Abstract: In total, we included 50 studies and 1916 participants in the review. We added 10 studies with 627 participants for this update. Altogether, we included 39 different treatments for pruritus in four different patient groups. The overall risk of bias profile was heterogeneous and ranged from high to low risk. However, 48 studies (96%) had a high risk of bias due to low sample size (i.e. fewer than 50 participants per treatment arm). Using GRADE criteria, we downgraded our judgement on the quality of evidence to moderate in seven and to low in three comparisons for our primary outcome (pruritus), mainly due to imprecision and risk of bias. In palliative care participants with pruritus of different nature, the treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, reduced pruritus by 0.78 points (numerical analogue scale from 0 to 10; 95% confidence interval (CI) −1.19 to −0.37; one RCT, N = 48, quality of evidence: moderate) compared to placebo. For participants suffering from uraemic pruritus (UP), gabapentin was more effective than placebo (visual analogue scale (VAS): 0 to 10), mean difference (MD) −5.91, 95% CI −6.87 to −4.96; two RCTs, N = 118, quality of evidence: moderate). The κ-opioid receptor agonist nalfurafine showed amelioration of UP (VAS 0 to 10, MD −0.95, 95% CI −1.32 to −0.58; three RCTs, N = 422, quality of evidence: moderate) and only few adverse events. Moreover, cromolyn sodium relieved UP participants from pruritus by 2.94 points on the VAS (0 to 10) (95% CI −4.04 to −1.83; two RCTs, N = 100, quality of evidence: moderate) compared to placebo. In participants with cholestatic pruritus (CP), data favoured rifampin (VAS: 0 to 100, MD −24.64, 95% CI −31.08 to −18.21; two RCTs, N = 42, quality of evidence: low) and flumecinol (RR > 1 favours treatment group; RR 1.89, 95% CI 1.05 to 3.39; two RCTs, N = 69, quality of evidence: low) and showed a low incidence of adverse events in comparison with placebo. The opioid antagonist naltrexone reduced pruritus for participants with CP (VAS: 0 to 10, MD −2.26, 95% CI −3.19 to −1.33; two RCTs, N = 52, quality of evidence: moderate) compared to placebo. However, effects in participants with UP were inconclusive (percentage difference −12.30%, 95% CI −25.82% to 1.22%, one RCT, N = 32). Furthermore, large doses of opioid antagonists (e.g. naltrexone) could be inappropriate in palliative care patients because of the risk of reducing analgesia. For participants with HIV-associated pruritus, it is uncertain whether drug treatment with hydroxyzine hydrochloride, pentoxifylline, triamcinolone or indomethacin reduces pruritus because the evidence was of very low quality (e.g. small sample size, lack of blinding). Different interventions tended to be effective for CP and UP. 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: In June 2016, we found 50 studies that tested 39 different drugs in 1916 people with itch. An ideal antipruritic (anti-itch) therapy is currently lacking. However, there was enough evidence to point out some possibly useful treatments for particular causes of the itch. These included gabapentin, nalfurafine and cromolyn sodium for itch associated with chronic kidney disease, and rifampicin and flumecinol for itch associated with liver problems. Paroxetine may be useful for palliative care patients whatever the cause of the itching, although evidence was only available from one study. Overall, most of the drugs caused few and mild side effects. Naltrexone showed by far the most side effects. Overall the evidence ranged from very low to moderate quality. 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 itch (pruritus) are needed.