Case 3: Discussion

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Concurrent use of methadone (Methadose) and antiretrovirals can generate significant drug-drug interactions in the care of HIV-infected individuals (Figure 1). Methadone is primarily metabolized by the cytochrome P450 enzyme system, a system also responsible for metabolism of many of the antiretrovirals. The two predominant isoenzymes involved with methadone metabolism are P450 2B6 (CYP2B6) and P450 (CYP2C19) [1]. Methadone may also partially inhibit these isoenzymes. The greatest potential for drug-drug interactions with concomitant use of methadone and antiretrovirals occurs with the use of either the non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs). In addition, the potential for interaction occurs with the nucleoside reverse transcriptase inhibitors (NRTIs) despite their dissimilar pathway of metabolism from methadone. All of these interactions may occur when either starting or stopping methadone, or when starting or stopping other medications. The exact amount of time for these interactions to occur and the severity of the interaction vary between individuals and depend on a number of factors, such as duration of methadone use, liver function, and presence of concomitant medical conditions.

Interaction of NRTIs and Methadone

Among the NRTIs, there are published reports of methadone interactions with zidovudine (Retrovir), didanosine (Videx), stavudine (Zerit), and abacavir (Ziagen) [2]. Methadone increased the plasma exposure of zidovudine by 40%, predominantly by decreasing zidovudine glucuronidation. The clinical significance of this interaction is unknown, but theoretically methadone could enhance zidovudine-related adverse effects. Neither didanosine nor stavudine significantly affect methadone levels. Conversely, methadone decreased the plasma exposure of didanosine (buffered tablet) and stavudine by 60% and 18%, respectively. Thus, use of methadone with buffered didanosine formulations would likely require a didanosine dose increase. The newer and more commonly used didanosine formulation (Videx EC), which is not buffered, eliminates the need for dose adjustment. Studies involving the concurrent use of methadone and abacavir have shown a statistically significant increase in methadone clearance, but the clinical significance was not apparent and the combination appears safe. In most instances, the effects of NRTIs on methadone levels appeared to be negligible and no methadone dose adjustments are required. With the use of abacavir and methadone, patients should be monitored for any signs or symptoms of withdrawal. Preliminary data suggest that tenofovir DF (Viread) does not significantly alter methadone levels. Despite documented methadone-related alterations in NRTI plasma levels, no formal study has examined methadone’s impact on intracellular NRTI drug concentrations, nor has any study determined methadone’s effect on NRTI-related adverse effects or virologic outcomes.

Interaction of NNRTIs and Methadone

The NNRTIs nevirapine (Viramune) and efavirenz (Sustiva) both act as inducers of the CYP2B6 enzyme and thus typically diminish plasma levels of similarly metabolized drugs. Numerous case reports and anecdotal observations exist for methadone withdrawal symptoms when persons taking methadone are started on either nevirapine or efavirenz. One study (n=8) found the concurrent use of nevirapine and methadone resulted in a 50% decrease in the area under the curve (AUC) of methadone, but required only a 16% mean increase in methadone dose [3]. A study with concomitant use of methadone and efavirenz (n=11) showed a greater than 60% reduction in methadone plasma levels and 9 of the 11 patients developed withdrawal symptoms that required approximately a 20% increase in methadone dose [4]. Thus, in the situation when a patient on a stable dose of methadone starts on either nevirapine or efavirenz, they should be observed for any signs or symptoms of methadone withdrawal. Any increase in methadone dose should be individualized and titrated upwards in small increments, as these interactions are highly variable. The only formal study to evaluate the effects of methadone on delavirdine (Rescriptor) demonstrated no impact on delavirdine concentrations. The effect of delavirdine on methadone was not studied but theoretically methadone levels could increase due to weak CYP2C19 inhibition by delavirdine. When using delavirdine and methadone concomitantly, it would be reasonable to monitor for signs and symptoms of opiate toxicity and reduce the methadone dose if necessary.

Interaction of PIs and Methadone

Multiple case reports and formal studies with nelfinavir (Viracept) demonstrated reduced methadone concentrations [5]. The clinical outcomes of this interaction have been highly variable, ranging from absence of withdrawal symptoms and no dose adjustments to increased severity of withdrawal symptoms over time that required dose adjustments. Ritonavir (Norvir)-boosted protease inhibitor regimens have also shown widely variable effects on methadone concentration. The majority of ritonavir-methadone interactions resulted in diminished methadone levels with varying clinical manifestations, ranging from withdrawal symptoms requiring methadone dose adjustment to insignificant clinical sequelae. The current recommendation is to monitor for potential methadone withdrawal and make appropriate methadone dosage adjustments if needed [6,7]. Single protease inhibitor regimens that consist of either amprenavir (Agenerase) or indinavir (Crixivan) appear to be safe when co-administered with methadone. Despite decreased methadone metabolite concentrations with amprenavir there were no changes in methadone pharmacodynamics [8]. In the indinavir study, no appreciable effect on indinavir AUC was observed, but the minimum concentrations were elevated and maximum concentrations diminished based on comparisons with historical controls [9]. Studies regarding atazanavir (Reyataz) and methadone interactions have not been performed. Overall, the interactions of the protease inhibitors and methadone can be highly variable and thus patients should be evaluated on an individual basis.

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Figure 1