acts as a substance P antagonist, where substance P is a neuropeptide that binds to NK1 to regulate histamine and prostaglandin production [70]. Several case reports have demonstrated the benefit of aprepitant use in patients with chronic pruritus [6]. Serlopitant is an NK1 receptor antagonist [71]. One phase II multicenter, randomized, placebo‐controlled study of patients with severe treatment‐refractory chronic pruritus of various or unknown etiologies showed evidence to suggest that compared to placebo, serlopitant at 5 mg/day may reduce pruritus intensity. Dosage of 1 mg was also significant in reducing VAS pruritus scales compared to placebo, whereas 0.25 mg was not [72].

5.2.2. Immune‐Modulating Therapies

5.2.2.1. Anti‐PDE4 (Apremilast)

5.2.2.1.1. SORT 2

Apremilast is an inhibitor of phosphodiesterase‐4 (PDE4). One phase 2a proof‐of‐concept open‐labeled single‐arm clinical trial of Apremilast in patients with CPUO had high dropout rates due to adverse effects (50%). Of the 3 patients who completed the study, 2 had absolute reduction in 24‐h NRS itch scores from 8 and 9.5 to 0 and reduction in DLQI score from 26 and 10 to 4 and 0, respectively, and the other patient did not demonstrate a reduction in NRS itch score but had a minimal reduction in DLQI score from 5 to 3 [73].

5.2.2.2. JAK Inhibitors (Abrocitinib SORT 2, Tofacitinib SORT 3, Baricitinib SORT 3)

In one study, 5 patients with severe refractory CPUO were treated off‐label with tofacitinib, a JAK1 inhibitor, at a dose of 5 mg twice daily. All patients showed a complete cessation of itch, as measured by NRS itch scores, after 1 month of treatment [74]. A retrospective analysis of 6 refractory CPUO cases also found a significant reduction in NRS score following tofacitinib treatment (mean NRS decreased from 8 to 2.16, p < 0.0001 after 7 days of tofacitinib treatment, 10 mg/daily) [75].

Additionally, in an Open‐Label Phase II study of 10 patients with CPUO, patients treated with 200 mg daily of abrocitinib for 12 weeks maintained a 53.7% (p = 0.01) decrease in PP‐NRS scores, with a −49.0% DLQI score (p = 0.02) [76].

In a case report, a patient with refractory CPUO was treated with baricitinib, a JAK1 and 2 inhibitor, for 2 weeks at a dose of 2 mg daily. The patient was virtually asymptomatic after the 2 weeks of treatment and continued to report complete freedom from itch, as measured by NRS scores, at a 3 month follow up [77].

5.2.2.3. Anti‐IL‐4Ra (Dupilumab)

5.2.2.3.1. SORT 3

A retrospective case series of 15 patients with CPUO suggests that dupilumab may reduce pruritus (NRS itch score) in a subset of patients with CPUO, with median baseline 24 h NRS itch scores reduced from 8 to 1 (mean reduction of 7 with SD 1.9) [78]. In another case series, 6 patients were treated with dupilumab, resulting in a complete resolution of symptoms in 5 individuals, while all patients experienced a notable improvement in pruritus [79]. Additionally, a major phase III trial is currently underway to evaluate the efficacy and safety of dupilumab in adults with CPUO aged 18–90 (NCT05263206).

5.2.2.4. Anti‐IL‐31Ra (Nemolizumab)

5.2.2.4.1. SORT 3

Evidence for nemolizumab in CPUO is extremely limited, consisting only of a small retrospective series in mixed chronic pruritus conditions, including a few individuals with CPUO. In a retrospective analysis of 12 patients with treatment‐resistant chronic pruritic disorders, including 3 patients with dupilumab‐refractory CPUO, nemolizumab resulted in rapid improvement in itch within 24–72 h. Two patients achieved complete resolution of pruritus (NRS 10 to 0), and 1 patient demonstrated significant improvement (NRS 8 to 3). Symptom relief was maintained at 1‐month follow‐up [80]. A phase II clinical trial is currently evaluating the efficacy and safety of nemolizumab in adults aged 18 years or older with CPUO (NCT07074977).

5.2.3. Opioid Receptor Targeted Therapies

5.2.3.1. Opioid Antagonists (Naltrexone, Butorphanol, Naloxone)

One study of naltrexone (SORT 2) at 50–150 mg/day by mouth showed considerable relief in an open‐labeled trial. Another open‐labeled trial in 1999, which used a dose of 50 mg/day, showed relief in 3/5 patients [81]. Butorphanol at 1 mg/day intranasal showed to be effective in a case report of a patient with intractable pruritus from refractory prurigo nodularis (PN). Another opioid antagonist, naloxone, was also shown to have provided complete relief of CPUO at a dose of 1.6 mg/h for 4 h [82].

5.2.4. Retinoids

5.2.4.1. Retinoids (Isotretinoin, Acitretin)

5.2.4.1.1. SORT 2

Obstruction of sweat glands has been associated with CPUO, and systemic steroids reduce sweat gland hyperkeratosis. A retrospective cohort analysis of 56 patients with CPUO was treated with systemic retinoids: isotretinoin (n = 41, 73.2%) or acitretin (n = 15, 26.8%). Mean itch score was reduced by 2.38 (p < 0.0001), as measured by NRS itch scores, at 3 months. The most common adverse effect was dryness [28].

5.3. Non‐Pharmacological Therapies (Tables 2 and 3)

Several non‐pharmacological interventions have been studied for CPUO. Phototherapy reduces inflammatory mediators and impairs nerve fiber transmission, with narrow‐band UVB (SORT 2) achieving complete remission in > 70% of 67 patients [83]. Acupuncture (SORT 3) provided itch relief in 7 of 10 patients in an uncontrolled pilot study, while hypnotherapy (SORT 3) significantly decreased pruritus scores in 11 patients over 56 days [84, 85].

Some of the agents discussed, such as serlopitant and topical cannabinoids, are not currently FDA‐approved or commercially available, and their discussion is included for scientific completeness rather than routine clinical use.

6. Discussion

While the precise pathogenesis of CPUO has yet to be elucidated, multiple potential pathways have been proposed. Current evidence suggests that immune dysregulation, particularly involving Th2 response, alongside inflammatory mediators such as eosinophils and JAK1 may contribute to disease development. Neuromodulators, such as TRPV4, GRPR, and BNP, may also play a role in the sensory transmission of an itch. Additionally, sweat duct obstruction and aging may also contribute to CPUO through skin barrier and structural dysfunction. Furthermore, significantly decreased levels of metabolites (isoleucine, L‐tyrosine, among others) have also been associated with CPUO, indicating a possible relationship to metabolism.

Based on our synthesis of the literature, treatment of CPUO should be personalized. CPUO does not have a distinct or consistent morphological clinical phenotype; rather, patients typically exhibit non‐inflamed or minimally inflamed skin with muted or scant primary lesions, and visible findings are usually limited to secondary excoriations or lichenification from chronic scratching [38]. Because conventional morphological phenotyping adds little discriminatory value in CPUO, this condition is particularly well suited for endotype‐based profiling and personalized therapeutic approaches grounded in presumed underlying pathophysiologic mechanisms. For example, therapy may begin with skin barrier restoration and topical antipruritic agents (e.g., moisturizers, pramoxine, menthol), particularly in older adults. In patients with evidence of Th2‐predominant inflammation (e.g., eosinophilia, elevated IL‐31), systemic immunomodulating therapies such as dupilumab or JAK inhibitors may be appropriate. In contrast, patients without systemic inflammation, especially those with spinal comorbidities or neuropathic features, may derive greater benefit from neuroactive agents such as gabapentin or pregabalin. Phototherapy may be considered for refractory disease.

Across all therapeutic categories, the certainty of evidence remains low, and reported benefits may overestimate true efficacy due to small sample sizes, lack of controls, and selective reporting. As no FDA‐approved treatments currently exist for CPUO, clinical judgment remains essential to guide effective management. Although biologics and JAK inhibitors show early promise, their high cost and limited availability pose significant access barriers, particularly in low‐resource settings [86]. As a result, real‐world treatment of CPUO often depends on more affordable therapies, underscoring the need for equitable access and cost‐aware clinical decision‐making. Due to limited availability and absence of regulatory approval, agents such as serlopitant and topical cannabinoids should not be considered standard of care at this time, but are discussed here for scientific completeness.

Our review has several strengths. It is the first to integrate both pathophysiologic mechanisms and therapeutic strategies in CPUO, supported by visual models that synthesize emerging immune, neural, and metabolic insights. We conducted a comprehensive, multi‐database search and applied the SORT algorithm to assess therapeutic evidence quality, offering an endotype‐based treatment framework that aligns with evolving precision medicine approaches. However, our review is limited by the heterogeneity and low quality of available evidence, as no randomized controlled trials (RCTs) have been published to date. Although several emerging therapies, including dupilumab, JAK inhibitors, and nemolizumab, show potential, the existing evidence base is composed primarily of small, uncontrolled studies with a high risk of bias. The absence of randomized or comparative trials necessitates a conservative interpretation of these findings, and all therapeutic conclusions should be considered exploratory. Additionally, the lack of standardized endpoints, inconsistent outcome reporting, and potential publication bias hinder cross‐study comparisons and pooled interpretation. While our review follows PRISMA 2020 guidelines for non‐quantitative systematic reviews, the absence of a registered protocol and the heterogeneous, predominantly non‐comparative study designs limited the use of conventional risk‐of‐bias tools. We therefore used the SORT framework as the most appropriate method for evaluating the available evidence, which may limit comparability of findings and should be interpreted with caution. These limitations highlight the need for well‐powered RCTs with harmonized outcome measures in CPUO research.

7. Conclusion

CPUO remains a diagnostically and therapeutically challenging condition, with multifactorial pathophysiology and limited high‐quality evidence to guide treatment. This systematic review synthesizes current insights into CPUO mechanisms, clinical evaluation, and therapeutic strategies, highlighting emerging immune and neurogenic pathways that may inform endotype‐driven care. However, the current literature is constrained by a lack of randomized controlled trials and standardized outcome measures. Future research should focus on prospective, well‐powered studies to validate treatment efficacy and refine targeted management approaches for this debilitating disorder.

Funding

The authors have nothing to report.

Disclosure

Medical writing, editorial and other assistance: No medical writing or editorial assistance was received in the preparation of this manuscript.

Conflicts of Interest

Dr. Kwatra is an advisory board member/consultant for AbbVie, Celldex Therapeutics, Galderma, Incyte Corporation, Novartis Pharmaceuticals Corporation, Pfizer, Regeneron Pharmaceuticals, and Kiniksa Pharmaceuticals and has served as an investigator for Galderma, Kiniksa Pharmaceuticals, Pfizer Inc., and Sanofi. He is also a recipient of a Dermatology Foundation Medical Dermatology Career Development Award and has received grant funding from the Skin of Color Society. The other authors declare no conflicts of interest.

Supporting information

Table S1: Supplementary Material.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.