Methadoneinteractions

Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 Clinical Impact: Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease, resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.

Intervention: If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine) Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9 Clinical Impact: The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone, resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.

Intervention: If concomitant use is necessary, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.

Examples: Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.

Intervention: For Patients Being Treated for Pain Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation).. If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose. For Patients Being Treated for Opioid Addiction Cessation of benzodiazepines or other CNS depressants is preferred in most cases of concomitant use. In some cases, monitoring in a higher level of care for taper may be appropriate. In others, gradually tapering a patient off of a prescribed benzodiazepine or other CNS depressant or decreasing to the lowest effective dose may be appropriate. Before co-prescribing benzodiazepines for anxiety or insomnia, ensure that patients are appropriately diagnosed and consider alternative medications and non-pharmacologic treatments. If concomitant use is warranted, strongly consider prescribing naloxone for the emergency treatment of opioid overdose, as is recommended for all patients in treatment for opioid use disorder.

Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Potentially Arrhythmogenic Agents Clinical Impact: Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).

Intervention: Evaluate patients closely for cardiac conduction changes.

Examples: Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.

Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.

Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets immediately if serotonin syndrome is suspected.

Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).

Intervention: The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms.

Intervention: Avoid concomitant use.

Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine.

Muscle Relaxants Clinical Impact: Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Intervention: Evaluate patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

Intervention: Evaluate patients for signs for diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.

Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets are used concomitantly with anticholinergic drugs. Paradoxical Effects of Antiretroviral Agents on Methadone Hydrochloride Tablets Concurrent use of certain antiretroviral agents with CYP3A4 inhibitory activity, alone and in combination, such as abacavir, amprenavir, darunavir+ritonavir, efavirenz, nelfinavir, nevirapine, ritonavir, telaprevir, lopinavir+ritonavir, saquinavir+ritonavir, and tipranavir+ritonavir, has resulted in increased clearance or decreased plasma levels of methadone. This may result in reduced efficacy of methadone hydrochloride tablets and could precipitate a withdrawal syndrome. Monitor methadone-maintained patients receiving any of these anti-retroviral therapies closely for evidence of withdrawal effects and adjust the methadone dose accordingly. Effects of Methadone Hydrochloride Tablets on Antiretroviral Agents Didanosine and Stavudine: Experimental evidence demonstrated that methadone decreased the area under the concentration-time curve (AUC) and peak levels for didanosine and stavudine, with a more significant decrease for didanosine. Methadone disposition was not substantially altered.

Zidovudine: Experimental evidence demonstrated that methadone increased the AUC of zidovudine, which could result in toxic effects. Effects of Methadone Hydrochloride Tablets on Antidepressants Desipramine: Blood levels of desipramine have increased with concurrent methadone administration.

Anti-Retroviral Agents: May result in decreased efficacy or, in certain cases, increased toxicity.

Potentially Arrhythmogenic Agents: Pharmacodynamic interactions may occur. Regularly evaluate patients closely for cardiac conduction changes. Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with methadone hydrochloride tablets because they may reduce analgesic effect of methadone hydrochloride tablets or precipitate withdrawal symptoms. Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of methadone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI.