This is an updated review originally published in 2004 and first updated in 2007. This version includes substantial changes to bring it in line with current methodological requirements. Methadone is a synthetic opioid that presents some challenges in dose titration and is recognised to cause potentially fatal arrhythmias in some patients. It does have a place in therapy for people who cannot tolerate other opioids but should be initiated only by experienced practitioners. This review is one of a suite of reviews on opioids for cancer pain.Objectives
To determine the effectiveness and tolerability of methadone as an analgesic in adults and children with cancer pain.Search methods
For this update we searched CENTRAL, MEDLINE, Embase, CINAHL, and clinicaltrials.gov, to May 2016, without language restriction. We also checked reference lists in relevant articles.Selection criteria
We sought randomised controlled trials comparing methadone (any formulation and by any route) with active or placebo comparators in people with cancer pain.Data collection and analysis
All authors agreed on studies for inclusion. We retrieved full texts whenever there was any uncertainty about eligibility. One review author extracted data, which were checked by another review author. There were insufficient comparable data for meta‐analysis. We extracted information on the effect of methadone on pain intensity or pain relief, the number or proportion of participants with 'no worse than mild pain'. We looked for data on withdrawal and adverse events. We looked specifically for information about adverse events relating to appetite, thirst, and somnolence. We assessed the evidence using GRADE and created a 'Summary of findings' table.Main results
We revisited decisions made in the earlier version of this review and excluded five studies that were previously included. We identified one new study for this update. This review includes six studies with 388 participants. We did not identify any studies in children.
The included studies differed so much in their methods and comparisons that no synthesis of results was feasible. Only one study (103 participants) specifically reported the number of participants with a given level of pain relief, in this case a reduction of at least 20% ‐ similar in both the methadone and morphine groups. Using an outcome of 'no worse than mild pain', methadone was similar to morphine in effectiveness, and most participants who could tolerate methadone achieved 'no worse than mild pain'. Adverse event withdrawals with methadone were uncommon (12/202) and similar in other groups. Deaths were uncommon except in one study where the majority of participants died, irrespective of treatment group. For specific adverse events, somnolence was more common with methadone than with morphine, while dry mouth was more common with morphine than with methadone. None of the studies reported effects on appetite.
We judged the quality of evidence to be low, downgraded due to risk of bias and sparse data. For specific adverse events, we considered the quality of evidence to be very low, downgraded due to risk of bias, sparse data, and indirectness, as surrogates for appetite, thirst and somnolence were used.
There were no data on the use of methadone in children.Authors' conclusions
Based on low‐quality evidence, methadone is a drug that has similar analgesic benefits to morphine and has a role in the management of cancer pain in adults. Other opioids such as morphine and fentanyl are easier to manage but may be more expensive than methadone in many economies.
Alexander B Nicholson, Graeme R Watson, Sheena Derry, Philip J Wiffen
Plain language summary
Methadone (an opioid drug) for treating people with cancer pain
Methadone taken by mouth provided good pain relief for most adults with moderate or severe cancer pain.
One person in two or three who gets cancer will suffer from pain that becomes moderate or severe in intensity. The pain tends to get worse as the cancer progresses. Methadone has been used for many years as one of a number of different pain killers for cancer pain.
In this updated review we set out to estimate how well methadone worked, how many people had side effects, and how severe those side effects were – for example, whether they were so severe that participants stopped taking their methadone.
In May 2016, we found just six studies with 388 adult participants. The studies were often small, and compared different preparations.
For pain relief there did not seem to be much difference between methadone and morphine. For most people pain was reduced from moderate or severe to mild or no pain with methadone. Methadone is associated with some unwanted effects, mainly sleepiness, constipation, and dry mouth. These can be severe enough to stop people taking methadone. No data were available about the use of methadone in children.
We would like to see more consistency in study design, and especially in study reporting, which should include information on unwanted effects and the outcome of pain reduced to tolerable levels, that is, no worse than mild pain, so that people with cancer are not bothered by pain.
Quality of the evidence
We rated the quality of the evidence from studies using four levels: very low, low, moderate, or high. Very low quality evidence means that we are very uncertain about the results. High quality evidence means that we are very confident in the results. The quality of the evidence was low or very low.
Alexander B Nicholson, Graeme R Watson, Sheena Derry, Philip J Wiffen
Implications for practice For patients with cancer pain
There is limited evidence from RCTs that methadone is effective in managing severe pain due to cancer in adults. Given the issues of difficulties around titration to an effective dose and also the possibility of severe adverse effects (particularly cardiac arrhythmias), it is unlikely to have a role as the first line of treatment.For clinicians managing cancer pain
Methadone is an opioid that has been used for many years to treat severe cancer pain although the evidence base from randomised controlled trials is sparse. If other opioids are not tolerated it may have a role, providing the issues of dose titration and possible severe adverse effects are considered. There is no information for use in paediatrics.For policy makers
Methadone has a role if other opioids are not tolerated, providing the issues of dose titration and possible severe adverse effects are considered. There is no information for use in paediatrics.For organisations or bodies making decisions about funding treatment options
Methadone has a place on formularies but needs to be managed by those clinicians specialising in pain management and palliative care.
Implications for research General implications
Research in this patient population is challenging, and no large, high‐quality trials with well‐managed bias have been conducted. A further consideration is the question of whether, with the increased concerns about the adverse effects of methadone on the prolongation of the QT interval, and greater recognition of significant methadone‐related drug interaction, methadone is likely to be used more widely than at present, even with further research. While it would be easy to suggest that further research is needed, in practice this is very unlikely to happen as this is an old drug and funding is not likely to be forthcoming.Implications for study design
The major problem with research involving methadone relates to its unique pharmacological characteristics. Repeated dose studies using methadone at fixed dose intervals is potentially hazardous in the early phase of pain management in a switch from another opioid, or when treating opioid‐naive patients.Implications for measurement and outcomes
As the distribution of response to analgesics is often bimodal, we strongly recommend the collection of dichotomous data in preference to mean pain scores. Data should be available to allow the estimation of the proportion of participants who achieve no worse than mild pain, defined as below 30 mm on a 100 mm VAS pain‐intensity scale. Adverse events should always be reported but we advocate specific reporting of events affecting appetite, thirst and consciousness in line with the Neuberger report (DH 2013).
Other considerations for future study design include:
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