Methadone with Lopinavir Interaction Details

Brand Names Associated with Methadone

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Jan 02, 2024

Interaction Effect

Increased risk of opioid withdrawal symptoms

Interaction Summary

Concomitant use of methadone and certain antiretroviral agents with CYP3A4 inhibitory activity, such as lopinavir has a paradoxical effect and may result in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of methadone and may cause a withdrawal syndrome. In pharmacokinetic studies, there was a decrease in methadone exposure and serum concentrations, and increased clearance . One study reported an increase in opiate withdrawal symptoms  and in a case report, a patient developed Torsade de pointes . Monitor methadone-maintained patients receiving an antiretroviral therapy closely for evidence of withdrawal effects and adjust the methadone dose appropriately .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Concomitant use of methadone and certain antiretroviral agents with CYP3A4 inhibitory activity, such as lopinavir, has a paradoxical effect and may result in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of methadone and may cause a withdrawal syndrome. If coadministered, monitor methadone-maintained patients receiving an antiretroviral therapy closely for evidence of withdrawal effects and adjust the methadone dose appropriately.

Mechanism Of Interaction

Unknown

Literature Reports

A) In a pharmacokinetic study, coadministration of lopinavir/ritonavir to HIV-negative adults receiving methadone maintenance therapy led to significant reductions in methadone exposure, peak/trough levels and clearance, and resulted in opiate withdrawal symptoms. Concomitant to their daily methadone dose, patients (n=15) received either lopinavir 400 mg/ritonavir 100 mg or ritonavir 100 mg alone for 7 days. Results showed that the methadone AUC significantly decreased by 26% from 9,199 mcg/hr/mL with methadone alone to 6,819 mcg/hr/mL in combination with lopinavir/ritonavir. Methadone clearance significantly increased to 14.14 L/hr compared to 9.97 L/hr with methadone alone. Both methadone Cmax and Cmin significantly decreased by 28% following coadministration of lopinavir/ritonavir; however, Tmax was not affected. Additionally, patients reported increased opiate withdrawal symptoms, which were assessed using the Objective Opiate Withdrawal Scale (OOWS). Scores increased from 0 to 2 at baseline to 0 to 5 after study completion. Withdrawal severity was proportional to decrease in methadone trough levels, and all subjects with withdrawal severity increases of 2 or more on the OOWS scale had sub-therapeutic methadone levels (less than 200 mcg/L). Coadministration of ritonavir alone with methadone had a modest, but nonsignificant, increase in methadone concentrations .

B) In a pharmacokinetic study, coadministration of lopinavir/ritonavir, as part of antiretroviral therapy (ART), to patients receiving methadone maintenance therapy led to decreased methadone exposure without causing opioid withdrawal symptoms. Patients (n=8; mean age 34 years) were administered methadone alone on day 1 of the study (mean dose 74 mg; range 40 to 100 mg). On days 2 through 14, patients received ART which included stavudine and didanosine (n=4), and zidovudine and lamivudine (n=4) plus lopinavir/ritonavir (dose not available) in addition to their daily methadone dose. Results showed that the mean AUC for methadone significantly decreased by 36%, decreasing from 10,835 nanograms (ng)/hr/mL; range, 3,829 to 12,638 ng/hr/mL) to 6,493 ng/hr/mL (range, 3,949 to 13, 692 ng/hr/mL). There was also a 44% reduction in mean Cmax for methadone. However, patients did not experience symptoms of opioid withdrawal during the study period or during the extended 6-week follow-up. The reduction in methadone AUC may have been caused by either induction of CYP450 isozymes and/or glucuronyltransferase by lopinavir/ritonavir, or induction of P-glycoprotein; altered plasma binding; or unequal effects on isomeric forms of methadone .

C) A 53-year-old, HIV-positive female taking methadone for opioid dependence developed Torsade de pointes (TdP) eight days after stopping combination antiretroviral therapy (ART). The patient had presented with abdominal discomfort and elevated lactate levels and the ART, which consisted of tenofovir 245 mg once daily, didanosine 250 mg once daily, fosamprenavir 700 mg twice daily, and lopinavir 400 mg/ritonavir 100 mg twice daily, was discontinued secondary to a diagnosis of symptomatic hyperlactatemia. The patient was also concurrently taking stable doses of methadone (75 mg twice daily), methylphenidate, oxazepam, and paroxetine. Eight days after stopping ART, the patient complained of palpitations and laboratory values revealed an unusually high methadone level (2640 nanomoles (nmol)/L), a corrected QT interval of 654 msec, and low electrolyte levels (potassium, 3.2 mmol/L; phosphate, 0.46 mmol/L; magnesium, 0.77 mmol/L). Upon admission all oral medications were stopped, and methadone was replaced by morphine. The patient required electromechanical conversion and intubation for 48 hours before the corrected QT interval returned to normal (420 msec) after 4 days. While other risk factors (gender, abnormal electrolytes) for QT prolongation were present in this case, a decrease in methadone metabolism (as evidenced by high plasma methadone levels) after discontinuation of ART therapy may have contributed to QT prolongation .

Methadone Overview

• Methadone is used to relieve severe pain in people who are expected to need pain medication around the clock for a long time and who cannot be treated with other medications. It also is used to prevent withdrawal symptoms in patients who were addicted to opiate drugs and are enrolled in treatment programs in order to stop taking or continue not taking the drugs. Methadone is in a class of medications called opiate (narcotic) analgesics. Methadone works to treat pain by changing the way the brain and nervous system respond to pain. It works to treat people who were addicted to opiate drugs by producing similar effects and preventing withdrawal symptoms in people who have stopped using these drugs.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.