Table 4.
Common interactions between methadone and buprenorphine with treatment for HIV infection and other comorbidities7,29
| Effect on methadone | Effect on buprenorphine | Antiretroviral medication | Comments | |
|---|---|---|---|---|
|
Nucleoside reverse transcriptase inhibitor
| ||||
| Abacavir | Increased clearance of methadone | Not studied | No effect | Unclear if increase in methadone clearance is caused by abacavir; monitor for symptoms of withdrawal |
| Didanosine | No effect | No effect | Methadone decreases didanosine AUC by 57% for buffered tablet, partly corrected by enteric-coated capsule to within range in historical controls | Enteric-coated capsule recommended for patients on methadone |
| Emtricitabine | Not studied | Not studied | Not studied | No expected pharmacokinetic interactions |
| Lamivudine | No effect | No effect | Not studied | Zidovudine-lamivudine co-formulation studied only; no effect on methadone |
| Stavudine | No effect | Not studied | Decrease in stavudine AUC12 h by 23% and Cmax by 44% | Changes unlikely to be clinically significant |
| Tenofovir | No effect | No effect | Not studied | ·· |
| Zidovudine | No effect | No effect | Increase in zidovudine AUC by 40% | Watch for zidovudine-related toxicity (symptoms and laboratory) when on methadone |
|
| ||||
|
Non-nucleoside reverse transcriptase inhibitors
| ||||
| Delavirdine | Increases methadone AUC by 19%; increases Cmax by 10% | Not studied | No effect with methadone | Possibly not clinically relevant, but should be used with caution since long-term effects (greater than 7 days) unknown |
| Efavirenz | Significant effect: decrease in mean methadone AUC by 57% | Significant effect: mean decrease in buprenorphine AUC by around 50%; no clinical symptoms of withdrawal | Not studied | Opiate withdrawal common with methadone; increase in methadone dose necessary; no change in buprenorphine dose |
| Nevirapine | Significant effect: decrease in mean methadone AUC by 46% | No effect | No effect on nevirapine with methadone or buprenorphine | Opioid withdrawal symptoms common with methadone; increase in methadone dose necessary |
| Etravirine | Studied with low dose (100 mg twice a day); no effect on methadone | Not studied in human beings | No effect when combined with methadone | No dose adjustments necessary |
|
| ||||
|
Protease inhibitors
| ||||
| Amprenavir | Decreases AUC of R-methadone by 13% | Not studied in human beings | Decrease in AUC by 30% | Decrease in AUC does not seem to be clinically significant |
| Atazanavir | No effect | When atazanavir combined with ritonavir, increased buprenorphine concentrations | No effect with methadone or buprenorphine | Oversedation possible with atazanavir-ritonavir; titrate buprenorphine dose slowly |
| Darunavir | AUC, Cmax, and Cmin decrease by 24–40% | Norbuprenorphine, but not buprenorphine AUC increases by 46%; no clinical symptoms | No effect of methadone on darunavir | Darunavir might precipitate opioid withdrawal symptoms in patients on methadone |
| Fosamprenavir | S-methadone but not R-methadone concentrations decreased | Not studied in human beings | Not studied | No clinically significant interactions reported |
| Indinavir | No effect | Not studied | Decreased Cmax between 16% and 28% and increased Cmin between 50–100% | Differences do not seem to be clinically significant |
| Lopinavir-ritonavir | Decreases methadone AUC by 26–36% | No effect | No effect by methadone or buprenorphine on antiretroviral drugs | Decrease in AUC of methadone caused by lopinavir; one study reported opioid withdrawal symptoms in 27% of patients; increase in methadone dose might be necessary in some patients |
| Nelfinavir | Decreases methadone AUC by 40% | Not studied | Decrease in AUC of active M8 metabolite by 48% but not on nelfinavir itself when combined with methadone | Despite decrease in methadone AUC, clinical withdrawal is usually absent and a priori dose adjustments are not needed; decrease in AUC of M8 unlikely to be clinically significant; TDM might be useful in patients with good adherence and virological failure |
| Ritonavir | Decreases methadone AUC by 37% in one study and no effect in another (see text) | Not studied | Not studied | No dose adjustment necessary |
| Saquinavir | Decreases methadone AUC by 20–32% | Not studied | Not studied | Saquinavir boosted with ritonavir studied; despite decrease in methadone AUC, clinical withdrawal was not reported |
| Tipranavir | Decreases methadone by 50%* | No effect | Buprenorphine decreases tipranavir concentrations by 19–25% | Methadone might need to be increased; no change in buprenorphine dose needed; TDM of tipranavir possibly needed when given with buprenorphine |
|
| ||||
|
Integrase inhibitors
| ||||
| Raltegravir | Methadone AUC unchanged when co-administered with raltegravir | Not studied; common metabolic pathway with UGT1A1 | No significant interactions with ART drugs | Titrate buprenorphine dose slowly |
|
| ||||
|
Entry inhibitors
| ||||
| Enfuvirtide | Not studied | Not studied | Not studied | No interactions anticipated; enfuvirtide given intramuscularly |
| Maraviroc | Not studied | Not studied | Not studied | ·· |
|
| ||||
|
Other common treatment drugs for HIV-related comorbidities
| ||||
| Rifampicin | Decreases methadone AUC by 30–65%; 70% of patients on methadone developed withdrawal symptoms 1–33 days after receiving rifampicin | Not studied in human beings | Substantial reduction in concentrations of all protease inhibitors, raltegravir, enfuvirtide, and nevirapine | Should not be combined with protease inhibitors or nevirapine; clinical pharmacodynamic studies support efavirenz given at 600 mg or 800 mg per day; raltegravir dose should be increased to 800 mg twice a day |
| Rifabutin | No significant interaction | Not studied in human beings | Protease inhibitors significantly increase rifabutin concentrations | In patients requiring a protease inhibitor, the rifabutin dose should be decreased to 150 mg thrice weekly |
| Ciprofloxacin | Not studied in human beings | Not studied in human beings | No significant change with enteric-coated didanosine formulation | No expected interaction |
| Ofloxacin | Not studied in human beings | Not studied in human beings | No significant interactions | No expected interaction |
| Clarithromycin | Not studied in human beings | Not studied in human beings | Atazanavir increases clarithromycin concentrations by 50% and can cause QT prolongation; darunavir, tipranavir, and lopinavir increase clarithromycin concentrations and increase side-effects; efavirenz and nevirapine decreases clarithromycin AUC by 39%; efavirenz associated with increased rash; fluconazole increases clarithromycin concentrations and is associated with QTc prolongation; clarithromycin increases maraviroc and saquinavir concentrations | Adjust clarithromycin with lopinavir or darunavir only if renal insufficiency; use azithromycin instead of clarithromycin when given with efavirenz, etravirine; decrease clarithromycin dose by 50% with atazanavir |
| Azithromycin | Not studied in human beings | Not studied in human beings | No change in azithromycin AUC; Cmax increased by 22% | Preferred over clarithromycin |
| Fluconazole | Increases methadone AUC levels by 35%; no signs or symptoms of opioid excess | Not studied in human beings | Several interactions, but not of clinical significance | No clinical need for dose adjustment |
| Pegylated interferon alfa | No interactions | Not studied in human beings | No interactions | No interaction with methadone; no expected interactions with buprenorphine or ART |
| Ribavirin | Not studied in human beings | Not studied in human beings | ·· | No interaction with methadone |
| Telbivudine | Not studied in human beings | Not studied in human beings | Not studied, might need caution with other thymidine analogues | Renally cleared; no expected interactions with methadone or buprenorphine |
| Entecavir | Not studied in human beings | Not studied in human beings | Not studied, might need caution with other guanosine analogues; use with ART that is virologically suppressive | Renally cleared; no expected interactions with methadone or buprenorphine |
|
| ||||
|
Common psychiatric medications
| ||||
| Amitriptyline | Increases methadone concentrations (via decreased clearance) | Not studied in human beings | Increased amitriptyline concentrations (dry mouth, hypotension, confusion) | Dry mouth, hypotension, confusion; monitor and adjust amitriptyline as indicated |
| Citalopram | No clinically signficant interaction | No clinically signficant interaction | Not studied in human beings | ·· |
| Desipramine | Associated with increased desipramine concentrations | Not studied in human beings | Desipramine levels decreased by 59% | Start with lower desipramine and monitor and adjust desipramine clinically |
| Duloxetine | May lead to increased duloxetine concentrations, not studied in human beings | Not studied in human beings | Not studied in human beings | ·· |
| Sertraline | No clinically signficant interaction | No clinically signficant interaction | Darunavir decreases sertraline AUC by 50% | Might need to titrate sertraline dose upwards |
| Mirtazapine | Not studied in human beings | Not studied in human beings | Not studied in human beings | No expected interactions |
| Fluvoxamine | Increases methadone concentrations; discontinuation associated with precipitation of opioid withdrawal symptoms | Not studied in human beings | Not studied in human beings | Monitor for symptoms of opioid excess and withdrawal depending on initiation and stopping of duloxetine, respectively |
| Fluoxetine | Might increase methadone concentration | Not studied in human beings | Increase in ritonavir AUC by 19% | No dose adjustment necessary |
| Haloperidol | Not studied in human beings | Not studied in human beings | Not studied in human beings | ·· |
| Risperidone | Decreases methadone concentrations | Not studied in human beings | Not studied in human beings | Monitor for symptoms of opioid withdrawal |
| Aripiprazole | Not studied in human beings | Not studied in human beings | Not studied in human beings | No anticipated interactions |
| Olanzapine | Not studied in human beings | Not studied in human beings | Ritonavir decreases olanzapine AUC by 50% | Increase olanzapine dose to symptoms |
| Quetiapine | Results in increased methadone concentrations | Not studied in human beings | Not studied in human beings | Monitor for symptoms of opioid excess |
| Carbamazepine | Decreases methadone concentrations; precipitates opioid withdrawal symptoms | Not studied in human beings | Decreases concentrations of many antiretroviral drugs and should be avoided when possible | Symptoms of withdrawal reported; monitor for symptoms of opioid withdrawal |
| Lamotrigine | No clinically signficant interaction | Not studied in human beings | Lopinavir and ritonavir decrease lamotrigine concentrations | ·· |
| Topiramate | Not studied in human beings | Not studied in human beings | Not studied in human beings | None expected; not hepatically metabolised |
| Valproic acid | No clinically signficant interaction | Not studied in human beings | Lopinavir, tipranavir, and ritonavir decrease valproic acid concentrations and valproic acid increases lopinavir concentrations | ·· |
| Diazepam or midazolam | Increase methadone concentrations; associated with increased sedation | No effect | Should avoid or use carefully with most boosted protease inhibitors | Monitor for symptoms of opioid excess |
See text for references. AUC=area under curve. AUC12 h=area under curve from 0 h to 12 h. Cmax=maximum concentration. Cmin=minimum concentration. TDM=therapeutic drug monitoring. UGT1A1=UDP-glucuronosyltransferase 1A1. ART=antiretroviral therapy.
*
Decrease in methadone not specified as AUC or Cmax.