BACKGROUND: 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.
BACKGROUND: This is the third updated version of a Cochrane review first published in Issue 4, 2003 of The Cochrane Library and first updated in 2007. Morphine has been used for many years to relieve pain. Oral morphine in either immediate release or modified release form remains the analgesic of choice for moderate or severe cancer pain.
OBJECTIVES: To determine the efficacy of oral morphine in relieving cancer pain, and to assess the incidence and severity of adverse events.
SEARCH METHODS: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 9); MEDLINE (1966 to October 2015); and EMBASE (1974 to October 2015). We also searched ClinicalTrials.gov (1 October 2015).
SELECTION CRITERIA: Published randomised controlled trials (RCTs) using placebo or active comparators reporting on the analgesic effect of oral morphine in adults and children with cancer pain. We excluded trials with fewer than 10 participants.
DATA COLLECTION AND ANALYSIS: One review author extracted data, which were checked by another review author. There were insufficient comparable data for meta-analysis to be undertaken or to produce numbers needed to treat (NNTs) for the analgesic effect. We extracted any available data on the number or proportion of participants with 'no worse than mild pain' or treatment success (very satisfied, or very good or excellent on patient global impression scales).
MAIN RESULTS: We identified seven new studies in this update. We excluded six, and one study is ongoing so also not included in this update. This review contains a total of 62 included studies, with 4241 participants. Thirty-six studies used a cross-over design ranging from one to 15 days, with the greatest number (11) for seven days for each arm of the trial. Overall we judged the included studies to be at high risk of bias because the methods of randomisation and allocation concealment were poorly reported. The primary outcomes for this review were participant-reported pain and pain relief.Fifteen studies compared oral morphine modified release (Mm/r) preparations with morphine immediate release (MIR). Fourteen studies compared Mm/r in different strengths; six of these included 24-hour modified release products. Fifteen studies compared Mm/r with other opioids. Six studies compared MIR with other opioids. Two studies compared oral Mm/r with rectal Mm/r. Three studies compared MIR with MIR by a different route of administration. Two studies compared Mm/r with Mm/r at different times and two compared MIR with MIR given at a different time. One study was found comparing each of the following: Mm/r tablet with Mm/r suspension; Mm/r with non-opioids; MIR with non-opioids; and oral morphine with epidural morphine.In the previous update, a standard of 'no worse than mild pain' was set, equivalent to a score of 30/100 mm or less on a visual analogue pain intensity scale (VAS), or the equivalent in other pain scales. Eighteen studies achieved this level of pain relief on average, and no study reported that good levels of pain relief were not attained. Where results were reported for individual participants in 17 studies, 'no worse than mild pain' was achieved by 96% of participants (362/377), and an outcome equivalent to treatment success in 63% (400/638).Morphine is an effective analgesic for cancer pain. Pain relief did not differ between Mm/r and MIR. Modified release versions of morphine were effective for 12- or 24-hour dosing depending on the formulation. Daily doses in studies ranged from 25 mg to 2000 mg with an average of between 100 mg and 250 mg. Dose titration was undertaken with both instant release and modified release products. A small number of participants did not achieve adequate analgesia with morphine. Adverse events were common, predictable, and approximately 6% of participants discontinued treatment with morphine because of intolerable adverse events.The quality of the evidence is generally poor. Studies are old, often small, and were largely carried out for registration purposes and therefore were only designed to show equivalence between different formulations.
AUTHORS' CONCLUSIONS: The conclusions have not changed for this update. The effectiveness of oral morphine has stood the test of time, but the randomised trial literature for morphine is small given the importance of this medicine. Most trials recruited fewer than 100 participants and did not provide appropriate data for meta-analysis. Only a few reported how many people had good pain relief, but where it was reported, over 90% had no worse than mild pain within a reasonably short time period. The review demonstrates the wide dose range of morphine used in studies, and that a small percentage of participants are unable to tolerate oral morphine. The review also shows the wide range of study designs, and inconsistency in cross-over designs. Trial design was frequently based on titration of morphine or comparator to achieve adequate analgesia, then crossing participants over in cross-over design studies. It was not clear if these trials were sufficiently powered to detect any clinical differences between formulations or comparator drugs. New studies added to the review for the previous update reinforced the view that it is possible to use modified release morphine to titrate to analgesic effect. There is qualitative evidence that oral morphine has much the same efficacy as other available opioids.
To evaluate the efficacy and tolerability of oxycodone in cancer-related pain, we conducted a systematic review of randomized controlled trials. Four studies, comparing oral oxycodone with either oral morphine (n = 3) or oral hydromorphone (n = 1), were suitable for meta-analysis. Standardized mean differences in pain scores comparing oxycodone with control groups were pooled using random-effects models. Overall, there was no evidence that mean pain scores differed between oxycodone and control drugs (pooled standardized mean difference, 0.04; 95% confidence interval [CI], -0.29 to 0.36; P = .8; I(2) = 62%). In meta-regression analyses, pain scores were higher for oxycodone compared with morphine (0.20; 95% CI, -0.04 to 0.44) and lower compared with hydromorphone (-0.36; 95% CI, -0.71 to 0.00), although these effect sizes were small. The efficacy and tolerability of oxycodone are similar to morphine, supporting its use as an opioid for cancer-related pain.
PURPOSE: To evaluate effectiveness and safety information of transdermal fentanyl (TDF) (Duragesic/Durogesic) and sustained-release oral morphine (SRM) in cancer pain (CP) and chronic non-cancer pain (NCP), a pooled analysis was conducted on datasets of published, open label, uncontrolled (no comparator group) and randomised controlled (with SRM as comparator) studies of TDF.
PATIENTS AND METHODS: Eight trials with treatment durations of at least 28 days met the inclusion criteria. The effectiveness analysis assessed changes in average pain and pain 'right now' scores between baseline and Day 28. The safety analysis evaluated the incidence of adverse events (AEs) reported within the first 28 days of treatment with TDF or SRM. Subgroup analyses included pain type, gender, age, weight, and body mass index.
RESULTS: Pooled efficacy data were available from 1220 patients; these showed that both TDF and SRM were effective in improving pain 'right now' scores (0-100 scale) from baseline to Day 28. The improvement was significantly more pronounced in the TDF treatment group (-26.7 +/- 31.3 for TDF, -18.7 +/- 30.9 for SRM, p = 0.002). This favourable effect of TDF was most apparent amongst patients with NCP. Data concerning AEs were available from over 2500 patients with CP (3 out of 10 patients) or chronic NCP (7 out of 10 patients). Significantly fewer patients in the TDF than in the SRM group reported any AE (72% vs. 87% respectively; p < 0.001), or an AE leading to the study drug being permanently discontinued (16% vs. 23% respectively; p < 0.001). Constipation and somnolence occurred considerably less frequently in the TDF than in the SRM treatment group. This difference was statistically significant in both the CP and NCP subgroups.
CONCLUSION: This pooled data analysis provides expanded insight into the safety and effectiveness profile of transdermal fentanyl in patients with chronic pain. It shows significantly improved pain relief with transdermal fentanyl compared with sustained-release oral morphine, and supports current evidence of favourable tolerability of transdermal fentanyl, particularly with regard to reduced constipation and somnolence.
Prescriptions for controlled-release oxycodone, a narcotic analgesic, recently contributed to a dramatic increase in pharmacy costs for a large private insurance company. To determine whether this agent offered clinical benefits over other available drugs that would justify its significantly greater cost, a systematic review of 16 clinical trials was undertaken. The review suggested that immediate-release and controlled-release preparations of oxycodone have similar efficacy and comparable side effect profiles. Controlled-release oxycodone has the advantage of less frequent dosing than immediate-release oxycodone; however, other agents may be dosed infrequently at much lower costs. For patients requiring a controlled-release opioid treatment, controlled-release morphine and methadone should be considered because they appear to be as effective as oxycodone and cost considerably less. Controlled-release oxycodone may be appropriate for some patients, particularly if they cannot tolerate other controlled-release or long-acting opioid analgesics.
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.
