Table 2.
Select treatment trials in patients with chronic kidney disease–associated pruritus (CKD-aP)
| Author, yr | Study design and population | Intervention | Mechanism of action | Itching severity tool | Results |
|---|---|---|---|---|---|
| Toxin removal | |||||
| Ko et al., 201338 | Prospective cohort, unicenter study including 111 HD patients with milder pruritus | Increase Kt/V ≥1.5 with use of high-flux dialyzer for 5 yr | More-efficient clearance of toxins that are pruritogenic | VAS | 15.3% with aggravated pruritus, 33.3% unchanged, and 51.4% improved |
| Chou et al., 200061 |
Retrospective cohort, 37 HD patients with secondary hyperparathyroidism, of which 22 had pruritus | Parathyroidectomy | Increase of Mg, Ca, and Phos might increase pruritus by metastatic cutaneous calcification (Ca x Phos) and stimulation of itch receptors | VAS and BRS | VAS decreased from 5.4 ± 3.2 to 1.8 ± 1.5 (P < 0.001) |
| Pederson et al., 198062 | Placebo-controlled, crossover, double-blind trial including 20 HD patients | Oral charcoal 6 g daily compared to placebo dextrose for 8 wk | Reduce GI absorption of uremic toxins that are pruritogenic | Uremic pruritus score | Reduction in uremic pruritus score (33% ± 15%) (P = 0.01) |
|
Peripheral neuropathy Gabapentin or pregabalin | |||||
| Gunal et al., 200452 | Randomized, placebo-controlled, double-blind crossover trial including 25 HD patients | Gabapentin 300 mg or placebo thrice weekly for 4 wk at the end of HD | Mimics the neurotransmitter GABA | VAS | Pruritus decreased to 1.2 ± 1.8 (gabapentin; P < 0.01) and to 7.6 ± 2.6 (placebo; P = 0.01) from a mean of 8.4 ± 0.94 |
| Yue et al., 201563 |
Randomized, prospective, double-blind study including 188 HD or PD patients | Pregabalin 75 mg twice weekly (PD) or daily (after HD), ondansetron 8 mg/d, or placebo for 12 wk | Suppresses release of presynaptic glutamate | VAS and modified Duo’s VAG scale | Pruritus improved in pregabalin group compared to ondansetron or placebo (P < 0.05) |
| Rayner et al., 201264 | Randomized trial including 71 CKD stage IV–V, HD, and PD patients with uremic pruritus | Gabapentin 100 mg or pregabalin 25 mg daily for 2 mo | As above | Pruritus scale (0–10) | Gabapentin relieved itching in 66% and pregabalin in 81% |
| Topical capsaicin | |||||
| Cho et al., 199765 |
Randomized, double-blind, placebo-controlled, crossover study including 22 HD patients with moderate to severe refractory pruritus | 2 subgroups with low PTH (≤35 pg/ml) or high PTH (≥35 pg/ml) assigned to capsaicin 0.025% cream or placebo-based cream for 8 wk | Depletes substance P, a potential pruritogen, from peripheral neurons | Pruritus score (mild, moderate, or severe) | Capsaicin cream was significantly more effective in improving the itching score (P < 0.001). 7 patients had complete resolution and 12 obtained significant relief (P < 0.01) |
| Serotonin antagonists | |||||
| Murphy et al., 200366 | Randomized, placebo-controlled, double-blind trial including 24 HD patients | Ondansetron 8 mg or placebo 3 times/d for 2 wk | 5-HT3, a potential pruritogen, receptor antagonist | VAS | Pruritus decreased by 16% during active treatment and 25% during placebo |
|
Immunomodulatory treatment Ultraviolet-B phototherapy | |||||
| Ko et al., 201167 | Single-blind, randomized, controlled trial for refractory uremic pruritus including 28 CKD stage III–V, HD, or PD patients | NB UV-B phototherapy 3× per wk for 6 wk or placebo with 10% incremental increase each session | UVB modulates T helper 1 and 2 lymphocyte differentiation and decreases production of IL-2 | VAS, sleep quality, and short-form McGill pain questionnaire | NB-UVB showed a significant improvement in VAS (P < 0.01) but not sleep quality |
| Gilchrest et al., 197768 | Randomized trial of 18 HD patients with severe pruritus | Exposure of UV A or B light therapy twice a wk for 4 wk | As above | Visual examination and severity of itching (none, mild, moderate, or severe) | 9 of 10 in the UVB group experienced dramatic improvement in pruritus (P < 0.01) |
| Gamma-linolenic acid | |||||
| Chen et al., 200669 | Prospective, randomized, double-blind, placebo-controlled, crossover study including 17 HD and PD patients in a single center with refractory uremic pruritus | GLA 2.2% cream or placebo once a day to entire body and to pruritic sites 3×/d for 2 wk with crossover after | GLA is an essential fatty acid associated with immune modulation of T lymphocytes and lymphokines | VAS and modified PS | Greater antipruritic effect with GLA than placebo with means of VAS (change ratio %)—(51.23% ± 29.41% vs. 14.97% ± 14.73%) and means of PS (change ratio %)— (40.36% ± 21.34% vs. 9.92% ± 11.62%; P < 0.01) |
| Yoshimoto-Furuie et al., 199970 | Double-blind, randomized trial including 16 HD patients with uremic pruritus | Oral supplementation with either ɣ-linolenic acid rich evening primrose oil (EPO) or linolenic acid (2 g/each) for 6 wk | As above | Questionnaire and visual inspection assessing dryness, pruritus, and erythema in a double-blind matter (5-grade) | EPO-exposed patients had significant improvement in the skin scores for the 3 different uremic skin symptoms and had increased levels of dihomo-ɣ-linolenic acid (precursor of PGE1) |
| Topical tacrolimus | |||||
| Duque et al., 200571 | Randomized, double-blind, vehicle-controlled study in a single US center including 22 HD patients with severe uremic pruritus | Topical tacrolimus ointment 0.1% 3× weekly or placebo for 4 wk only on pruritic areas | Prevents transcription of messenger RNA for various inflammatory cytokines (IL-2) in Th1 and Th2 | VAS and 3-point Liekert scale | No difference in severity between groups |
| Opioid | |||||
| Difelikefalin | |||||
| Fishbane et al., 202019 | Double-blind, randomized placebo-controlled study including 378 HD patients with moderate to severe pruritus at 56 US sites | 2 groups: i.v. difelikefalin (CR845) (0.5 μg/kg of dry BWT) or placebo 3× per wk for 12 wk | Peripherally restricted, selective kappa opioid receptor agonist | 24-hour WI-NRS, 5-D itch scale, and Skindex-10 scale | Primary: improvement of ≥3 points from baseline at wk 12 in weekly mean 24-h WI-NRS (51.9% vs. 30.9%, P < 0.01) Secondary: improvement of 5-D itch scale (–5 ± 0.3 vs. –3.7 ± 0.3) and the Skindex-10 scale (–17.2 ± 1.3 vs. 12 ± 1.2) |
| Naltrexone | |||||
| Pauli-Magnus et al., 200025 | Randomized, double-blind, placebo-controlled crossover study including 23 HD and PD patients with persistent pruritus | Naltrexone sequence (50 mg/d) or matched placebo with crossover for 4 wk | μ-opioid receptor antagonist | VAS, modified Pauli-Magnus scale | Pruritus decreased by 29.2% vs. 16.9% (placebo) on the VAS (P = 0.1) and by 17.6% vs. 22.3% (placebo) on the detailed score (P = 0.6) |
| Nalfurafine | |||||
| Kumagai et al., 201072 | Randomized, double-blind, placebo-controlled study including 337 HD patients with CKD-aP | Randomized 1:1:1 to 5 μg, 2.5 μg of nalfurafine or placebo for 2 wk | Peripheral κ-opioid receptor agonist that inhibits substance P, suppresses CNS μ | VAS | 5 and 2.5 μg of nalfurafine significantly improved pruritus intensity compared to placebo (P < 0.01) |
| Nalbuphine hydrochloride extended release | |||||
| Mathur et al., 201773 |
Multicenter, randomized, double-blind, placebo-controlled trial including 373 HD patients with moderate to severe pruritus | Randomized 1:1:1 to nalbuphine 120 mg, 60 mg, or placebo for 8 wk | μ-opioid receptor antagonist and κ-opioid receptor agonist | Numerical rating scale (0–10) | The mean NRS declined by 3.5 (nalbuphine 120 mg) vs. 2.8 (placebo; P = 0.02), no significant difference between nalbuphine 60 mg and placebo |
| Acupuncture | |||||
| Che-Yi et al., 200574 |
Randomized controlled trial including 40 HD patients with refractory pruritus | Acupuncture 3 times weekly or sham control for 1 and 3 mo | Block spinal cord release of opioid-like substances | Pruritus score questionnaire | Acupuncture had a significant reduction of pruritus at 4 and 12 wk vs. sham (P < 0.01) |
| Other | |||||
| Xerosis treatment | |||||
| Balaskas et al., 201175 | Randomized, double-blind, intraindividual, multicentric clinical study including 100 HD patients with moderate to severe CKD-aP | Applied twice/d an emulsion with glycerol 15%/paraffin 10% on 1 leg and the emulsion alone on the other leg for 7 d | Moisturizing and emollient therapy with high hydrating and covering properties | El Gammal Score | 73% reduction in El Gammal score in the treatment group vs. 44% in the comparator (P < 0.01) Pruritus severity decreased by 75% with treatment |
BWT, body weight; BRS, behavior rating scale; Ca, Calcium; CNS, central nervous system; EPO, erythropoietin; El Gammal, clinical score to grade pruritus; GI, gastrointestinal; GLA, gamma-linolenic acid; HD, hemodialysis; IL, interleukin; Mg, magnesium; NB, narrowband; NRS, numerical rating scale; PD, peritoneal dialysis; PGE1, prostaglandin E1; Phos, phosphorus; PTH, parathyroid hormone; PS, pruritus score; QOL, quality of life; UV, ultraviolet; WI-NRS, Worst Itching Intensity Numerical Rating Scale; VAS, visual analog scale.