Deaths From Methadone Overdose Disproportionate to Number of Prescriptions

Thomas R. Collins

February 08, 2010

February 8, 2010 (San Antonio, Texas) — A national review of unintentional overdose deaths involving opioids has shown that a disproportionate number of them are related to methadone use, researchers said here at the American Academy of Pain Medicine 26th Annual Meeting.

In this review, 30% of such deaths involve methadone, whereas only 5% of the nation’s opioid prescriptions are written for methadone. Researchers noted that the problems appeared to center on those prescribed methadone for pain and not those receiving methadone at treatment centers for addiction.

"Although methodologies differ, rendering data inconsistent, methadone was found to represent a disproportionate number of opioid-related deaths," the researchers, led by Lynn Webster, MD, founder of the Salt Lake City, Utah—based Life Source Foundation, which funded the study, conclude.

"Solutions must be multifactorial, should address harm from methadone as well as other opioids, and should be incorporated into any REMS [risk and evaluation strategies] program."

Jump in Deaths

Poisoning deaths related to opioids jumped 260% in 2005 over levels seen in 2001, the study authors note. In response, the US Food and Drug Administration (FDA) announced in February 2009 that REMS would be required for certain opioids to ensure their benefits outweigh the risks.

To find out more about what was behind the steep increase in deaths, a panel of experts in pain medicine and public policy convened to look at causes and risk factors for opioid-related overdose deaths and make recommendations to reduce them.

Dr. Webster and colleagues studied malpractice cases forwarded by lawyers, looked to PubMed for relevant information, and reviewed other local and federal sources.

Although the data available vary from state to state and researchers cannot tell which cases involve patients who simply took more medication than they’re told to take by their physicians, researchers point to a number of reasons for the outsized role of methadone in the deaths.

A chief reason, the panel concluded, is that conversion tables — used by physicians to transition patients from one opioid to another — recommend too much methadone for most patients.

Through 2006, for example, the FDA recommended a starting dose of 80 mg/day, said Dr. Webster. That recommendation has since been changed to 30 mg/day.

“For most individuals, starting them at 80 mg/day, they would die,” Dr. Webster said.

Metabolism Varies

Adding to the difficulty is that there is a wide range among patients in how quickly methadone is metabolized, and there is no inexpensive way to determine in advance how they will respond.

Experts also pointed to payer policies that require methadone or generic morphine to be tried on a patient before brand-name medications are used.

“If a provider chooses to use methadone and (the patient) happens to be a slow metabolizer and they have a lot of pain, that places them at a significant risk,” Dr. Webster said.

He added that although it was thought that the risk of respiratory depression diminished once a patient reached a steady dose in their long-term opioid therapy, this is actually not the case. Up to 70% of patients in his chronic pain practice, averaging 282 mg of morphine equivalent a day, had sleep apnea, he said.

“It is a multipronged problem; there’s not one thing that’s caused this — there are multiple things that all add up,” Dr. Webster said. “But clearly, this is the low-hanging fruit.”

Finally, other likely contributors were thought to be the presence in patients receiving methadone of unanticipated medical and psychiatric comorbidities, including substance use disorders, and the presence of other central nervous system depressant drugs, such as alcohol, benzodiazepines, or antidepressants.

Association Not Causality

Ajay Wasan, MD, from Harvard Medical School in Boston, Massachusetts, and cochair of the meeting, said it is difficult to assess the significance of the numbers and how it should influence the prescribing of methadone because methadone is so abused on the street.

“Unfortunately, state governments, regulatory agencies, many people outside of pain medicine, interpret that to mean that the more you prescribe, the more deaths you created and caused without actually kind of understanding all these different links that are involved,” he said.

“Association is fundamentally different than causality and it doesn’t necessarily mean that it’s a public health hazard,” Dr. Wasan added.

This study did not receive commercial support. Dr. Webster and Dr. Wasan have disclosed no relevant financial relationships.

American Academy of Pain Medicine (AAPM) 26th Annual Meeting: Poster 228. Presented February 3-5, 2010.

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