According to this year’s Severinghaus Lecturer, the labeling approved by the Food and Drug Administration for methadone is wrong. So are the published clinical guidelines for the use of methadone to treat pain and drug addiction in both adult and pediatric patients.
The short explanation is that methadone metabolism and clearance are mediated predominately by enzyme CYP2B6, said Evan Kharasch, M.D., Ph.D., Russell D. and Mary B. Shelden Professor of Anesthesiology, Director of Clinical and Translational Research in the Department of Anesthesiology and Professor of Biochemistry and Molecular Biophysics at Washington University, St. Louis.
Current labeling and clinical guidelines erroneously identify CYP3A as the enzyme responsible for methadone metabolism.
While both enzymes are members of the cytochrome P450 family, the two are enhanced and inhibited differently by different pharmaceuticals in common clinical use. Adjustment of methadone dosing based on an expected interaction with CYP3A could have severe, potentially fatal effects on methadone metabolism, clearance and plasma concentration.
Dr. Kharasch recounted the discovery of the true metabolic pathway for methadone during the John W. Severinghaus Lecture on Translational Science, “Basic Science to Clinical Practice: The Tale of Long-Acting Opioids,” Tuesday.
The problem is not that the basic science leading to the approval of methadone and warnings of CYP3A interactions was wrong, he explained. The problem is that the interaction warning was based on extrapolations of in vitro data. The basic science pointing to CPY3A as a mediator in methadone metabolism was never verified in clinical trials.
“Clinical guidelines for the use of methadone need to be rewritten,” Dr. Kharasch said. “We need to tell the community that the current guidelines and the current label are based on incorrect extrapolations of in vitrodata. More accurate clinical guidelines may improve the use of methadone, improve the treatment of pain and substance abuse, and improve patient safety.”
The gap in translational research became obvious as methadone use increased. Total prescriptions rose 1,300 percent from 1997 to 2006. Adverse events skyrocketed 1,800 percent between 1997 and 2004. Fatalities increased nearly 400 percent between 1999 and 2004, the years with the greatest increase in use.
“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.
By the late 1990s, it was clear that there is substantial inter-individual variability in the activity of methadone. The agent is highly susceptible to drug interactions, elimination can vary up to 100-fold and oral dosing is subject to autoinduction of clearance.
Clinical results include withdrawal, toxicity, respiratory depression, inadequate analgesia, breakthrough pain and a substantial risk of overdose in the first two weeks of oral dosing.
Clinical research using healthy volunteers found that the conventional wisdom – methadone metabolism and clearance mediated by CYP3A – is wrong, Dr. Kharasch explained.
Subsequent laboratory work identified CYP2B6 as a predominant enzyme responsible for methadone metabolism in vitro, findings that were confirmed in clinical research. Clinical studies also confirmed that CYP2B6 inhibitors such as ticlopidine decrease methadone metabolism and clearance, increasing plasma concentrations.
Researchers also found that CYP2B6 has more than 20 common alleles. One subtype, .4, markedly increases CYP activity, leading to increased metabolism and lower plasma concentrations. Another subtype, .6, markedly decreases CYP activity, leading to lower metabolism and plasma concentrations five times higher than normal.
“We have already seen editorial calls to revise the 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.”