Interactions potent between HIV agents, opiates.
"It may be that methadone is not the best opiate therapy for everyone with HIV who is opioid dependent," Dr. McCance-Katz said at the annual meeting of the American Academy of Addiction Psychiatry. "These drug interactions are so potent, it is important to know if there are optimal combinations of opiate therapies and HIV medications."
Through the cytochrome P-450 system, many antiretroviral agents interact with opioids, including methadone, levomethadyl acetate (LAAM), and buprenorphine. HIV drugs that induce metabolism of methadone can cause symptoms of opiate withdrawal between doses; HIV drugs that inhibit such metabolism can cause opiate toxicity.
Such interactions can lead to nonadherence to antiretroviral regimens, viral resistance, and illicit drug use "in an attempt to self-medicate some of these noxious drug interactions that often go unrecognized," said Dr. McCance-Katz, chair of the division of addiction psychiatry, Virginia Commonwealth University, Richmond.
Drug toxicities that are additive can be a significant risk to patients. Because of the clinically significant interactions, the Food and Drug Administration now requires methadone interaction data before approval of a new antiretroviral agent.
Researchers are assessing alternatives to methadone for HIV patients. Buprenorphine, for example, may not have the same liabilities as methadone in combination with antiretroviral therapy, she said. "I'm still looking at the data, but we don't see the toxicities with buprenorphine and LAAM that we see with methadone."
Methadone-maintained patients who use efavirenz as part of highly active antiretroviral therapy require a 50% increase in methadone concentration, from 80 mg/dL at baseline to 120 mg/dL, according to research by Dr. McCance-Katz. With buprenorphine, the mean 17.2-mg/dL dosage did not change when efavirenz was added. "We did not have to increase the opiate dose for anyone, and we did not have to restabilize people as a result."
Not all of methadone's effects on HIV drugs are via cytochrome P-450 metabolism. For example, didanosine and stavudine concentrations drop to subtherapeutic levels when these drugs are taken with methadone. Methadone decreases gastrointestinal motility, and didanosine and stavudine are particularly sensitive to stomach acid.
Dr. McCance-Katz highlighted some specific interactions between methadone and agents that combat HIV:
* Delavirdine mesylate inhibits cytochrome P-450, leading to a significant increase in methadone concentrations--the half-life is extended by almost 50%. "We would worry about accumulation," she said. "With LAAM, we see even more dramatic effects and LAAM metabolites, which have implications for cardiac toxicity."
* Nevirapine is similar to delavirdine, causing a decrease of about 50% in methadone area-under-the-curve concentrations. Withdrawal symptoms can occur if methadone dosages are not increased.
* Nelfinavir mesylate shows a "dramatic drop" in 7-day plasma levels when given with methadone. "Interestingly, we did not see withdrawal in these patients. We think that is because nelfinavir is a very good competitor for protein binding--so there was more free methadone available to protect them from opiate withdrawal."
* Kaletra, a combination of lopinavir and ritonavir, causes methadone levels to become subtherapeutic. Dr. McCance-Katz observed withdrawal symptoms in these patients. "But we did not know if it was an effect of lopinavir, ritonavir, or both." When ritonavir was studied alone, the nonsignificant increase in methadone level implicated lopinavir as the component interacting with methadone.
BY DAMIAN MCNAMARA
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|Title Annotation:||Across Specialties|
|Publication:||Clinical Psychiatry News|
|Date:||Apr 1, 2005|
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