Pharmacological interventions for pruritus in adult palliative care patients

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reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data.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.