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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Oral methadone for chronic noncancer pain: a systematic literature review of reasons for administration, prescription patterns, effectiveness, and side effects

JA Sandoval, AD Furlan, and A Mailis-Gagnon.

Review published: 2005.

CRD summary

This review assessed the indications, prescription, effectiveness and side-effects of oral methadone for the treatment of chronic non-cancer pain. The authors concluded that the use of oral methadone is based on uncontrolled studies and further research is needed. This review was generally well conducted and its conclusions can be considered reliable, although the effectiveness results may be overrated.

Authors' objectives

To assess the indications, prescription patterns, effectiveness and side-effects of oral methadone for the treatment of chronic non-cancer pain. This abstract will report on the effectiveness and side-effects only.


MEDLINE (1966 to June 2003) and EMBASE (1988 to July 2003) were searched for studies published in English, French, Spanish or Portuguese. Studies in other languages were included if sufficient information was reported in an English abstract. The search terms were reported. The reference lists of retrieved articles, reviews and text books were also checked and experts in the field were contacted.

Study selection

Study designs of evaluations included in the review

Studies of any design were eligible for inclusion.

Specific interventions included in the review

Studies of oral methadone were eligible for inclusion. Where reported, the maximum dose ranged from 20 to 930 mg/day.

Participants included in the review

Studies of participants, of any age and gender, with chronic pain of non-cancer origin were eligible for inclusion. The included participants had non-malignant pain (including neuropathic pain), post-herpetic neuralgia, post-stroke pain, sciatica, back pain, headaches and limb pain. Where reported, the ages of the participants ranged from children to 88 years old and there were similar numbers of men and women.

Outcomes assessed in the review

Studies that reported a pain outcome, including visual analogue scale (VAS), percentage of pain relief, use of rescue analgesic medication and patient satisfaction, were eligible for inclusion.

How were decisions on the relevance of primary studies made?

Two independent reviewers determined the eligibility of included studies. Any disagreements were resolved by consensus, with a third reviewer consulted if necessary.

Assessment of study quality

Controlled studies were assigned a quality score from zero to 5, based on the Jadad scale, in order to assess randomisation, blinding, and the reporting of withdrawals and drop-outs. High-quality studies were defined as those with 3 or more points, while low-quality studies had 2 points or less. The validity of uncontrolled studies was not assessed.

The authors did not state how many reviewers performed the quality assessment.

Data extraction

The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction.

Data were extracted on the effectiveness of pain relief and side-effects reported in each included study. The authors categorised effectiveness as 'meaningful, non-meaningful or unclassifiable'. 'Meaningful' relief was defined as one of the following: statistically significant change in any quantitatively measured outcome; 'satisfactory' or 'acceptable' pain relief in well-defined categorical outcomes; or 'worthwhile' relief obtained through narratives based on the consensus of the three reviewers. 'Non-meaningful' relief was defined as one of the following: relief less than 30% of the pain reduction; 'mild' or 'no' relief of the original pain. 'Unclassifiable relief' was when the degree of relief was not defined.

Methods of synthesis

How were the studies combined?

The results of each included study were tabulated and presented in a narrative, grouped by study design. The results for side-effects were also presented graphically.

How were differences between studies investigated?

Differences were apparent by tabulation of the studies.

Results of the review

Twenty-one studies (n=545) were included in the review: one randomised controlled trial (RCT; n=19), 7 case series (n=495) and 13 case reports (n=31).

One RCT, rated as high-quality, found that a statistically significant well-defined analgesic effect was seen for 20 mg/day methadone compared with placebo (based on 11 patients), but not for a dose of 10 mg/day. In the uncontrolled studies, methadone was associated with 'meaningful' pain relief results in 59% of patients, 'non-meaningful' in 40% and 'unclassifiable' in 1%. No conclusions could be drawn for specific pain syndromes, owing to the lack of available data.

The side-effects most frequently reported in the RCT and 10 of the 20 uncontrolled studies were considered minor. Such side-effects included nausea, vomiting, headache, somnolence, dizziness and constipation.

Authors' conclusions

The use of oral methadone for non-cancer pain is based on one high-quality, but small, randomised crossover placebo-controlled trial and uncontrolled studies. Well-designed controlled studies are needed to provide more accurate information on the efficacy of methadone in pain syndromes, in particular neuropathic pain.

CRD commentary

The review addressed a broad research question and this was reflected in the inclusion criteria. Several relevant sources were searched for eligible studies and attempts were made to minimise both publication and language bias. The authors used procedures to minimise bias at the study selection stage. The quality of the controlled studies was assessed using a published tool and the decision not to assess the quality of uncontrolled studies was appropriate. It was unclear whether procedures were undertaken to minimise reviewer error and bias in the data extraction or quality assessment.

The authors reported adequate details of each of the included studies, which highlighted clinical and methodological variation across the included studies, and tabulated the results clearly. However, the definitions used to categorise the effectiveness of pain relief seemed arbitrary and cannot be considered reliable, although this is unlikely to have affected the overall conclusion. The authors stated that the effectiveness result is likely to be overrated and should be interpreted with caution. In summary, the authors' conclusion appears to have been based on the best available evidence and is likely to be reliable.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that well-designed, large RCTs are needed to outline the effectiveness of oral methadone in well-defined non-cancer syndromes. In particular, studies are needed to look at methadone as a first-choice drug in neuropathic pain given its special action on N-methyl-D-aspartate receptors.

Bibliographic details

Sandoval J A, Furlan A D, Mailis-Gagnon A. Oral methadone for chronic noncancer pain: a systematic literature review of reasons for administration, prescription patterns, effectiveness, and side effects. Clinical Journal of Pain 2005; 21(6): 503-512. [PubMed: 16215336]

Indexing Status

Subject indexing assigned by NLM


Administration, Oral; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Methadone /administration & dosage /adverse effects; Narcotics /administration & dosage /adverse effects; Pain /classification /drug therapy; Pain Measurement; Review Literature as Topic



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 16215336

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