Interactions Between Heroin and Antiretrovirals?

Michael L. Lim, PharmD; Angela D.M. Kashuba, BScPhm, PharmD, DABCP


April 17, 2002


Are there any data describing pharmacologic interactions between heroin and antiretrovirals? Or, assuming that these experiments cannot be done, how are drugs in this class most likely to be affected by concurrent heroin use?

Response from Michael L. Lim, PharmD and Angela D.M. Kashuba, BScPhm, PharmD, DABCP

Unfortunately, no data exist on drug interactions between heroin and antiretrovirals. Ethical and study design challenges have prevented these studies from being undertaken. Recently, interest has risen in the potential for clinically significant interactions between antiretroviral drugs and illicit drugs. For example, case reports suggest that the protease inhibitor ritonavir can dramatically increase the effects and toxicity of the methamphetamine derivative ecstasy (MDMA).[1,2] In 1999, the National Institute on Drug Abuse convened a workshop to discuss interactions between antiretrovirals and drugs of abuse and the need for research to expand the limited information available.[3,4]

In the absence of drug interaction data with heroin, 3 situations should be evaluated: (1) Would antiretrovirals be expected to alter the metabolic disposition of heroin? (2) Would heroin have any significant effects on the metabolism of antiretroviral agents? and (3) Would either of these agents have significant effects on drug transporter activity?

Following intravenous injection, heroin (diacetylmorphine) is deacetylated by esterases to form the active metabolite 6-acetylmorphine, which is subsequently further deacetylated to morphine.[5,6] Heroin's conversion to 6-acetylmorphine and morphine occurs extremely rapidly; heroin's half-life is estimated to be 2-3 minutes. Antiretrovirals would not be expected to affect this metabolism of heroin to morphine. Morphine is then glucuronidated to morphine-3-glucuronide and morphine-6-glucuronide by UDP-glucuronosyltransferases. Morphine-6-glucuronide is also a potent opioid agonist.[7] Since ritonavir has been reported to induce the glucuronidation pathway, it may in theory increase the pharmacodynamic effects of heroin. However, it is currently unknown whether antiretroviral administration would have clinically significant effects on morphine metabolism. In addition, heroin is not expected to affect antiretrovirals through any pharmacokinetic interactions.

Another potential mechanism for antiretroviral drug interactions involves P-glycoprotein, an efflux pump that restricts drug transport across membranes, including the blood-brain barrier.[8] Ritonavir is a potent inhibitor of P-glycoprotein. Because morphine and morphine-6-glucuronide are both P-glycoprotein substrates,[9] ritonavir may facilitate access of these opiates to the central nervous system, resulting in enhanced analgesic, and potentially toxic, effects. Studies in rat models support the plausibility of this interaction; however, the clinical relevance remains uncertain.[10,11] It is also unclear how genetic polymorphisms in drug transporters would affect this potential interaction.

At the present time, there are no clinical data or anecdotal experience to suggest that antiretrovirals would predictably influence the effects of heroin. However, heroin's potentially deleterious effects on medication adherence, risk behavior, and transmission of HIV and hepatitis C virus cannot be underestimated or ignored. In some cases, patient and provider decisions to initiate or continue antiretrovirals may be influenced by current drug use. Optimally, substance abuse issues should be addressed before initiation of antiretrovirals, although methadone may also be involved in clinically significant drug interactions. For example, when the NNRTIs nevirapine or efavirenz were added to patients receiving methadone maintenance therapy, methadone concentrations were decreased by 50% to 60% (24-hour area under the curve) and some patients experienced withdrawal symptoms.[12,13] Protease inhibitors (lopinavir/ritonavir, ritonavir/saquinavir, and nelfinavir) have been reported to decrease methadone concentrations, although the clinical significance of these changes is uncertain.[14,15] Providers should be aware of the potential for these interactions when initiating or discontinuing antiretrovirals because methadone dose adjustments may be necessary. As with all patients, close monitoring and follow-up are needed.


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