Methadone - Drug Monograph

Introduction

Methadone is a synthetic opioid agonist medication primarily used in medication-assisted treatment (MAT) for opioid use disorder (OUD). It is also indicated for the management of severe, chronic pain that requires daily, around-the-clock opioid treatment and for which alternative treatment options are inadequate. Methadone was first synthesized in Germany in 1937 and has been used clinically in the United States since 1947. As a long-acting opioid, it plays a crucial role in harm reduction strategies and addiction treatment protocols worldwide.

Mechanism of Action

Methadone exerts its effects primarily as a full agonist at the mu-opioid receptor in the central nervous system. Its pharmacological profile includes:

• Binding to opioid receptors, producing analgesia and suppressing opioid withdrawal symptoms
• N-methyl-D-aspartate (NMDA) receptor antagonism, which may contribute to its efficacy in neuropathic pain
• Inhibition of serotonin and norepinephrine reuptake
• Unlike shorter-acting opioids, methadone has a long elimination half-life (15-60 hours), which allows for sustained receptor occupancy and smoother plasma levels, reducing cravings and withdrawal symptoms in opioid dependence

Indications

1. Medication-assisted treatment (MAT) for opioid use disorder (as part of a comprehensive treatment program) 2. Management of pain severe enough to require daily, around-the-clock opioid treatment and for which alternative treatment options are inadequate

• Management of opioid withdrawal symptoms
• Treatment of refractory neuropathic pain syndromes

Dosage and Administration

• Initial dose: 20-30 mg orally once daily, with possible additional 5-10 mg doses if needed (maximum 40 mg on first day)
• Titration: Increase by 5-10 mg every 3-7 days based on response and withdrawal symptoms
• Maintenance: Typically 60-120 mg daily (range 40-120 mg)
• Must be administered under supervision in federally certified opioid treatment programs

• Opioid-naïve patients: 2.5-10 mg every 8-12 hours
• Conversion from other opioids: Use specific methadone conversion protocols due to nonlinear pharmacokinetics
• Titrate slowly with close monitoring (every 3-7 days)

• Hepatic impairment: Reduce dose by 50-75% and monitor closely
• Renal impairment: Use with caution; no specific dosage adjustment recommended
• Elderly: Start with lower doses and titrate slowly
• Pediatrics: Safety and efficacy not established for OUD treatment

Pharmacokinetics

Contraindications

• Known hypersensitivity to methadone
• Significant respiratory depression
• Acute asthma or other obstructive airway conditions in unmonitored settings
• Paralytic ileus
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuation

Warnings and Precautions

1. Life-threatening respiratory depression 2. QT interval prolongation and serious arrhythmias (torsades de pointes) 3. Accidental ingestion by children can be fatal 4. Potential for abuse and diversion

• Risk of addiction, abuse, and misuse
• Neonatal opioid withdrawal syndrome with prolonged use during pregnancy
• Adrenal insufficiency with chronic use
• Severe hypotension
• Risks in patients with increased intracranial pressure, head injury, or brain tumors
• Gastrointestinal effects including reduced motility

Drug Interactions

• CYP3A4 inhibitors (ketoconazole, erythromycin, ritonavir): Increase methadone levels
• CYP3A4 inducers (rifampin, carbamazepine, phenytoin): Decrease methadone levels
• Benzodiazepines and other CNS depressants: Additive respiratory depression
• QT-prolonging agents (antipsychotics, antiarrhythmics, antibiotics): Increased risk of torsades de pointes
• MAOIs: Risk of serotonin syndrome

Adverse Effects

• Constipation
• Nausea
• Sedation
• Sweating
• Dry mouth

• Respiratory depression
• QT prolongation and torsades de pointes
• Hypotension
• Seizures
• Adrenal insufficiency
• Androgen deficiency
• Severe allergic reactions

Monitoring Parameters

• Comprehensive substance use history
• ECG for QT interval assessment
• Liver and renal function tests
• Pregnancy test when appropriate
• Assessment of respiratory status

• QT interval monitoring (baseline and periodically)
• Respiratory rate and oxygen saturation
• Signs of oversedation or intoxication
• Withdrawal symptoms and craving assessment
• Liver and renal function (periodically)
• Therapeutic drug monitoring in specific cases
• Assessment of diversion and misuse behaviors

Patient Education

• Take exactly as prescribed; do not adjust dose without medical supervision
• Never share medication with others
• Avoid alcohol and other CNS depressants
• Be aware of delayed sedation effects (can occur hours after dosing)
• Report any chest pain, palpitations, or dizziness immediately
• Use caution when driving or operating machinery
• Maintain adequate hydration and fiber intake to prevent constipation
• Inform all healthcare providers about methadone use
• Keep medication securely stored away from children and others
• Understand that methadone treatment for OUD is typically long-term
• Participate in comprehensive addiction treatment including counseling

• Discuss risks and benefits with healthcare provider
• Methadone is preferred over illicit opioid use during pregnancy
• Neonatal abstinence syndrome may occur
• Methadone is excreted in breast milk but generally considered compatible with breastfeeding

References

1. Substance Abuse and Mental Health Services Administration. (2020). Medications for Opioid Use Disorder. Treatment Improvement Protocol (TIP) Series 63. 2. FDA. (2020). Methadone Hydrochloride Prescribing Information. 3. Krantz MJ, Martin J, Stimmel B, et al. (2009). QTc interval screening in methadone treatment. Annals of Internal Medicine, 150(6):387-395. 4. World Health Organization. (2009). Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence. 5. Chou R, Fanciullo GJ, Fine PG, et al. (2009). Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. The Journal of Pain, 10(2):113-130. 6. American Society of Addiction Medicine. (2020). National Practice Guideline for the Treatment of Opioid Use Disorder. 7. Webster LR, Cochella S, Dasgupta N, et al. (2011). An analysis of the root causes for opioid-related overdose deaths in the United States. Pain Medicine, 12 Suppl 2:S26-35.