New findings may significantly improve the safety of methadone, a drug widely used to treat cancer pain and addiction to heroin and other opioid drugs, according to researchers at Washington University School of Medicine in St. Louis and the University of Washington in Seattle.
The researchers discovered that the body processes methadone differently than previously believed. Those incorrect assumptions about methadone have been making it difficult for physicians to understand how and when the drug is cleared from the body and may be responsible for unintentional under- or overdosing, inadequate pain relief, side effects and even death.
For many years, methadone has been a mainstay in the treatment of opioid addiction. Taken orally, it suppresses withdrawal and reduces cravings. In recent years, doctors have prescribed methadone more frequently as an effective treatment for acute, chronic and cancer pain. Use of the drug for pain treatment rose 1,300 percent between 1997 and 2006. As more methadone was prescribed, however, adverse events increased by approximately 1,800 percent, and fatalities were up more than 400 percent (from 786 to 3,849) between the years 1999 and 2004.
"Unfortunately, increased methadone use for pain has coincided with a significant increase in adverse events and fatalities related to methadone," says principal investigator Evan D. Kharasch, M.D., Ph.D., an anesthesiologist and clinical pharmacologist at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis. "The important message is that guidelines used by clinicians to direct methadone therapy may be incorrect."
Kharasch, the Russell D. and Mary B. Shelden Professor and director of the Division of Clinical and Translational Research in Anesthesiology at the School of Medicine, and his colleagues report the findings in the March issue of the journal Anesthesiology and online in the journal Drug and Alcohol Dependence.
The investigators wanted to understand how protease inhibitors, drugs that keep the immune system functioning in patients with HIV, interact with methadone. For years, the enzyme P4503A was believed to be responsible for clearing methadone from the body. But when healthy volunteers were given a low dose of methadone together with protease inhibitors that caused profound decreases in the activity of P4503A, there was no reduction in the clearance of methadone.
There were two reasons to study what happened to methadone when taken together with those drugs: First, HIV-AIDS patients may receive methadone for pain and, in some cases, for accompanying substance abuse problems, along with one or more protease inhibitors. In addition, many protease inhibitors interact with the P4503A enzyme that traditionally was thought to be important to methadone clearance. In these studies, Kharasch and his team looked at interactions among methadone, the P4503A enzyme in the intestine and liver and the protease inhibitors nelfinavir, indinavir and ritonavir.
They gave study volunteers a combination of the protease inhibitors ritonavir and indinavir. Both drugs profoundly inhibited the actions of the enzyme. If that enzyme were responsible for methadone clearance, then inhibiting it should have caused methadone to build up in the body. But the researchers found that it had no effect on methadone levels.
Volunteers in the second study received the protease inhibitor nelfinavir. Again, the drug inhibited the action of the P4503A enzyme. That should have meant methadone concentrations would rise, but they actually decreased by half.
"For more than a decade, practitioners have been warned about drug interactions involving the enzyme P4503A that might alter methadone metabolism," Kharasch says. "The package insert says inhibiting the enzyme may cause decreased clearance of methadone, but our research demonstrates that P4503A has no effect on clearing methadone from the body. So the package insert appears to be incorrect, or certainly needs to be reevaluated, as do guidelines that explain methadone dosing and potential drug interactions."
That can be dangerous, Kharasch explains, because a clinician may prescribe too much or too little methadone for patients taking drugs that interact with P4503A, having been informed that they also would influence methadone clearance. Too little methadone will not relieve pain. Too much can contribute to the unintentional build-up of methadone in the system, which can cause slow or shallow breathing and dangerous changes in heartbeat. Physicians could be unintentionally prescribing methadone incorrectly.
"The highest risk period for inadequate pain therapy or adverse side effects is during the first two weeks a patient takes methadone," Kharasch says. "If we can provide clinicians with better dosing guidelines, then I believe we will be able to better treat pain and limit deaths and other adverse events."
About a dozen related liver enzymes are part of the P450 family, and Kharasch believes another enzyme from that family may be the one actually involved in methadone metabolism and clearance. His laboratory is determined to identify the correct enzyme to limit over-and under-dosing of patients taking methadone to improve addiction and pain treatment as well as patient safety. Currently, he's testing the related enzyme P4502B. Laboratory studies and preliminary clinical results indicate that P4502B may be involved, but he says more clinical research is needed.
"The research also is important for the treatment of HIV-AIDS," Kharasch says. "Protease inhibitors can interfere with the activity of P4503A but increase the activity of P4502B. This paradox is highly unusual, and because these two enzymes metabolize so many prescription drugs, there are many potential drug interactions that we'll be able to understand better if we can get a better handle on how these pathways absorb drugs into the system and clear them from the body."
This research was supported by grants from the National Institute on Drug Abuse of the National Institute of Health and by an NIH grant to the University of Washington General Clinical Research Center.
- Kharasch et al. Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity. Drug and Alcohol Dependence, 2009; DOI: 10.1016/j.drugalcdep.2008.12.009
- Kharasch et al. Methadone Pharmacokinetics Are Independent of Cytochrome P4503A (CYP3A) Activity and Gastrointestinal Drug Transport. Anesthesiology, 2009; 110 (3): 660 DOI: 10.1097/ALN.0b013e3181986a9a
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