Synthetic opioid, full mu-receptor agonist
Brand names: Dolophine, Methadose
Updated · Methodology
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.
ICD-10: R52.2 · ICD-11: MG30
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.
AEMPS summary of product characteristics (section 4.6): data on the safety of methadone in pregnant women are insufficient, so risks and benefits are weighed carefully before use because of possible effects on the fetus and newborn, including respiratory depression, low birth weight, neonatal abstinence syndrome and a higher rate of fetal death. Some observational studies have reported congenital malformations and neurodevelopmental disorders in children of women treated with methadone for opioid use disorder during pregnancy, but study limitations and confounding by maternal, family and socio-environmental factors mean that no conclusions can be drawn about the role of methadone. Increased methadone clearance and reduced plasma levels have been reported in pregnancy, and the dose may need to be raised if withdrawal symptoms develop. Methadone should not be used during labour because of the risk of gastric stasis and aspiration pneumonia in the mother and of fetal distress.
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.
According to the Metasedin SmPC, grapefruit juice can increase methadone bioavailability by slowing its metabolism. More methadone in the blood means more drowsiness, a higher risk of slow breathing and a longer QT interval, with a risk of torsade de pointes. The safest course is to avoid grapefruit juice during treatment.
Source: AEMPS: Ficha técnica de Metasedin 5 mg (metadona) (2026)
10 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
Methadone prolongs QT, and its SmPC ties torsade mainly to doses above 100 mg a day. The same label warns about serotonin syndrome with SSRIs. The citalopram SmPC lists ongoing treatment with any drug capable of prolonging the QT interval among its contraindications, with no exceptions.
Symptoms
QTc prolongation on ECG, palpitations, dizziness, syncope, with torsade at the far end. Serotonin syndrome is tracked separately: agitation, confusion, tremor, myoclonus, sweating, hyperthermia. Arrhythmia risk is higher with hypokalaemia, hypomagnesaemia and bradycardia.
Management
The pair sits in the citalopram SmPC contraindications, so the question is which drug stays, not how far to cut the dose. Opioid substitution is not interrupted for an antidepressant, so the question is settled on the antidepressant side. If the pair is already running, an ECG with QTc is taken before the start and at every methadone dose increase, with potassium and magnesium kept normal.
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.
Sources
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).
Sources
Mechanism
Strong CYP3A4 inhibitor. Methadone rises 2-3 fold.
Symptoms
Sedation, respiratory depression, QT prolongation.
Management
Reduce methadone by 25%, ECG monitoring.
Sources
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.
Sources
Mechanism
Fluconazole moderately inhibits CYP3A4 and CYP2C9 and strongly inhibits CYP2C19 (fluconazole SmPC). All of them take part in methadone metabolism, so methadone blood levels can rise (fluconazole and methadone labels). Both drugs prolong the QT interval: fluconazole blocks cardiac potassium channels directly, and methadone prolongs QT especially at high doses, above 100 mg a day according to the Spanish methadone SmPC.
Symptoms
Methadone excess: drowsiness, slow shallow breathing, pinpoint pupils; in severe cases life-threatening respiratory depression. QT prolongation on the ECG, palpitations, fainting, torsades de pointes.
Management
The combination is not contraindicated but needs monitoring. Fluconazole can raise methadone levels, and the methadone dose may need adjustment (fluconazole SmPC). The US methadone label () advises considering a methadone dose reduction until the effect is stable when an inhibitor is added, and frequent checks for respiratory depression and sedation; after fluconazole is stopped, methadone levels fall and withdrawal signs can appear. Use fluconazole with caution in conditions that predispose to arrhythmia; low potassium and advanced heart failure raise the risk (fluconazole SmPC). The Spanish methadone SmPC lists CYP3A4 inhibitors, fluconazole among them, as a QT risk factor and advises an ECG before methadone starts, two weeks later and before a dose increase (methadone SmPC).
Sources
Mechanism
Rifampicin strongly induces liver enzymes, including CYP3A4 and CYP2B6, which mainly clear methadone (rifampicin SmPC). Rifampicin 600 mg/day reduced the oral bioavailability of methadone from 70% to 50% (rifampicin SmPC), and in patients stable on methadone, serum levels fell markedly and withdrawal symptoms appeared (US Food and Drug Administration () methadone label). After rifampicin is stopped, the induction fades and methadone levels rise again (methadone FDA label).
Symptoms
Opioid withdrawal on the previous methadone dose: restlessness, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, and also irritability, anxiety, back and joint pain, abdominal cramps, insomnia, nausea, vomiting, diarrhoea, and increased blood pressure, respiratory rate or heart rate. After rifampicin is stopped, if the methadone dose is not reduced, sedation and respiratory depression can follow, up to a fatal overdose.
Management
The pair is not banned. While the patient takes rifampicin, a higher methadone dose may be needed (methadone and rifampicin SmPCs). The US Food and Drug Administration () methadone label advises, if the combination is necessary, to consider raising the methadone dose until stable effects are reached and to watch for withdrawal signs. After rifampicin is stopped, a lower methadone dose is considered and the patient is seen at frequent intervals to catch sedation and respiratory depression early (methadone FDA label). The rifampicin SmPC warns that doses of other drugs may need adjusting both when rifampicin is started and when it is stopped.
Sources
Mechanism
Ritonavir inhibits CYP3A4 but at the same time speeds up other methadone elimination pathways, including glucuronidation. The net result is lower methadone exposure: in a study, methadone AUC fell by 36% (ritonavir label). This can bring on withdrawal symptoms.
Symptoms
Methadone levels usually fall, and a patient on maintenance therapy develops withdrawal signs: watery eyes, runny nose, sneezing, yawning. If the methadone dose was raised and ritonavir is later stopped, methadone levels can rise: drowsiness, slow shallow breathing. Methadone prolongs the QT interval on the ECG; marked prolongation can cause fainting and torsades de pointes.
Management
The combination can be used with monitoring. After ritonavir is started, watch a patient on methadone closely for withdrawal signs and raise the methadone dose if needed, guided by clinical response (ritonavir and methadone labels). If ritonavir is stopped, watch for drowsiness and slowed breathing and consider lowering the methadone dose: the US methadone label () asks for this with any change in concomitant drugs that can raise methadone levels. The Spanish methadone SmPC lists CYP3A4 inhibitors, ritonavir among them, as a risk factor for QT prolongation. Record an ECG before methadone starts, two weeks later and before each dose increase. Low potassium, calcium or magnesium also raise the risk, so these patients need closer monitoring (methadone SmPC).
Sources
Verbatim lines from the interaction sections, in the language of the label
«Inhibidores de la Monoaminooxidasa (IMAOs): Los IMAOs pueden potenciar y prolongar los efectos depresores de metadona. También pueden producir estimulación del sistema nervioso central. Por…»AEMPS, section 4.5 · Open on CIMA
«Trastorno por consumo de opioides (abuso y farmacodependencia): Se debe hacer un seguimiento a los pacientes para detectar signos de comportamiento de búsqueda de fármacos (p. ej., solicitud de…»AEMPS, section 4.4 · Open on CIMA
«DRUG INTERACTIONS: 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…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: Intervention: The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.»FDA, section 7 · Open on DailyMed
«Metadona y prolongación del intérvalo QT: El riesgo de metadona de prolongar el intervalo QT puede verse aumentado cuando se administra con medicamentos que producen alteraciones electrolíticas y con…»AEMPS, section 4.5 · Open on CIMA
«Anticonvulsivos (como fenitoína, fenobarbital, carbamazepina y primidona): Su administración concomitante induce el metabolismo de metadona, pudiendo dar lugar a una reducción de los niveles…»AEMPS, section 4.5 · Open on CIMA
«Inhibidores de la isoenzima CYP3A4: El aclaramiento de metadona disminuye principalmente con medicamentos que inhiben la actividad de la isoenzima 3A4 del citocromo P450, tales como algunos…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Intervention: If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Evaluate patients at frequent…»FDA, section 7 · Open on DailyMed
«Inhibidores de la isoenzima CYP3A4: El aclaramiento de metadona disminuye principalmente con medicamentos que inhiben la actividad de la isoenzima 3A4 del citocromo P450, tales como algunos…»AEMPS, section 4.5 · Open on CIMA
«Metadona y prolongación del intérvalo QT: El riesgo de metadona de prolongar el intervalo QT puede verse aumentado cuando se administra con medicamentos que producen alteraciones electrolíticas y con…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of methadone hydrochloride tablets and/FDA, section 7 · Open on DailyMed
«Anticonvulsivos (como fenitoína, fenobarbital, carbamazepina y primidona): Su administración concomitante induce el metabolismo de metadona, pudiendo dar lugar a una reducción de los niveles…»AEMPS, section 4.5 · Open on CIMA
«Anticonvulsivos (como fenitoína, fenobarbital, carbamazepina y primidona): Su administración concomitante induce el metabolismo de metadona, pudiendo dar lugar a una reducción de los niveles…»AEMPS, section 4.5 · Open on CIMA
«Antibióticos: Rifampicina: La administración concomitante de rifampicina puede dar lugar a una reducción de los niveles plasmáticos y una mayor excreción urinaria de metadona. Puede ser necesario…»AEMPS, section 4.5 · Open on CIMA
«El uso simultáneo con fármacos que también pueden provocar una prolongación del intervalo QT, como los antiarrítmicos de clase Ia y III, determinados neurolépticos, antidepresivos tricíclicos y…»AEMPS, section 4.3 · Open on CIMA
«La administración conjunta de hidroxizina con fármacos que se sabe que prolongan el intervalo QT y/AEMPS, section 4.5 · Open on CIMA
«Drug Interactions: Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine…»FDA, section 4 · Open on DailyMed
«CONTRAINDICATIONS: Rasagiline is contraindicated for use with meperidine, tramadol, methadone, propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors, because of risk of…»FDA, section 4 · Open on DailyMed
«CONTRAINDICATIONS: • EMSAM (selegiline transdermal system) is contraindicated with selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine, sertraline, and paroxetine); serotonin and…»FDA, section 4 · Open on DailyMed
«Metadona : aumento del riesgo de depresión respiratoria, la cual puede ser letal en caso de sobredosis. Además, se puede producir una disminución de las concentraciones plasmáticas de metadona con el…»AEMPS, section 4.5 · Open on CIMA
«Uso con medicamentos que prolongan el intervalo QT: Debido a que el tratamiento de deprivación de andrógenos puede prolongar el intervalo QT, se recomienda precaución cuando se administre abiraterona…»AEMPS, section 4.5 · Open on CIMA
«Tomar precaución cuando se usen amitriptilina y metadona concomitantemente debido a la posibilidad de efectos aditivos sobre el intervalo QT y el riesgo aumentado de efectos cardiovasculares graves…»AEMPS, section 4.5 · Open on CIMA
«Potential for Other Drugs to Affect Clozapine: Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine. Drugs that cause QT…»FDA, section 7 · Open on DailyMed
«Established and Other Potentially Significant Interactions: Narcotic Analgesics For treatment of opioid dependence: buprenorphine buprenorphine/FDA, section 7 · Open on DailyMed
«Medicamentos que pueden estar afectados por darunavir potenciado con ritonavir: Un ensayo clínico que asocia medicamentos metabolizados por los citocromos CYP2C9, CYP2C19 y CYP2D6 demostró un aumento…»AEMPS, section 4.5 · Open on CIMA
«- Inhibidores de CYP2D6: El dextrometorfano se metaboliza por el CYP2D6 y tiene un elevado metabolismo de primer paso. El uso concomitante de inhibidores potentes de la enzima CYP2D6 puede aumentar…»AEMPS, section 4.5 · Open on CIMA
«Established and Other Potentially Significant Drug Interactions: Narcotic analgesic: Methadone ↓ methadone * Monitor for signs of methadone withdrawal and increase methadone dose if required to…»FDA, section 7 · Open on DailyMed
«Metadona: Fluconazol puede aumentar la concentración sérica de metadona. Puede ser necesario un ajuste de la dosis de metadona.»AEMPS, section 4.5 · Open on CIMA
«Drugs that Prolong the QT Interval: Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution in combination with other drugs that cause QT prolongation. These…»FDA, section 7 · Open on DailyMed
«Medicamentos con estrecho margen terapéutico: La administración conjunta de fluvoxamina con medicamentos de estrecho margen terapéutico (como tacrina, teofilina, metadona, mexiletina, fenitoína…»AEMPS, section 4.5 · Open on CIMA
«Medicamentos que ocasionan “torsades de pointes”, pero sin limitarse a: otros fármacos: (ej. bepridil, cisaprida, difemanil, eritromicina IV, halofantrina, mizolastina, pentamidina, esparfloxacino…»AEMPS, section 4.5 · Open on CIMA
«Analgésicos; Anestésicos: Alfentanilo, Buprenorfina (IV y sublingual), Cannabinoides, Metadona, Sufentanilo»AEMPS, section 4.5 · Open on CIMA
«Inducción farmacocinética de enzimas metabolizantes: La administración conjunta de metamizol con bupropión, efavirenz, metadona, valproato, ciclosporina, tacrólimus o sertralina puede disminuir los…»AEMPS, section 4.5 · Open on CIMA
«Analgésicos: Cuando se coadministre metadona con ritonavir dosificado como potenciador farmacocinético o como agente antirretroviral puede ser necesario un aumento de la dosis de metadona debido a la…»AEMPS, section 4.5 · Open on CIMA
«Established and Other Potentially Significant Drug Interactions: Analgesics, Opioid: tramadol, propoxyphene, methadone, fentanyl ↑ analgesics ↓ methadone ↑ fentanyl A dose decrease may be needed for…»FDA, section 7 · Open on DailyMed
«Dado que la bradicardia constituye un factor de riesgo en la aparición de torsades de pointes, se debe observar con precaución e incluso puede requerirse una monitorización clínica (ECG), si se…»AEMPS, section 4.5 · Open on CIMA
«Clinically-Significant Drug Interactions: Methadone Use with caution SS»FDA, section 7 · Open on DailyMed
«Opioides: Se recomienda monitorizar frecuentemente las reacciones adversas y toxicidad relacionadas con metadona, incluida la prolongaci ó n del intervalo QTc. Puede ser necesario reducir la dosis de…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Methadone Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects…»FDA, section 7 · Open on DailyMed
«Drugs Having Clinically Important Interactions with Alprazolam: Examples Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine…»FDA, section 7 · Open on DailyMed
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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.
AEMPS summary of product characteristics (section 4.6): data on the safety of methadone in pregnant women are insufficient, so risks and benefits are weighed carefully before use because of possible effects on the fetus and newborn, including respiratory depression, low birth weight, neonatal abstinence syndrome and a higher rate of fetal death. Some observational studies have reported congenital malformations and neurodevelopmental disorders in children of women treated with methadone for opioid use disorder during pregnancy, but study limitations and confounding by maternal, family and socio-environmental factors mean that no conclusions can be drawn about the role of methadone. Increased methadone clearance and reduced plasma levels have been reported in pregnancy, and the dose may need to be raised if withdrawal symptoms develop. Methadone should not be used during labour because of the risk of gastric stasis and aspiration pneumonia in the mother and of fetal distress.
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.
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