Methadone (Dolophine®)
| Methadone |  |
|---|---|
| Brand Names | Dolophine®, Methadose® |
| Drug Class | Opioid (Full μ-agonist) |
| Primary Indication | Opioid Use Disorder, Severe Pain |
| Receptor Activity | Full μ agonist + NMDA antagonist |
| Relative Potency | Variable (nonlinear) |
| QT Prolongation | Yes |
| Half-Life | 24–36+ hours |
| Controlled Substance | Schedule II |
| FDA Approval | 1947 |
Overview
Methadone is a synthetic full μ-opioid receptor agonist with additional NMDA receptor antagonism.
It is used for both severe chronic pain and medication-assisted treatment of opioid use disorder (MOUD).
Methadone has a long and variable half-life, which increases risk for delayed respiratory depression and accumulation.
Mechanism of Action
Receptor Activity
- Full μ-opioid receptor agonist
- NMDA receptor antagonist
- Weak inhibition of serotonin and norepinephrine reuptake
Clinical Implications
- Potent analgesia
- Beneficial in neuropathic pain (NMDA blockade)
- No ceiling effect (full agonist)
Indications
- Opioid Use Disorder (maintenance therapy)
- Chronic severe pain
- Cancer-related pain
In OUD:
- Dispensed through certified opioid treatment programs
Contraindications
Absolute:
- Significant respiratory depression
- Known QT prolongation
- Torsades de pointes
Relative / Caution:
- Concomitant QT-prolonging medications
- Hepatic impairment
- Electrolyte abnormalities (hypokalemia, hypomagnesemia)
- Concomitant CNS depressants
Dosing
Pain:
- Low initial doses (e.g., 2.5–10 mg every 8–12 hours)
- Slow titration required
Opioid Use Disorder:
- Initial: 20–30 mg
- Titrate carefully
- Maintenance typically 60–120 mg/day
Important:
- Analgesic duration shorter than elimination half-life
- Risk of accumulation with repeated dosing
See:
Pharmacokinetics
Absorption:
- Oral
Bioavailability:
- High (~70–90%)
Metabolism:
- Hepatic (CYP3A4, CYP2B6, CYP2D6)
Half-life:
- 24–36 hours (may exceed 50 hours in some patients)
Elimination:
- Hepatic metabolism with biliary and renal excretion
Half-life is much longer than analgesic duration.
Adverse Effects
Common:
- Sedation
- Constipation
- Nausea
Serious:
- Respiratory depression
- QT prolongation
- Torsades de pointes
- Physical dependence
Delayed respiratory depression can occur due to accumulation.
Drug Interactions
QT-prolonging drugs:
- Fluoroquinolones
- Macrolides
- Antipsychotics
CYP3A4 inhibitors (↑ levels):
- Azoles
- Protease inhibitors
CYP inducers (↓ levels):
- Rifampin
- Carbamazepine
CNS depressants:
- Benzodiazepines
- Alcohol
Monitoring
Clinical:
- Sedation
- Respiratory rate
Cardiac:
- Baseline ECG
- Periodic QT interval monitoring
Electrolytes:
- Potassium
- Magnesium
Clinical Pearls
- Long half-life → risk of delayed respiratory depression.
- Analgesic duration shorter than elimination half-life.
- QT prolongation is dose-related.
- Useful in neuropathic pain due to NMDA antagonism.
- No ceiling effect (full μ agonist).
- Used in structured opioid treatment programs for OUD.
Toxicity
Overdose:
- CNS depression
- Respiratory depression
- Prolonged QT interval
Treatment:
- Cardiac monitoring
Reversal may require repeated naloxone dosing due to long half-life.
Comparison Within Class
Compared to Morphine:
- Much longer half-life
- NMDA antagonism
- QT prolongation risk
Compared to Buprenorphine:
- Full agonist vs partial
- No ceiling effect
- Higher overdose risk
Compared to Fentanyl:
- Less potent
- Much longer duration