Abstract

Background

Neuropathic pain, which is caused by a lesion or disease affecting the somatosensory system, may be central or peripheral in origin. Neuropathic pain often includes symptoms such as burning or shooting sensations, abnormal sensitivity to normally painless stimuli, or an increased sensitivity to normally painful stimuli. Neuropathic pain is a common symptom in many diseases of the nervous system. Opioid drugs, including morphine, are commonly used to treat neuropathic pain. Most reviews have examined all opioids together. This review sought evidence specifically for morphine; other opioids are considered in separate reviews.

Objectives

To assess the analgesic efficacy and adverse events of morphine for chronic neuropathic pain in adults.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for randomised controlled trials from inception to February 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries.

Selection criteria

We included randomised, double‐blind trials of two weeks' duration or longer, comparing morphine (any route of administration) with placebo or another active treatment for neuropathic pain, with participant‐reported pain assessment.

Data collection and analysis

Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables.

Main results

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.

Authors' conclusions

There was insufficient evidence to support or refute the suggestion that morphine has any efficacy in any neuropathic pain condition.

Author(s)

Tess E Cooper, Junqiao Chen, Philip J Wiffen, Sheena Derry, Daniel B Carr, Dominic Aldington, Peter Cole, R Andrew Moore

Abstract

Plain language summary

Morphine for neuropathic pain in adults

Bottom line

There is very low quality evidence that morphine taken by mouth has any important effect on pain in people with moderate or severe neuropathic pain.

Background

Neuropathic pain comes from damaged nerves. It is different from pain messages that are carried along healthy nerves from damaged tissue (a fall or cut, or arthritic knee). Neuropathic pain is often treated by different medicines (drugs) to those used for pain from damaged tissue, which we often think of as painkillers. Medicines that are sometimes used to treat depression or epilepsy can be effective in some people with neuropathic pain. Opioid painkillers are sometimes used to treat neuropathic pain.

Opioid painkillers are drugs like morphine. Morphine is derived from plants or synthesised by chemists. Morphine is widely available for use as a painkiller, usually given by mouth.

Our definition of a good result was someone with a high level of pain relief and able to keep taking the medicine without side effects making them want to stop.

Study characteristics

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.

Key results

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.

Quality of the evidence

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.

Author(s)

Tess E Cooper, Junqiao Chen, Philip J Wiffen, Sheena Derry, Daniel B Carr, Dominic Aldington, Peter Cole, R Andrew Moore

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For people with neuropathic pain

There is no convincing evidence that oral morphine at doses up to 180 mg/day is effective in relieving neuropathic pain in the longer term.

For clinicians

There is no convincing evidence that morphine at doses up to 180 mg/day is effective in relieving neuropathic pain in the longer term. There is no good evidence demonstrating high levels of analgesia (at least 50% pain reduction, for example) in good quality studies lasting at least 12 weeks. That does not exclude the possibility that an as‐yet undefined subgroup of people may get a good response with morphine.

For policy makers

There is no convincing evidence that morphine at doses up to 180 mg/day is effective in relieving neuropathic pain in the longer term. There is no good evidence demonstrating high levels of analgesia (at least 50% pain reduction, for example) in good quality studies lasting at least 12 weeks. That does not exclude the possibility that an as‐yet undefined subgroup of people may get a good response with morphine.

For funders

There is no strongly convincing evidence to support the suggestion that morphine has any efficacy in relieving neuropathic pain, but we cannot exclude the possibility that an as‐yet undefined subgroup of people may get a good response with morphine. In the absence of any additional supporting evidence, morphine should probably be available only at the discretion of a pain specialist with particular expertise in neuropathic pain.

Implications for research 

General

The design of studies in neuropathic pain, and the outcomes, are well understood, but as the number of people experiencing good pain relief with morphine over the longer term (12 weeks) is likely to be small, an enriched‐enrolment randomised‐withdrawal (EERW) design might provide the highest sensitivity to detect a signal (Moore 2015c). Since combination therapy for neuropathic pain has been reported to be more effective than monotherapy with any drug (Chaparro 2012), and combination therapy is common clinical practice, studies examining morphine in combination with a gabapentinoid or antidepressant could be of interest.

Design

Reporting of clinically relevant outcomes using appropriate imputation for withdrawal would improve the relevance of the findings for clinical practice. The use of EERW designs for comparison with classic trial designs indicates that good quality EERW designs of long duration may be appropriate for neuropathic pain.

Stratification by phenotype might be an interesting possibility for future studies (Baron 2017), as well as the possibility of measuring pain scores with activity (including dynamic tactile allodynia) versus at rest or on average/worst/best over prior 24 hours.

While pain is important, other outcomes relating to function, sleep, fatigue, and quality of life are important, and are probably closely linked (Hoffman 2010).

Measurement (endpoints)

Assessment of neuropathic pain and other symptoms should be based on dichotomous participant‐reported outcomes of confirmed clinical utility.

Comparison between active treatments

Without knowing whether morphine is effective, there seems little point in comparing it with other treatments.

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