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McNicol ED, Ferguson MC, Schumann R Methadone for neuropathic pain in adults. Cochrane Database Syst Rev. 2017 May 17;5:CD012499. doi: 10.1002/14651858.CD012499.pub2.
Discipline Area Score
Nurse 6 / 7
Physician 4 / 7
Abstract

BACKGROUND: 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.

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

SEARCH METHODS: 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.

SELECTION CRITERIA: 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.

DATA COLLECTION AND ANALYSIS: 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.

MAIN RESULTS: 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.

AUTHORS' CONCLUSIONS: 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.

Comments from MORE raters

Nurse rater

As a Nurse Practitioner who manages acute and chronic pain syndromes which can be commonly associated with neuropathic symptoms, it is important to know that methadone is being considered. However, the studies which have been evaluated do not provide enough support for routine use of methadone for neuropathic pain. Additional, more rigorous trials are required to support the use of methadone in management of neuropathic pain.

Nurse rater

It's always good to have the evidence even if it tells us there really isn't any.

Nurse rater

More information needs to be included about treatment contamination with other (non-opioids and non-narcotic) types of pain medication in this population before drawing conclusions. Limited details are included and clinical trials should carefully collect details that may influence outcomes.

Nurse rater

There is very limited evidence to judge the effectiveness of methadone in neuropathic pain. However, epidemiological data suggesting an increased risk of adverse events in people receiving methadone versus other opioids (CDC 2012; Ray 2015), imply that methadone should not be considered a first-line opioid.

Nurse rater

This article provides very useful information for clinicians who treat neuropathic pain in adult patients.

Nurse rater

With the increasing issue of opoid usage, a study demonstrating non-usefulness of them is good whether study of poor quality or not.

Physician rater

Given that the pendulum is swinging away from use of opioids for any chronic pain, and given the unique place that methadone has for treatment of opioid dependence, this review is unlikely to change current practice.

Physician rater

There is very low quality evidence to support the use of methadone for adults with neuropathic pain, as in the previous review.

Physician rater

This is a robust systematic review showing that the evidence on methadone in neuropathic pain is scarce and of poor quality. This is useful to know for clinicians, considering that alternative effective treatments for this condition are available.
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