Methadone is a synthetic opioid used to treat moderate to severe pain and for opioid substitution (methadone maintenance programmes). Requires special monitoring due to accumulation risk and QT prolongation.
Also known as: methadone, dolophine, metadone cloridrato
CYP3A4 inhibitor + opioid: methadone levels significantly increased. Risk of excessive sedation and respiratory depression.
Ritonavir is a potent inhibitor of CYP3A4 and CYP2B6, the main enzymes metabolising methadone. CYP2B6 is responsible for ~70% of methadone metabolism, and CYP3A4 contributes ~20%. Co-administration with ritonavir can increase methadone levels 2-4-fold, depending on ritonavir dose and CYP2B6 genetic polymorphism. CYP2B6 poor metabolisers (frequency ~2-5% in African populations) have even higher risk. Methadone prolongs QTc — increased levels may cause torsades de pointes. Monitor QTc before and during co-administration. If QTc >500 ms, consider ritonavir alternative or reduce methadone dose.
Potent CYP3A4 inhibitor + opioid: methadone levels increased 2-4-fold. Risk of excessive sedation, respiratory depression, and QTc prolongation.
Ritonavir strongly inhibits CYP3A4 and CYP2B6, the main metabolic pathways for methadone. Methadone levels may increase 2-4-fold. Risk of QTc prolongation and respiratory depression.
Sedation, respiratory rate, ECG (QTc), signs of respiratory depression.
Respiratory depression, QTc >500 ms, syncope.
Avoid combination if possible. If necessary, reduce methadone dose by 50-75% and monitor closely. Consider ECG for QTc.
DailyMed/FDA — approved Methadone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=092d78eb-6423-495c-bf0d-e6532bea7138
CYP3A4 inhibitor + opioid: methadone levels increased. Risk of sedation and respiratory depression.
Fluconazole moderately inhibits CYP3A4, one of the metabolic pathways for methadone (responsible for ~20% of metabolism). The effect is less pronounced than with ritonavir or ketoconazole, but clinically significant. Methadone levels may increase 1.5-2-fold, especially in CYP2D6 poor metabolisers who depend more on CYP3A4. Monitoring should include sedation, respiratory rate, and ECG (QTc). The effect is more pronounced with high fluconazole doses (>200 mg/day) and prolonged treatments.
CYP3A4 inhibitor + opioid: methadone levels increased 1.5-2-fold. Risk of sedation and respiratory depression.
Fluconazole inhibits CYP3A4, reducing methadone metabolism. Levels may increase 1.5-2-fold. More pronounced effect in CYP2D6 poor metabolizers.
Sedation, respiratory rate, signs of respiratory depression.
Respiratory depression, excessive sedation.
Monitor for signs of sedation and respiratory depression. Consider reducing methadone dose by 25-50% if prolonged treatment.
DailyMed/FDA — approved Methadone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=092d78eb-6423-495c-bf0d-e6532bea7138
Food may increase oral methadone bioavailability. Modest effect.
Maintain consistency: always with or always without food. Changes may affect levels.
Extensive hepatic metabolism. Significant accumulation in hepatic impairment. Risk of prolonged respiratory depression.
Reduce dose by 50-75%. Monitor closely. Consider non-hepatic alternatives.
DailyMed/FDA — approved Methadone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=092d78eb-6423-495c-bf0d-e6532bea7138
Renal metabolites (normethadone) may accumulate. Moderate clinical effect — methadone is primarily hepatic.
Dose adjustment rarely needed. Monitor for signs of accumulation.
DailyMed/FDA — approved Methadone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=092d78eb-6423-495c-bf0d-e6532bea7138
Used in pregnancy for opioid substitution (MMT). Benefit outweighs risk. Neonates may present with neonatal abstinence syndrome.
All trimesters: use only in MMT with close obstetric monitoring.
Excreted in breast milk. Compatible with breastfeeding at stable doses. Monitor infant for sedation.
Reliable contraception is recommended during opioid substitution.
DailyMed/FDA — approved Methadone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=092d78eb-6423-495c-bf0d-e6532bea7138
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Mu opioid receptor agonist (analgesia) and NMDA receptor antagonist (pain tolerance). Used in opioid substitution and chronic pain. Long and unpredictable effect.
Mu-opioid agonist with NMDA antagonist activity and sigma receptor activation. Inhibits serotonin and noradrenaline reuptake (adjunct antidepressant action).
Almost complete oral absorption (80-90%). Bioavailability: 70-80%. Peak: 1-6 h. Variable between individuals.
Metabolised by CYP2B6 (major), CYP3A4, and CYP2C19. Active metabolites. Significant genetic variability in CYP2B6 affects levels.
8-59 h (highly variable). Mean: 25 h. Cumulative effect — titrate dose slowly.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
