====== Methadone (Dolophine®) ======

<WRAP right 340px>
<WRAP infobox>
^ Methadone | {{ :neuro:opioids:methadone_enantiomers_labelled.svg?200 |}} |
| Brand Names | Dolophine®, Methadose® |
| Drug Class | [[neuro:opioids:start|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 |
</WRAP>
</WRAP>

===== 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.

<WRAP clear></WRAP>

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===== 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)  

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===== Indications =====

  * Opioid Use Disorder (maintenance therapy)  
  * Chronic severe pain  
  * Cancer-related pain  

In OUD:
  * Dispensed through certified opioid treatment programs  

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<WRAP contra>
===== 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  

</WRAP>

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<WRAP details>
===== 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:
  * [[neuro:opioids:equianalgesic_dosing|Equianalgesic Dosing Guide]]

</WRAP>

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<WRAP details>
===== 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.

</WRAP>

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<WRAP details>
===== Adverse Effects =====

Common:
  * Sedation  
  * Constipation  
  * Nausea  

Serious:
  * Respiratory depression  
  * QT prolongation  
  * Torsades de pointes  
  * Physical dependence  

Delayed respiratory depression can occur due to accumulation.

</WRAP>

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<WRAP details>
===== Drug Interactions =====

QT-prolonging drugs:
  * Fluoroquinolones  
  * Macrolides  
  * Antipsychotics  

CYP3A4 inhibitors (↑ levels):
  * Azoles  
  * Protease inhibitors  

CYP inducers (↓ levels):
  * Rifampin  
  * Carbamazepine  

CNS depressants:
  * Benzodiazepines  
  * Alcohol  

</WRAP>

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<WRAP monitoring>
===== Monitoring =====

Clinical:
  * Sedation  
  * Respiratory rate  

Cardiac:
  * Baseline ECG  
  * Periodic QT interval monitoring  

Electrolytes:
  * Potassium  
  * Magnesium  

</WRAP>

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<WRAP pearls>
===== 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.  

</WRAP>

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===== Toxicity =====

Overdose:
  * CNS depression  
  * Respiratory depression  
  * Prolonged QT interval  

Treatment:
  * [[neuro:opioids:naloxone|Naloxone]]  
  * Cardiac monitoring  

Reversal may require repeated naloxone dosing due to long half-life.

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===== Comparison Within Class =====

Compared to [[neuro:opioids:morphine|Morphine]]:
  * Much longer half-life  
  * NMDA antagonism  
  * QT prolongation risk  

Compared to [[neuro:opioids:buprenorphine|Buprenorphine]]:
  * Full agonist vs partial  
  * No ceiling effect  
  * Higher overdose risk  

Compared to [[neuro:opioids:fentanyl|Fentanyl]]:
  * Less potent  
  * Much longer duration  

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===== Related =====

  * [[neuro:opioids:start|Opioids]]
  * [[neuro:opioids:buprenorphine|Buprenorphine]]
  * [[neuro:opioids:naltrexone|Naltrexone]]
  * [[neuro:opioids:naloxone|Naloxone]]