This review replaces an earlier review, “Methadone for chronic non-cancer pain in adults”. This review serves to update the original and includes only studies of neuropathic pain. Methadone belongs to a class of analgesics known as opioids, that are considered the cornerstone of therapy for moderate-to-severe postsurgical pain and pain due to life-threatening illnesses; however, their use in neuropathic pain is controversial. Methadone has many characteristics that differentiate it from other opioids, which suggests that it may have a different efficacy and safety profile.

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

We searched the following databases: CENTRAL (CRSO), MEDLINE (Ovid), and Embase (Ovid), and two clinical trial registries. We also searched the reference lists of retrieved articles. The date of the most recent search was 30 November 2016.

We included randomised, double-blind studies of two weeks’ duration or longer, comparing methadone (in any dose, administered by any route, and in any formulation) with placebo or another active treatment in chronic neuropathic pain.

We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. There were insufficient data to perform pooled analyses. We assessed the overall quality of the evidence for each outcome using GRADE and created a ‘Summary of findings’ table.

We included three studies, involving 105 participants. All were cross-over studies, one involving 19 participants with diverse neuropathic pain syndromes, the other two involving 86 participants with postherpetic neuralgia. Study phases ranged from 20 days to approximately eight weeks. All administered methadone orally, in doses ranging from 10 mg to 80 mg daily. Comparators were primarily placebo, but one study also included morphine and tricyclic antidepressants.

The included studies had several limitations related to risk of bias, particularly incomplete reporting, selective outcome reporting, and small sample sizes.

There were very limited data for our primary outcomes of participants with at least 30% or at least 50% pain relief. Two studies reported that 11/29 participants receiving methadone achieved 30% pain relief versus 7/29 participants receiving placebo. Only one study presented data in a manner that allowed us to calculate the number of participants with at least 50% pain relief. None of the 19 participants achieved a 50% reduction in pain intensity, either when receiving methadone or when receiving placebo. No study provided data for our other primary outcomes of Patient Global Impression of Change scale (PGIC) much or very much improved (equivalent to at least 30% pain relief) and PGIC very much improved (equivalent to at least 50% pain relief).

For secondary efficacy outcomes, one study reported maximum and mean pain intensity and pain relief, and reported statistically significant improvements versus placebo for all outcomes with 20 mg daily doses of methadone, but not with 10 mg daily doses. The second study reported differences in pain reduction between methadone (n = 26) and morphine (n = 38) and found morphine to be statistically superior. The third study reported the number of responders (variously defined) for several pain and functional outcomes and found methadone to be statistically superior to placebo for the outcomes of categorical pain intensity and evoked pain. In the two studies that reported data, 0/29 participants withdrew due to lack of efficacy, whereas 4/29 participants withdrew due to adverse events while taking methadone versus 3/29 while taking placebo.

One study reported incidences for several individual adverse events, but found a statistically significant increased incidence for methadone over placebo for only one event, dizziness. The other studies did not report data in a manner that enabled us to analyze adverse events. There were no serious adverse events or deaths reported.

We assessed the quality of the evidence as very low for all efficacy and safety outcomes using GRADE, primarily because of the heterogeneity of study designs and populations, short durations, cross-over methodology, and few participants and events.

The three studies provide very limited, very low quality evidence of the efficacy and safety of methadone for chronic neuropathic pain, and there were too few data for pooled analysis of efficacy or harm, or to have confidence in the results of the individual studies. No conclusions can be made regarding differences in efficacy or safety between methadone and placebo, other opioids, or other treatments.

Bottom line
There is no good evidence to support or reject the suggestion that methadone works in any neuropathic pain condition.

Background
Neuropathic pain is pain coming from a damaged nervous system. It is different from pain messages that are carried along healthy nerves from damaged tissue (e.g. from a fall or cut, or an arthritic knee). Neuropathic pain is often treated by different medicines (drugs) from those used for pain from damaged tissue, which we often think of as painkillers. There are different types of neuropathic pain, with different causes. Some medicines that are used to treat depression or epilepsy can be very effective in some people with neuropathic pain by altering the signal that is carried along nerves that transmit painful stimuli (something that results in a change in how the body works). Sometimes opioid painkillers are used to treat neuropathic pain. Opioid painkillers are drugs such as morphine. Morphine is derived from plants, but many opioids are also made by chemical synthesis rather than being extracted from plants. Methadone is one of these synthetic opioids. Methadone has many characteristics that make it different from other opioids, which may influence its effectiveness or the side effects that patients experience.

Study characteristics
In November 2016, we searched for clinical trials where methadone was used to treat neuropathic pain in adults. We found three small studies, enrolling 105 participants, that met our requirements for the review. The studies were all quite different in their design: the methods of two studies reflected how frequently methadone is prescribed in practice, in that participants received it twice or three times daily. One trial had a more experimental design. All three trials had two phases. The lengths of the studies varied, from 20 days to around eight weeks for each phase. The studies were similar in that all administered low doses of methadone, which may or may not reflect the doses typically prescribed in clinical practice.

Key findings
Two studies looked at how many participants got at least 30% pain relief. Eleven of 29 participants receiving methadone achieved 30% pain relief versus seven of 29 receiving placebo. In one study, none of the 19 participants achieved a 50% reduction in pain intensity, either when receiving methadone or when receiving placebo (a sugar pill). These reductions in pain intensity have been shown to be important to patients. In addition, one study found improvements in average and maximum pain intensity and pain relief when comparing methadone with placebo.

In the two studies that reported dropouts from the study, none of 29 participants dropped out because they thought methadone or the placebo was not helping their pain; whereas four of 29 dropped out because of side effects while taking methadone and three of 29 while taking placebo.

One study reported how many participants had specific side effects, and found increased dizziness with methadone compared to placebo. There were no serious side effects or deaths reported. There was so little information from these studies that we concluded there was no convincing evidence to support or reject a meaningful benefit for methadone versus placebo or any other treatment.

Quality of the evidence
We rated the quality of the evidence as very low because there were only three small studies with different designs, and with few participants and events. In addition, the studies were probably not long enough to show how well methadone would work (or how safe it would be) over a longer time period. Very low quality evidence means that we are very uncertain about the results.