Critical error in methadone label, guidelines

An error in the package insert and clinical guidelines may contribute to the high rates of patient harm associated with methadone. The package insert approved by the Food and Drug Administration incorrectly identifies CYP3A as the enzyme responsible for the metabolism of methadone in the human body. A different enzyme, CYP2B6, mediates methadone metabolism, clearance, and serum concentrations.

The error could have profound effects on drug utilization review for patients taking methadone, as well as on dosing, clinical activity, morbidity, and mortality, said Evan Kharasch, MD, PhD, professor and director, Clinical and Translational Research in Anesthesiology and professor, Biochemistry and Molecular Biophysics at Washington University, St. Louis. Kharasch delivered his warning during a presentation on translational research at the American Society of Anesthesiologists annual meeting.    

Increased risk

“Practitioners who avoid methadone or alter methadone dosing in patients known to be taking drugs which inhibit CYP3A may be doing so needlessly,” he told Drug Topics. “Drugs known to alter the activity of CYP2B6 may alter methadone metabolism and clearance, and should be evaluated as such.”

Both enzymes are members of the cytochrome P450 family, but the two are enhanced and inhibited differently by different drugs in common clinical use. Ritonavir (Norvir, AbbVie), for example, is often used in antiviral regimens because it is a powerful inhibitor of CYP3A and can potentiate the activity of antiviral agents metabolized by the enzyme.

Inhibition of CYP3A would be expected to decrease metabolism of methadone and increase plasma levels, prompting dose adjustments for methadone or avoidance of the agent altogether. But ritonavir also induces CYP2B6 in the liver, increasing methadone metabolism and clearance, and leading to decreased plasma concentrations of the drug. Practitioners whose choices result from errors in labeling and clinical guidelines could unknowingly put patients at increased risk of overdosing or underdosing with methadone.

“Methadone is a highly effective drug but also a drug with significant adverse events when used by an individual who does not fully understand its use,” Dr. Kharasch said. “Clinical guidelines for the use of methadone need to be rewritten. More accurate clinical guidelines may improve the use of methadone, improve the treatment of pain and substance abuse, and improve patient safety.”

The basic science used to support the current labeling and clinical guides was incomplete, he said. In vitro data identifying CYP3A as the primary mediator for methadone metabolism was never verified in clinical trials.

Skyrocketing AEs

That gap in translational research became obvious as methadone use increased. Total prescriptions for methadone rose 1,300% between 1997 and 2006. Adverse events skyrocketed 1,800% between 1997 and 2004. Fatalities increased nearly 400% between 1999 and 2004, the years with the greatest increase in methadone prescribing.

By the late 1990s, it was becoming clear that there is significant interindividual variability in the activity of methadone. The drug is susceptible to drug interactions, elimination can vary up to a hundredfold, and oral dosing is subject to autoinduction of clearance.

Clinical consequences include withdrawal, toxicity, respiratory depression, inadequate analgesia, breakthrough pain, and a substantial risk of overdose during the first two weeks of oral use.

What researchers found

Clinical research using healthy volunteers found that the conventional wisdom on methadone metabolism and clearance mediated by CYP3A is wrong. Subsequent laboratory work identified CYP2B6 as a predominant enzyme responsible for methadone metabolism in vitro, activity that was subsequently confirmed in clinical research. Clinical work confirmed that CYP2B6 inhibitors such as ticlopidine (Ticlid, a branded Roche product no longer available in the United States) decrease methadone metabolism and clearance, increasing plasma concentrations and clinical activity.

Researchers also found that CYP2B6 has more than 20 common alleles. One subtype, CYP2B6.4, markedly increases CYP activity, leading to increased methadone metabolism and lower plasma concentrations. Another subtype, CYP2B6.6, markedly decreases CYP activity, leading to lower methadone metabolism and plasma concentrations five times higher than normal.

“We have already seen editorial calls to revise labeling and clinical recommendations in light of these findings,” Dr. Kharasch said. “It is in the hands of regulatory agencies to move forward with these new data.”