Abstract: We identified five randomised, double-blind, cross-over studies with treatment periods of four to seven weeks, involving 236 participants in suitably characterised neuropathic pain; 152 (64%) participants completed all treatment periods. Oral morphine was titrated to maximum daily doses of 90 mg to 180 mg or the maximum tolerated dose, and then maintained for the remainder of the study. Participants had experienced moderate or severe neuropathic pain for at least three months. Included studies involved people with painful diabetic neuropathy, chemotherapy-induced peripheral neuropathy, postherpetic neuralgia criteria, phantom limb or postamputation pain, and lumbar radiculopathy. Exclusions were typically people with other significant comorbidity or pain from other causes. Overall, we judged the studies to be at low risk of bias, but there were concerns over small study size and the imputation method used for participants who withdrew from the studies, both of which could lead to overestimation of treatment benefits and underestimation of harm. There was insufficient or no evidence for the primary outcomes of interest for efficacy or harm. Four studies reported an approximation of moderate pain improvement (any pain-related outcome indicating some improvement) comparing morphine with placebo in different types of neuropathic pain. We pooled these data in an exploratory analysis. Moderate improvement was experienced by 63% (87/138) of participants with morphine and 36% (45/125) with placebo; the risk difference (RD) was 0.27 (95% confidence interval (CI) 0.16 to 0.38, fixed-effects analysis) and the NNT 3.7 (2.6 to 6.5). We assessed the quality of the evidence as very low because of the small number of events; available information did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different was very high. A similar exploratory analysis for substantial pain relief on three studies (177 participants) showed no difference between morphine and placebo. All-cause withdrawals in four studies occurred in 16% (24/152) of participants with morphine and 12% (16/137) with placebo. The RD was 0.04 (-0.04 to 0.12, random-effects analysis). Adverse events were inconsistently reported, more common with morphine than with placebo, and typical of opioids. There were two serious adverse events, one with morphine, and one with a combination of morphine and nortriptyline. No deaths were reported. These outcomes were assessed as very low quality because of the limited number of participants and events. There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.

Plain-language summary: In February 2017, we searched for clinical trials in which morphine was used to treat neuropathic pain in adults. Five studies satisfied the inclusion criteria, randomising 236 participants to treatment with morphine, placebo, or other drugs. Studies lasted four to seven weeks. Few studies reported beneficial outcomes that would be regarded as clinically relevant. Four small studies reported that pain was reduced by between a quarter and a third in some people. This level of pain reduction was experienced by 6 in 10 participants with morphine and 4 in 10 with placebo. Between 1 and 2 in 10 participants withdrew from treatment with both morphine and placebo, but the reasons were not given. Side effects were poorly reported, but were more common with morphine than with placebo, and included drowsiness, dizziness, constipation, feeling sick, dry mouth, and decreased appetite. The evidence was of very low quality. This means that the research did not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different is very high. Small studies like those in this review tend to overestimate results of treatment compared to the effects found in larger, better designed studies. There were other problems that might lead to over-optimistic results. The very low quality evidence and the lack of any important benefit mean that we need new, longer-lasting, large trials before we will know if morphine is useful for the treatment of neuropathic pain.