methadone
Opioid receptor agonist· Brands: Dolophine, Methadose, Physeptone, Amidone, Symoron, HeptadonIMIVPOSC
Mechanism of action
Methadone is a synthetic opioid that acts as a potent agonist at the mu-opioid receptor, producing analgesia, sedation and euphoria. It also acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor, which may contribute to its effectiveness in neuropathic pain and in inhibiting opioid tolerance. In addition, methadone inhibits the reuptake of serotonin and noradrenaline, which may further enhance its analgesic properties. These combined actions give methadone a unique profile among opioids, with a long duration of action and potential for use in opioid substitution therapy.
Pharmacokinetics
Methadone is well absorbed after oral administration, with peak plasma concentrations occurring approximately 2 to 4 hours after ingestion. It is highly bound to plasma proteins and has a large volume of distribution due to its lipophilicity, leading to extensive tissue distribution and slow elimination. Methadone is metabolised in the liver, primarily by CYP3A4 and CYP2B6, to inactive metabolites that are excreted in bile and urine. The elimination half-life is long and highly variable, ranging from about 15 to 60 hours, which necessitates cautious dosing and careful monitoring, especially during initiation of therapy. Due to enterohepatic recirculation, the drug is excreted predominantly in faeces.
Indications & dosing
Opioid dependence (maintenance therapy)
Initiate at 20-30 mg once daily; titrate to effect. Supervised dosing initially.
- adult · PO: 20–30 mg once daily · Initiate at 20-30 mg once daily; titrate to effect. Supervised dosing initially.
Opioid dependence (detoxification)
Initial dose as for maintenance; gradually reduce over several weeks.
- adult · PO: 20–30 mg once daily · Initial dose as for maintenance; gradually reduce over several weeks.
Chronic pain
Use low initial doses due to accumulation; titrate carefully.
- adult · PO: 2.5–5 mg every 8-12 hours · Use low initial doses due to accumulation; titrate carefully.
Contraindications & precautions
- Respiratory depression · Risk of severe respiratory depression, especially in opioid-naive patients.
- Acute severe asthma or chronic obstructive pulmonary disease with acute exacerbation · Opioids can worsen respiratory function.
- Paralytic ileus · Opioids reduce gastrointestinal motility.
- Known QT interval prolongation or history of torsades de pointes · Methadone can prolong QT interval; use with caution or avoid if other risk factors present.
- Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days · Risk of serotonin syndrome and severe adverse reactions.
- Monitor for QT prolongation; perform ECG before and after initiation, especially with high doses or risk factors.
- Be aware of CYP450 interactions; methadone is metabolised by CYP3A4 and CYP2B6, and may interact with many drugs.
- Use extreme caution in patients with hepatic or renal impairment; dose reduction may be necessary.
- Consider risk of overdose and dependence; methadone has a long half-life and cumulative effects.
- Titrate slowly and monitor for signs of respiratory depression, especially during initiation and dose changes.
Adverse effects
- Constipation
- Nausea and vomiting
- Sedation or drowsiness
- Respiratory depressionserious
- QT interval prolongationserious
- Hypotension
- Dizziness
- Sweating
Interactions
- diazepammajorAvoid concurrent use if possible. If unavoidable, use the lowest effective doses, prescribe with extreme caution, and advise the patient to avoid alcohol and other CNS depressants. Monitor for excessive sedation, respiratory rate, and oxygen saturation, particularly during initiation and dose adjustments. Consider prescribing naloxone for emergency use.
- phenytoinmajorAvoid concurrent use if possible. If co-prescription is necessary, closely monitor the patient for signs of opioid withdrawal. Consider increasing the methadone dosage, with careful titration based on clinical response. Monitor plasma methadone concentrations where available, particularly after initiating or discontinuing phenytoin. Re-evaluate the methadone dose when phenytoin is stopped, as methadone levels may rise and cause toxicity. Involve the patient and relevant specialists in dose adjustments.
- carbamazepinemajorMonitor closely for signs of opioid withdrawal, especially when starting or stopping carbamazepine. Consider increasing the methadone dose as needed, guided by clinical response and therapeutic drug monitoring of methadone concentrations. Adjust the methadone dose when carbamazepine is discontinued to avoid toxicity. Consider alternatives to carbamazepine where possible, or use caution with ECG monitoring if QT prolongation risk is high.
- efavirenzmajorMonitor patients closely for signs of opioid withdrawal when starting efavirenz. An increase in the methadone dose may be necessary; dose should be titrated based on clinical response. Reassess after stopping efavirenz, as methadone levels may rise.
- rifampicinmajorAvoid concomitant use if possible. If co-prescription is essential, consider increasing the methadone dose guided by clinical response and monitor for withdrawal symptoms. Monitor plasma methadone concentrations if available. If rifampicin is stopped, reduce the methadone dose as appropriate to prevent toxicity.
- amiodaronemajorAvoid co-prescription where possible. If the combination is necessary, obtain a baseline ECG and electrolyte measurements (potassium, magnesium), and repeat ECG regularly during therapy, especially after dose changes. Correct any electrolyte abnormalities. Consider alternative therapies that do not prolong the QT interval. Monitor for signs of arrhythmia and advise the patient to report palpitations or syncope.
Renal & hepatic adjustment
- eGFR 0–29: Use with caution; monitor closely for opioid toxicity. No dose adjustment is required, but increased sensitivity may occur.
- Hepatic impairment (mild): Use with caution; consider dose reduction based on clinical response.
- Hepatic impairment (moderate): Reduce initial dose and titrate slowly; monitor for signs of opioid toxicity.
- Hepatic impairment (severe): Avoid methadone use due to increased risk of toxicity; if essential, use with extreme caution and consider dose reduction. (avoid)
Monitoring, pregnancy & toxicity
- Pain relief and opioid efficacy · At start of therapy and periodically
- Respiratory rate and sedation · Frequently during dose titration and with concurrent sedatives
- ECG / QT interval · Before initiating therapy, and periodically in patients at risk of QT prolongation
- Serum electrolytes (potassium, magnesium) · Before initiating therapy if QT risk factors present, and periodically as required
- Signs of opioid toxicity or withdrawal · During dose adjustments and maintenance
- Pregnancy: Methadone is used for substitution therapy in opioid-dependent pregnant women. Continue maintenance dosing; doses should be supervised and adjusted to avoid withdrawal. Neonatal abstinence syndrome may occur in the newborn and requires monitoring.
- Toxicity: Respiratory depression, miosis, bradycardia, hypotension, hypothermia · Maintain airway, administer oxygen, and give naloxone. Because methadone has a long half-life, repeated doses or a continuous naloxone infusion may be required. Monitor for recurrence of respiratory depression.
- Toxicity: CNS depression leading to coma and seizure · Provide supportive care and naloxone. Monitor for cardiac arrhythmias and QT prolongation.
- Toxicity: QT prolongation and torsades de pointes · Obtain ECG, correct hypokalemia and hypomagnesemia, and avoid other QT-prolonging agents. Consider discontinuation of methadone if arrhythmia occurs.
Antidotes & reversal
- Naloxone · Long half-life requires prolonged observation, repeated doses or infusion; obtain ECG for QTc.
Clinical notes
Methadone is used in the management of opioid dependence and for chronic pain management where alternative analgesics are inadequate. Because of its long and variable half-life, methadone requires careful titration, generally starting with low doses and increasing slowly to avoid accumulation and overdose. It is not suitable for acute pain management. Methadone is associated with QT interval prolongation, and caution is advised when combined with other QT-prolonging drugs or in patients with cardiac disease. Interactions with CYP450 inhibitors or inducers can alter plasma levels significantly. Monitoring for signs of respiratory depression and sedation is essential, particularly during dose initiation and adjustment. Patient education on the risks of accidental overdose, particularly in combination with benzodiazepines, is critical. Methadone should be prescribed under specialist supervision according to local and national guidelines.
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BNF; local formulary; manufacturer's prescribing information.