New information points to safer methadone use for treatment of pain and...(. The investigators wanted to unders...),Health

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
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