From the Guidelines
When taking methadone, it is crucial to exercise caution with medication interactions, and generally safe options include acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen, and many antibiotics such as penicillins and cephalosporins, as noted in recent guidelines 1. However, even with these safer options, consulting a healthcare provider before combining medications is essential. Medications to avoid include benzodiazepines, other opioids, alcohol, certain antidepressants (particularly MAOIs), some antipsychotics, and certain HIV medications, as they can cause dangerous respiratory depression or serotonin syndrome when combined with methadone 1. Some medications can also affect methadone levels in the blood, such as rifampin, phenytoin, and carbamazepine, which can decrease methadone effectiveness, while others like fluconazole may increase methadone concentration 1. Always informing all healthcare providers about methadone use is vital to prevent potentially dangerous drug interactions. Key considerations include:
- Avoiding medications that can increase the risk of serotonin syndrome or respiratory depression
- Being cautious with medications that can affect methadone levels
- Informing all healthcare providers about methadone use to ensure safe medication management
- Consulting healthcare providers before starting or stopping any medications while on methadone
- Prioritizing medications with predictable pharmacokinetics and pharmacodynamics to minimize unintentional overdose risk, as recommended in recent guidelines 1.
From the FDA Drug Label
Phenytoin In a pharmacokinetic study with patients on methadone maintenance therapy, phenytoin administration (250 mg b.i. d. initially for 1 day followed by 300 mg QD for 3 to 4 days) resulted in an approximately 50% reduction in methadone exposure and withdrawal symptoms occurred concurrently. St John’s Wort, Phenobarbital, Carbamazepine Administration of methadone along with other CYP3A4 inducers may result in withdrawal symptoms. Cytochrome P450 Inhibitors Since the metabolism of methadone is mediated primarily by CYP3A4 isozyme, coadministration of drugs that inhibit CYP3A4 activity may cause decreased clearance of methadone The expected clinical results would be increased or prolonged opioid effects. Thus, methadone-treated patients coadministered strong inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole) with methadone should be carefully monitored and dosage adjustment should be undertaken if warranted. Some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine) may increase methadone plasma levels upon coadministration with methadone and result in increased opiate effects and/or toxicity Voriconazole Repeat dose administration of oral voriconazole (400mg Q12h for 1 day, then 200mg Q12h for 4 days) increased the Cmax and AUC of R-methadone by 31% and 47%, respectively, in subjects receiving a methadone maintenance dose (30 to 100 mg QD).
The medications that are not safe to take with Methadone include:
- CYP3A4 inducers such as:
- Phenytoin
- St John’s Wort
- Phenobarbital
- Carbamazepine
- Potentially arrhythmogenic agents such as:
- Class I and III antiarrhythmics
- Some neuroleptics and tricyclic antidepressants
- Calcium channel blockers
- Drugs capable of inducing electrolyte disturbances such as:
- Diuretics
- Laxatives
- Mineralocorticoid hormones
- CNS depressants such as:
- Alcohol
- Benzodiazepines
- Illicit drugs that cause central nervous system depression
Medications that may be safe to take with Methadone, but require careful monitoring and dosage adjustment include:
- Strong inhibitors of CYP3A4 such as:
- Azole antifungal agents (e.g., ketoconazole)
- Selective serotonin reuptake inhibitors (SSRIs) such as:
- Sertraline
- Fluvoxamine
- Voriconazole
From the Research
Medication Interactions with Methadone
The following medications may interact with methadone:
- There is no specific list of safe medications to take with methadone provided in the studies 3, 4, 5, 6, 7.
- However, it is known that methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6, which may lead to interactions with other medications that affect these enzymes 3.
- Methadone users often have comorbidities and are prescribed drugs that may interact with methadone, making it critical for healthcare providers to have adequate information on these interactions 3, 4.
Precautions for Methadone Use
To ensure safe use of methadone:
- Healthcare providers should educate and counsel patients on methadone safety 7.
- Electrocardiography should be used to identify persons at greater risk for methadone-associated arrhythmia 7.
- Alternative opioids should be used in patients at high risk of complications related to corrected electrocardiographic QTc interval prolongation 7.
- Careful dose initiation and titration of methadone, as well as diligent monitoring and follow-up, are necessary 7.
Importance of Monitoring
Regular monitoring is essential for patients taking methadone, as interactions with other medications can lead to increased or decreased methadone drug levels, resulting in potential overdose or withdrawal 3, 4.