Case 3: Discussion
Concurrent use of methadone (Dolophine, Methadose) and antiretrovirals can generate significant drug-drug interactions and thus impact the care of HIV-infected individuals. Methadone consists of a racemic mixture of R and S enantiomers, and R-methadone is the active form. The metabolism of methadone primarily occurs via the cytochrome P450 enzyme system, a system also responsible for the metabolism of many antiretroviral medications. Five P450 isoenzymes play a role in the enzymatic degradation process of methadone: CYP 3A4, CYP 2B6, CYP 2C8, CYP 2C19, and CYP 2D6[1,2]. Among these five P450 isoenzymes, it appears that CYP 2B6, and to a lesser extent CYP 2C19, are the main enzymes responsible for methadone metabolism. In addition, some metabolism of methadone occurs through demethylation, which forms inactive metabolites that are excreted in the bile and urine. Methadone may also partially inhibit these P450 isoenzymes. The greatest potential for drug-drug interactions with concomitant use of methadone and antiretrovirals occurs with the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PIs)[1,3]. Surprisingly, drug-drug interactions can occur with the use of nucleoside reverse transcriptase inhibitors (NRTIs) and methadone, despite dissimilar pathways of metabolism. Issues related to drug-drug interactions may occur when either starting or stopping methadone, or when starting or stopping antiretroviral medications. The onset and severity of these interactions depends on a number of factors, such as duration of methadone use, hepatic function, and presence of concomitant medical conditions. Further, the clinical impact of a drug-drug interaction that alters methadone levels may cause highly variable clinical effects. For example, a drug-drug interaction that causes a 30% reduction in methadone levels may generate major withdrawal symptoms in one patient, but not cause noticeable withdrawal symptoms in another patient.
Interaction of NRTIs and Methadone
Among the NRTIs, several have a potentially significant drug-drug interaction with methadone[1,4,28], but none require routine dose adjustments (Figure 1). The concurrent use of methadone and abacavir (Ziagen) causes an increase in methadone clearance of about 20%, but this interaction does not appear to have clinical relevance. Available data suggest that zidovudine (Retrovir), stavudine (Zerit), tenofovir (Viread), lamivudine (Epivir), and emtricitabine (Emtriva) do not significantly alter methadone levels[1,5,6,7]. No routine methadone dose adjustments are required because of concomitant use of NRTIs. Methadone increased the plasma AUC of zidovudine by 29 to 43%[8,9], predominantly by decreasing zidovudine glucuronidation. The clinical significance of this interaction is unknown, but theoretically methadone could enhance zidovudine-related adverse effects, such as headache, anemia, myalgias, and fatigue. In contrast, methadone lowers the stavudine AUC by 23%. Methadone does not likely have a significant impact on lamivudine or emtricitabine levels, since both of these medications undergo elimination in an unchanged form in the urine. Methadone decreases the AUC of didanosine when taken in the buffered tablet didanosine formulation, but does not significantly interact with the newer and more commonly used didanosine capsule (Videx EC). 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), efavirenz (Sustiva), and rilpivirine (Edurant) act as inducers of the CYP2B6 enzyme (Figure 2) and thus typically diminish plasma levels of methadone. Numerous case reports and anecdotal observations have described methadone withdrawal symptoms in persons taking methadone after they start a regimen that contains either nevirapine or efavirenz. One small study involving 8 patients found the concurrent use of methadone and nevirapine resulted in a 50% decrease in the area under the curve (AUC) of methadone, but required only a 16% mean increase in methadone dose. Several additional reports have described major withdrawal symptoms in patients on methadone after starting nevirapine[11,12]. Similarly, 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. Rilpivirine causes moderate decreases in the levels of R-methadone (the active form of methadone), but no dose adjustments are recommended when initiating co-administation of these two medications. In the situation when a patient on a stable dose of methadone starts on nevirapine, efavirenz, or rilpivirine, 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. If withdrawal symptoms are apparent, the methadone dose is typically increased in 10 mg increments every 2 to 3 days until symptoms resolve. In a study involving 14 HIV-negative subjects on chronic methadone, etravirine (Intelence) slightly increased methadone levels, but no dose adjustment of methadone was needed. The rarely used medication delavirdine (Rescriptor) is a weak inhibitor of CYP2C19 inhibition and theoretically could increase methadone levels. Methadone does not significantly alter the levels of any of the NNRTIs.
Interaction of Ritonavir-Boosted PIs and Methadone
Ritonavir (Norvir)-boosted PI regimens typically lower methadone levels (Figure 3), with the clinical impact of these interactions ranging from insignificant or minor symptoms of withdrawal to major withdrawal symptoms that require methadone dose adjustment. Ritonavir diminishes plasma methadone levels primarily through increased renal clearance and induced hepatic metabolism of methadone. Several reports have shown lopinavir-ritonavir (Kaletra) causes moderate reductions in methadone levels, but usually without causing methadone withdrawal symptoms[16,17,18]. In a pharmacokinetic and pharmacodynamic study, 26 HIV-negative adults on chronic methadone received fosamprenavir (Lexiva) 700 mg twice daily plus ritonavir 100 mg twice daily and this resulted in a 18% reduction in R-methadone levels, but none of he subjects had withdrawal symptoms. In a similar study involving eight HIV-negative subjects on a stable methadone regimen, the addition of darunavir (Prezista) 600 mg twice daily and ritonavir 100 mg twice daily caused a 15% reduction in R-methadone levels; four of the subjects had mild withdrawal symptoms, but none required a methadone dose adjustment. In another study involving HIV-negative persons on chronic methadone, saquinavir 1000 mg twice daily plus ritonavir 100 mg twice daily caused a 18% reduction in R-methadone levels, but no clinically significant adverse effects. Tipranavir plus ritonavir reduces methadone levels by about 50%, presumably via induction of CYP2C19 and intestinal p-glycoprotein. Ritonavir-boosted indinavir (Crixivan) does not impact methadone levels. Taken together, available data have shown that most ritonavir-boosted PIs cause significant but modest reductions in methadone levels; patients receiving a ritonavir-boosted protease inhibitor do not need automatic adjustments of methadone doses, but should undergo monitoring for potential methadone withdrawal and receive appropriate methadone dosage adjustments if needed[16,17]. Methadone does not significantly alter the levels of any of the ritonavir-boosted PIs.
Interaction of PIs (without Ritonavir) and Methadone
Protease inhibitors given without ritonavir can also interact with methadone (Figure 4). Multiple case reports and formal studies have demonstrated that nelfinavir (Viracept) reduces methadone levels [23,24]. The clinical outcomes of this interaction have been highly variable, ranging from absence of opioid withdrawal symptomsand no dose adjustment required, to severe withdrawal symptoms that required significant dose adjustments. Single protease inhibitor regimens that consist of atazanavir, fosamprenavir (Lexiva), or indinavir (Crixivan) appear to be safe when co-administered with methadone. In the indinavir study, which involved 12 HIV-negative individuals, no appreciable effect on indinavir AUC was observed, but the minimum concentrations were elevated and maximum concentrations diminished based on comparisons with historical controls. 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.
Interaction of Medications in Other Antiretroviral Classes and Methadone
Use of medications in other Integrase Strand Transfer Inhibitors, CCR5 Antagonists, or Fusion Inhibitors does not create any major problems for patients taking methadone. Investigators studied the impact of the integrase strand transfer inhibitor raltegravir (Isentress) in 12 HIV-negative subjects on chronic methadone and coadministration of raltegravir did not result in any clinically meaningful alteration in methadone levels. The CCR5 antagonist maraviroc (Selzentry) and the fusion inhibitor enfuvirtide (Fuzeon) do not have any known significant interaction with methadone.
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