Moderate-to-severe chronic pain
Third line
Full μ-opioid agonist for moderate-to-severe chronic cancer and non-cancer pain. SED uses methadone for opioid rotation in morphine tolerance and when a neuropathic pain component is present.
Synthetic opioid, full mu-receptor agonist
ATC code: N07BC02 (Methadone)
Brand names
Dolophine, Methadose
Methadone is a full mu-opioid receptor agonist with a long half-life (T1/2 24–36 hours). It is used in opioid substitution therapy and for chronic pain refractory to other opioids. The drug blocks the hERG potassium channel and markedly prolongs the QT interval, especially at doses above 100 mg/day, with reported cases of torsades de pointes. Methadone also acts as a weak NMDA antagonist and inhibits serotonin reuptake; serotonergic reactions have been reported with SSRIs, SNRIs, and linezolid. Methadone is fully prohibited from circulation in Russia.
Third line
Full μ-opioid agonist for moderate-to-severe chronic cancer and non-cancer pain. SED uses methadone for opioid rotation in morphine tolerance and when a neuropathic pain component is present.
9 pairs found. Sorted from critical to minor.
Mechanism
Additive QT prolongation from two strong QT prolongers + amiodarone inhibits CYP3A4 (methadone rises).
Symptoms
QTc above 500 ms, syncope, torsades de pointes risk.
Management
Combination contraindicated.
Sources
Mechanism
Clarithromycin inhibits CYP3A4 (raises methadone) and itself prolongs QT. Dual torsades risk in OST patient.
Symptoms
QT above 500 ms, syncope.
Management
Combination contraindicated. Alternative – azithromycin.
Mechanism
Dual QT prolongation, especially with methadone above 80 mg/day.
Symptoms
QTc above 500 ms, syncope, torsades de pointes risk.
Management
Combination contraindicated.
Mechanism
Methadone is an opioid with serotonergic activity and QT prolongation. Combined with phenelzine causes serotonin syndrome and additive QT effect.
Symptoms
Hyperthermia, myoclonus, respiratory depression, QT prolongation.
Management
Combination contraindicated. For OST in an MAOI patient, switch methadone to buprenorphine (less serotonergic).
Mechanism
Ritonavir has dual action: inhibits CYP3A4 (raises methadone) and induces CYP2B6 (lowers methadone). Net effect – unpredictable level swings plus additive QT prolongation.
Symptoms
Opioid withdrawal or overdose symptoms within 3-7 days. QT prolongation.
Management
For OST in HIV patient – ECG before and after ARV start, daily clinical monitoring for withdrawal/overdose signs first week. Alternative opioid – buprenorphine.
Mechanism
Fluconazole inhibits CYP3A4 and CYP2B6 – the main methadone metabolism enzymes. Methadone concentration rises by 35% with QT prolongation. Methadone alone prolongs QT above 80 mg/day; fluconazole amplifies this.
Symptoms
Drowsiness, respiratory depression (rate below 12/min), miosis, ECG QTc above 500 ms. Severe cases: fatal arrhythmia.
Management
Reduce methadone by 25% when starting fluconazole, ECG before and after. With methadone above 80 mg/day or QT risk factors, choose an alternative antifungal (isavuconazole, terbinafine for superficial infections).
Mechanism
Strong CYP3A4 inhibitor. Methadone rises 2-3 fold.
Symptoms
Sedation, respiratory depression, QT prolongation.
Management
Reduce methadone by 25%, ECG monitoring.
Mechanism
Methadone prolongs QT (especially above 80 mg/day). Moxifloxacin adds 10-20 ms. Torsades de pointes risk.
Symptoms
QTc above 500 ms, syncope, torsades de pointes risk.
Management
Alternative – levofloxacin or other class.
Mechanism
Rifampicin induces CYP3A4 and CYP2B6. Methadone falls 70% – opioid withdrawal within 5-7 days.
Symptoms
Agitation, sweating, muscle pain, diarrhoea, mydriasis after 5-7 days.
Management
For TB in OST patient – increase methadone by 50-100% with clinical monitoring. After rifampicin withdrawal – downward titration.
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FDA Category C. Methadone is the WHO and SEPB preferred substitution therapy for opioid dependence in pregnancy. Maternal opioid withdrawal carries higher fetal risk than methadone maintenance. About 60% of exposed newborns develop neonatal abstinence syndrome requiring inpatient management.
Compatible. Hale L3. Transfers into milk (RID about 2–3%) without reaching clinically meaningful infant concentration at stable maintenance doses. WHO and AAP consider it compatible; breastfeeding can reduce the severity of neonatal abstinence syndrome. Infant sedation and respiration are monitored.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
Methadone is evaluated for the following indications with varying evidence strength: Moderate-to-severe chronic pain (evidence tier B). See the full indication matrix with dosing and citations above on this page.
Common side effects of Methadone (≥ 1 in 100): Sedation, Constipation, Nausea and vomiting, Sweating, Erectile dysfunction. See the Safety section for uncommon and serious reactions.
FDA category C. FDA Category C. Methadone is the WHO and SEPB preferred substitution therapy for opioid dependence in pregnancy. Maternal opioid withdrawal carries higher fetal risk than methadone maintenance. About 60% of exposed newborns develop neonatal abstinence syndrome requiring inpatient management.
Compatible. Hale L3. Transfers into milk (RID about 2–3%) without reaching clinically meaningful infant concentration at stable maintenance doses. WHO and AAP consider it compatible; breastfeeding can reduce the severity of neonatal abstinence syndrome. Infant sedation and respiration are monitored.
Methadone is contraindicated in: Hypersensitivity to methadone; Respiratory depression; Severe asthma or COPD; Paralytic ileus; MAOI use within the past 14 days. Full list in the Safety section.