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Chemical structure of methadone.

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Methadone appears to be involved in a large proportion of opioid-related deaths in the U.S., researchers found.

A third of the deaths related to this painkiller class implicated methadone, although the addiction-recovery drug represents less than 5% of opioid prescriptions, according to Lynn Webster, MD, of Lifetree Pain Clinic in Salt Lake City, and colleagues.

They reported the findings in a special issue ofÊPain Medicine devoted to assessing the causes of recent increases in opioid-related deaths Ñ the prevention of which Òshould be a central focus for everyone working in the field of pain medicine,Ó Webster said in a statement.

The researchers conducted a review of the literature and state and federal government sources to assess the frequency of and risk factors for opioid-related overdose deaths over the past decade.

National data have shown tremendous increases in opioid-related overdose deaths beginning in the early 2000s, the researchers found, consistent with recent calls by the Obama administration to curb theÊprescription painkiller epidemic.

Their study, however, found a high proportion of methadone-related deaths when controlling for the number of prescriptions dispensed, which hasnÕt been noted in prior analyses.

They also saw significantly more calls to poison centers for methadone than for other painkillers Ñ there were 10 times more calls for methadone than for oxycodone (OxyContin) and four times as many as there were for hydrocodone (Vicodin).

In terms of emergency department admissions, methadone was involved in 30% of all overdoses, but, again, after controlling for the number of prescriptions, there were 23 times as many visits for methadone as for hydrocodone and six times more visits than for oxycodone, Webster and colleagues wrote.

They noted that the methadone-related deaths have more to do with prescriptions for pain management than with opioid treatment programs.

Webster said overdose deaths seen with methadone could be attributed to physician error Ñ a lack of knowledge, particularly about dosing at which to start the drug, titrating those doses too rapidly, and the inaccuracy of dose conversion tables. The researchers noted that a recent review found a wide variance in successful conversion ratios.

The deaths may also be attributable to patient nonadherence Ñ especially if they are mixing methadone with alcohol, benzodiazepines, or other painkillers, which significantly increases the risk of death Ñ as well as comorbid substance use disorders.

Ultimately, Webster and colleagues said, the causes of opioid-related deaths are multifactoral, so solutions must address Òprescriber behaviors, patient contributory factors, nonmedical use patterns, and systemic failures.Ó

Strategies to reduce opioid-related deaths should be empirically tested, should not reduce access to needed therapies, should address the risk from methadone and other opioids, and be incorporated into the FDAÕs forthcoming risk evaluation and mitigation strategy (REMS) for long-acting opioids, Webster and colleagues wrote.

ÒSimply reducing the amount of opioids prescribed would be likely to harm legitimate patients needing pain relief, whereas determined nonmedical users would be likely to seek alternative sources,Ó they wrote. ÒRather, the focus should be on physician education leading to appropriate screening and monitoring of opioid candidates.Ó

ÒBetter medical decision making should be the goal,Ó they concluded, Ònot decreased opioid prescribing.Ó

In an accompanying editorial, Webster wrote that the main goal of the supplement was to identify the major risk factors for opioid overdose deaths, since major increases have Òbrought intense scrutiny to the pain medicine field.Ó

Webster also criticizedÊrecent legislation in Washington state to set certain dosing limits on prescription opioids, noting that the Òconsequences of what appear to be economically or politically driven ÔsolutionsÕ in the absence of empirically driven science are unknown but worrisome.Ó

Yet some researchers take issue with the study for failing to identify the push for clinicians to prescribe opioids for moderate to severe chronic pain Ñ often resulting in long-term therapy Ñ as a major contributor to increases in deaths.

ÒThe authors point to dosing errors, patient nonadherence, comorbid mental health and substance use disorders as the root causes for opioid overdose deaths. This explanation suggests that if we could simply identify the bad patients and the bad doctors we wouldnÕt have a problem,Ó said Andrew Kolodny, MD, of Maimonides Medical Center in Brooklyn, N.Y.

ÒThis does not give sufficient recognition to the inherent dangers of opioids,Ó he continued. ÒThis has been the preferred understanding of the problem favored by pharmaceutical companies. Even ÔgoodÕ patients make mistakes when using opioids, and the research on how to identify patients likely to intentionally misuse opioids is weak.Ó


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