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 involves the cytochrome P450 enzyme system. Five P450 isoenzymes play a role in the enzymatic degradation process of methadone: CYP3A4, CYP2B6, CYP2C9, CYP 2C19, and CYP 2D6.[,] Among these five CYP450 isoenzymes, it appears that CYP2B6, and to a lesser extent CYP2C19, are the main pathways for methadone metabolism. In addition, some metabolism of methadone occurs through demethylation, which forms inactive metabolites, which are excreted in the bile and urine. Methadone may also partially inhibit these CYP450 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), which have similar pathways of metabolism.[,] Potential 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. Clinically significant drug-drug interactions do not occur with methadone and nucleoside reverse transcriptase inhibitors (NRTIs), integrase strand transfer inhibitors (INSTIs), or C-C chemokine receptor type 5 (CCR5) antagonists.
Interaction of NRTIs and Methadone
Among the NRTIs, several have drug-drug interactions with methadone, but none require routine dose adjustments (Figure 1).[,,] The concurrent use of methadone and abacavir (Ziagen) may increase methadone clearance by 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.[,,,] No routine methadone dose adjustments are required with concomitant use of NRTIs. Methadone increases the plasma area under the curve (AUC) of zidovudine by 29 to 43%, 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. Accordingly, patients on methadone and zidovudine should undergo monitoring for zidovudine-related adverse effects. 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 old buffered tablet didanosine formulation, but does not significantly interact with the didanosine capsule (Videx EC). No formal study has examined methadone's impact on intracellular NRTI drug concentrations.
Interaction of NNRTIs and Methadone
The NNRTIs nevirapine (Viramune), efavirenz (Sustiva), and rilpivirine (Edurant) act as inducers of the CYP2B6 enzyme and thus typically diminish plasma levels of methadone; a dose increase in methadone is often necessary if used concurrently with efavirenz or nevirapine with methadone (Figure 2).[,] 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.[,] 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 (active form of methadone), but no dose adjustments are recommended. 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 did not require methadone dose adjustments. .
Interaction of PIs and Methadone
The impact of PIs on methadone ranges from no significant alteration of methadone plasma levels to substantial decreases, particularly with ritonavir (Norvir)-boosted PI regimens (Figure 3). Ritonavir diminishes methadone plasma levels primarily through increased renal clearance and induced hepatic metabolism. Several reports have shown lopinavir-ritonavir (Kaletra) causes moderate reductions in methadone levels, but usually without causing methadone withdrawal symptoms.[,,] 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, which resulted in a 18% reduction in R-methadone levels, but none of the subjects experienced withdrawal symptoms. A small 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. 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. Unboosted atazanavir (Reyataz) does not significantly alter methadone levels. Studies have not been performed with unboosted fosamprenavir and methadone, but one study with amprenavir and methodone demonstrated a 21% decrease in methadone Cmin when used with amprenavir. Available data have demonstrated 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 as needed.[,] Methadone does not significantly alter the levels of any of the ritonavir-boosted PIs. The impact of cobicistat (Tybost)-boosted PIs on methadone has not been well studied.
Interaction of Medications in Other Antiretroviral Classes and Methadone
The use Integrase Strand Transfer Inhibitors (INSTIs) with methadone does not cause significant alterations in methadone plasma levels (Figure 4). Investigators studied the impact of the integrase strand transfer inhibitor raltegravir (Isentress) in 12 HIV-negative subjects on chronic methadone. Coadministration of raltegravir did not result in clinically significant alteration in methadone plasma levels. Similarly, a study with dolutegravir (Tivicay) showed coadministration with methadone had no impact on methadone plasma levels. In addition use of CCR5 Antagonists or Fusion Inhibitors does not create any major problems for patients taking methadone. The CCR5 antagonist maraviroc (Selzentry) and the fusion inhibitor enfuvirtide (Fuzeon) do not have any known significant interactions with methadone.