Table shows the interactions of ARVs with methadone and buprenorphine. Most of the interactions are ARV effects on methadone metabolism. Several NNRTIs strongly induce CYP3A4 and have been shown to lower methadone plasma concentrations and cause methadone withdrawal symptoms such as anxiety, abdominal cramps, and muscle and joint pain. The NNRTI efavirenz decreased methadone area under the curved (AUC) 55% and required methadone dose increases on average by 52% [24
•]. Similarly, when methadone maintenance patients were started on the NNRTI nevirapine, methadone AUC decreased by 63%, resulting in opioid withdrawal among 9 of 10 patients, and requiring an average 20% increase in methadone dose [25
Interactions between antiretroviral medications, methadone, and buprenorphine
The NNRTI etravirine induces CYP3A4 but inhibits CYP2C19, another route of methadone metabolism. A study of etravirine given over 14 days showed slightly increased methadone AUC, and no need for methadone dose adjustment [26
For the NNRTIs known to induce methadone metabolism, methadone dose increases are often needed. However, an immediate methadone dose increase could result in opioid toxicity since it cannot be predicted who will develop opiate withdrawal or severity. Therefore, a dose increase prior to onset of objective signs and symptoms of opiate withdrawal is not recommended. Moreover, CYP enzyme induction requires the synthesis of new enzymes, generally over 7 to 21 days, which is therefore the time frame for onset of opiate withdrawal and need for a methadone dose increase. Because methadone providers manage methadone dose in these patients, it is important for HIV providers to let methadone treatment providers know when a new ARV with inducing properties is initiated, so that they can monitor for opioid withdrawal symptoms and then adjust the methadone dose as needed.
Conversely, when inducers are stopped (such as when primary providers decide to stop them, or when patients decide to stop or decrease the medication on their own, or when patients are unable to get a medication refilled due to financial issues), methadone levels increase, resulting in possible sedation, constipation, respiratory depression, cardiac arrhythmias, and other toxicities. When methadone patients receiving CYP3A4-inducing ARVs experience methadone toxicity, this may be due to cessation of or nonadherence to these ARVs. For example, efavirenz can cause dizziness, somnolence, insomnia, or confusion. If patients decrease or stop this medication to avoid these side effects, they may be at risk for opioid toxicity. Methadone patients who have had their dose increased to accommodate efavirenz or nevirapine need to be monitored closely for possible methadone toxicity in case they go off these medications unexpectedly.
Although in vitro studies indicate that the PIs inhibit CYP3A4, many have been found to decrease rather than increase methadone concentrations in humans, possibly due to other metabolic processes such as renal clearance or induction of other CYP enzymes. Several PIs are associated with reduced methadone AUC as well as methadone withdrawal symptoms, including darunavir/ritonavir [27
] and lopinavir/ritonavir [28
•]. A case report described how a patient developed Torsades de Pointes (cardiac arrhythmia reported in association with methadone) after stopping lopinavir/ritonavir, due to failure to reduce the methadone dose that had been increased when lopinavir/ritonavir was started [29
•]. Nelfinavir decreased methadone AUC, but no withdrawal was observed [30
•]. In a study with healthy volunteers not on methadone maintenance, nelfinavir decreased methadone plasma concentrations 40% despite 50% CYP3A4 inhibition, by increasing renal clearance [20
•]. Similarly, ritonavir decreased methadone concentrations despite CYP3A4 inhibition, also by increasing renal clearance [31
•]. Tipranavir/ritonavir has been shown to reduce methadone serum concentration 50% [32
], despite CYP3A4 inhibition. The mechanism may be its induction of CYP2C19 and intestinal p-glycoprotein [33
Fortunately, there are several PIs without significant effects on methadone AUC, including the CYP3A4 inhibitors atazanavir [34
], indinavir/ritonavir [21
•], saquinavir/ritonavir [35
•], and the mixed CYP3A4 inhibitor and inducer fosamprenavir/ritonavir [36
In sum, studies of methadone maintenance patients starting efavirenz, nevirapine, and several PIs have evidenced decreased methadone concentrations and withdrawal symptoms requiring methadone dose increases when these medications are started and methadone dose decreases when they are stopped. For efavirenz and nevirapine, these drug interactions are consistent with their induction of CYP3A4. In contrast, for many PIs these drug interactions are opposite to their inhibition of CYP3A4 and thus most likely due to other mechanisms.