Besides being one of the least expensive opioid analgesics, methadone has characteristics that differentiate it from other opioids and suggest that it may have a different efficacy and safety profile. Researchers in Denmark conducted a Cochrane Systematic Review to assess the analgesic efficacy and safety of methadone in the treatment of chronic noncancer pain, but they found little relevant supportive evidence.
Researchers at the Danish Pain Research Center in Aarhus, Denmark, conducted an extensive literature review to identify both randomized controlled trials (RCTs) and non-randomized studies of methadone use in chronic noncancer pain (CNCP) in adults [Haroutiunian et al. 2012]. Their search covered the Cochrane Central Register of Controlled Trials, MEDLINE (from 1950 to November 2011), and EMBASE (1980 to November 2011), together with reference lists in retrieved papers and reviews.
The researchers included RCTs with pain assessment as either the primary or secondary outcome. Lower-quality evidence from quasi-randomized studies, cohort trials, and case-control trials also was considered for inclusion since the investigators suspected that benefits and risks of methadone in CNCP were not adequately addressed in RCTs.
The literature searches yielded 49 potentially relevant studies, of which only 3 were adequate to meet inclusion criteria: 2 RCTs and 1 non-randomized study, involving a total of 181 participants. Both RCTs were cross-over studies, one involving 19 participants with diverse neuropathic pain syndromes and the other involving 76 participants with postherpetic neuralgia — study duration was 20 days and approximately 8 weeks, respectively. The non-randomized study retrospectively evaluated 86 outpatients during an average of roughly 9 months. Here are specific outcomes…
- One RCT examined average pain intensity and pain relief, and found statistically significant improvements with methadone versus placebo for both outcomes, with 10 mg and 20 mg daily doses of methadone.
- The second RCT investigated differences in pain reduction between methadone and morphine, with morphine being statistically superior.
- The non-randomized study found that methadone was effective in proportionately fewer participants than in those prescribed other long-acting opioids: ie, 28% versus 42%, 33%, and 50% for morphine, oxycodone, and transdermal fentanyl, respectively.
- Incidences of adverse events were assessed in 1 RCT, but a significant difference between methadone and placebo was found for only one event, dizziness (P = 0.04).
The researchers conclude that the 3 studies of reasonable quality provide very limited evidence of methadone’s efficacy for CNCP. Furthermore, there were too few data for a pooled meta-analysis of efficacy or harm, or to have confidence in the results of the individual studies. Therefore, they concede that on the basis of available evidence no conclusions can be affirmed regarding differences in efficacy or safety between methadone and placebo, other opioids, or other treatments.
COMMENTARY: Systematic reviews and meta-analyses were discussed in a previous UPDATE [here], and approaches endorsed by the Cochrane Collaboration are among the most rigorous and thorough. Therefore, a strikingly unexpected finding of this study by Haroutiunian et al. was there are so few studies of reasonable quality examining methadone for chronic noncancer pain.
Methadone has been available since the 1940s and was originally used as an analgesic; however, early applications in children and adults revealed how difficult methadone can be to safely prescribe and its widespread use for analgesia was disparaged until roughly 1999. However, there have been problems associated with the resurgence of methadone prescribed for pain.
As we noted in an UPDATE last July [here], the U.S. Centers for Disease Control and Prevention (CDC) reported that methadone accounted for 4.4 million (1.7%) of the 257 million opioid analgesic prescriptions in 2009; however, about 5,000 persons died of methadone-related overdose, which accounted for approximately 30% of all deaths associated with prescription opioids. Methadone-related deaths reportedly increased 6-fold from 1999 to 2009 [see Figure].
Methadone appears to carry greater risks than other opioids because it tends to build up in the body and can incur respiratory depression or, allegedly, cardiac rhythm disturbances. CDC researchers stress, however, that methadone has been used safely and effectively for decades in treating opioid addiction, and that modality does not appear to be part of the current problems.
In an excellent commentary article, Reisfield and Friedman [2012] recently observed, “The paradox is that, whereas methadone maintenance therapy has reduced the mortality associated with opioid addiction, methadone analgesic therapy for chronic pain has been an outsized source of opioid-related deaths.” They further note that patients with substance use disorders and comorbid pain are at particularly high risk of adverse events with methadone analgesic therapy.
As an opioid analgesic, methadone is a relatively inexpensive generic product, so there may have been little incentive (or funding) through the years to conduct high quality studies of its efficacy or safety for CNCP, as Haroutiunian and colleagues found in their literature search. And, apparently, there may have been negligible motivation on the parts of methadone manufacturers to invest extensively in practitioner education on safe prescribing. In the CDC data [Figure above] there appears to be a decline in methadone prescribing for pain during recent years, with an associated waning of death rates; but, it is unknown whether this trend was a data artifact or will continue.
REFERENCES:
> Haroutiunian S, McNicol ED, Lipman AG. Methadone for chronic non-cancer pain in adults. Cochrane Database Syst Rev. 2012(Nov);11:CD008025 [abstract here].
> Reisfield GM, Friedman CK. Methadone in the Chronic Pain Patient With a Substance Use Disorder. J Pain Palliative Care Pharmacother. 2012;26:368-370 [abstract here].
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7 comments:
I wish I had this article prior to my physician prescribing me methadone several days ago. Of all the other opioid's I've been on. I'm finding that this drug doesn't seem to provide enough analgesic effect versus the newer medications for my CNCP.
Thank you for posting this article to educate us.
In response to Mr. Luna, above -- methadone is most safely started at a low dose and increased very slowly and gradually over time. So, it could take many days (or a few weeks) before it reaches full pain-relieving effect. Meanwhile, never take more methadone than you are prescribed.
I have noticed that since oxycontin and opanaER have been reformulated that MANY patients aren't getting the relief from pain as they once did before these were changed, so I know many patients are switching back to methadone because it works better than the new formulas. Also many patients have complained about stomach issues and also that the new formulas aren't releasing the correct amounts of medicine they should. They don't last, take hours to start working, and eating after dosing causes ineffectiveness of those medicines. So many patients that have been on opiate therapy for several years are going to methadone because it works and they're able to eat meals without withdraw feelings being a problem. I look for this to continue happening until a better pain medicine is on the market that really works as the older formulas once did. They don't disolve or release like they used too. I've seen someone take one of the newer OP oxycontin for the first time and start to withdraw, wondering if they missed a dose from the switch with the first dose of it.it happened to myself as well. Now that proves it. Legitimate patients as my mother and myself,I'm sure many others would agree with my statement. If they have tried both older and new formula.
I agree with the post left above. Methadone to me is the best pain medication out there and nothing works like methadone ,its a one of a kind pain medication.One must be very careful with methadone, its many times stronger than morphine . One must respect this medication it stays in your body a long time. All other long acting pain medications no longer work like they use to thanks to people that abused it. To me methadone is the best medication for long term Chronic pain relief.
Mark S. Barletta
So methadone for treating opioid dependence is remarkably safe, while the same medication prescribed for pain management is associated with a substantial risk of death. Does anyone believe the answer to this seeming paradox might lie in the fact that until the end of 2006 FDA and the manufacturer RECOMMENDED a potentially lethal dose of methadone when given for analgesia (up to 80 mg per day without any reference to tolerance or distinction between opiate-naive patients and others)? And yet, for decades, the same FDA had imposed a mandatory maximum 30mg initial dose of methadone when used in treatment of dependency. And what has FDA done since 2006 to call attention to the radical change in its recommendation for analgesic dosage (new maximum 30 mg/day!)? Seemingly absolutely nothing. To the contrary: it has diverted attention away form the dosage question by advisories and alerts discussing “respiratory perturbatiuons” and QTc intervals. Think about it!
Thank you, Dr. Newman, for your important comments. I think that most people who know about the methadone labeling problems agree that it was misleading and hazardous. However, shouldn't both the FDA and methadone manufactureres share the blame for not getting the word out about safe dosing practices sooner and more extensively?
It seems the FDA is more concerned about the safety of drug abusers than people that suffer from chronic pain.
Both Opana ER and OxyContin had to be reformulated because drug abusers where crushing the tablet snorting it or injecting it.
Why do we the pain sufferers of America have to pay the price when a excellent time released opioid is manufactured and it works great
but was taken off the market because of potential abuse. This is why methadone seems to be the one pain medication that drug abusers cant abuse.
Generic versions of the widely abused painkiller Opana are set to hit the U.S. market at the start of the New Year after drug maker Endo Health Solutions (NASDAQ: ENDP) lost its bid to halt their release.
Why is it the words widely abused are used in this report. Opana ER was never meant for drug abusers in the first place.
It seems suffering people of America are put second in line when a good time released pain medication is made then pulled off the market because of potential abuse. Is this fair for all that suffer.
Never in my life have I seen and heard such ridiculous standards , lets pull all pain medications off the shelves of pharmacies so drug abusers don’t abuse them, this makes me sick.
This whole situation about what the FDA deems enough for any one pain patients is ridiculous, its my understanding that a pain patient must be titrated upward till they find their level of relief using a time released pain medication.
I don’t understand why everyone is making this so difficult.
Mark S. Barletta
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