What is the recommended initial dose and titration schedule for methadone in opioid‑dependent and opioid‑naïve patients with pain, including maximum dose, QT‑interval monitoring, and dose adjustments for elderly or hepatic impairment?

Methadone Dosing Guidelines

Initial Dosing for Opioid-Dependent Patients (Addiction Treatment)

For patients initiating methadone for opioid use disorder, start with 20-30 mg as a single supervised dose when withdrawal symptoms are present but no signs of sedation or intoxication exist, never exceeding 30 mg on day one. 1

Day 1 Protocol

• Administer initial dose under supervision when patient shows withdrawal symptoms without sedation 1
• Wait 2-4 hours after initial dose to assess peak effect before any same-day adjustment 1
• If withdrawal persists at peak, may add 5-10 mg 1
• Total day 1 dose must not exceed 40 mg 1

Week 1 Titration

• Adjust dose based on withdrawal control at expected peak activity (2-4 hours post-dose) 1
• Use cautious increases—deaths have occurred from cumulative effects during first several days 1
• Remind patients the dose will "hold" longer as tissue stores accumulate 1

Maintenance Dosing

• Titrate to 80-120 mg/day for most patients to achieve clinical stability (prevents withdrawal for 24 hours, reduces craving, blocks euphoria from other opioids) 1
• For short-term detoxification, stabilize at approximately 40 mg/day in divided doses for 2-3 days, then decrease gradually 1

Initial Dosing for Opioid-Naïve Patients (Pain Management)

For opioid-naïve patients with pain, start with the equivalent of 5-10 MME as a single dose or 20-30 MME/day total, using the lowest dose on product labeling. 2

Cancer Pain Initiation

• Start at doses lower than calculated due to long half-life (8 to >120 hours), high potency, and interindividual pharmacokinetic variation 2
• Provide adequate short-acting breakthrough medications during titration 2
• Methadone initiation should be performed by or in consultation with an experienced pain or palliative care specialist 2
• Monitor for drug accumulation and adverse effects particularly over first 4-7 days 2
• Steady state may not be reached for several days to 2 weeks 2

Titration for Pain

• Wait at least 5 half-lives before increasing dose 2
• Wait at least one week before increasing methadone dose specifically to ensure full effects of previous dose are evident 2
• Increase by smallest practical amount 2
• Avoid rapid escalation—methadone's analgesic duration (4-8 hours) is shorter than its elimination half-life (8-59 hours), causing delayed peak respiratory depression that persists longer than analgesia 1

Maximum Dose Considerations

There is no absolute maximum dose, but doses ≥100 mg/day require heightened monitoring due to increased risk of QTc prolongation and cardiac events. 2

• Doses ≥120 mg associated with QTc prolongation and torsades de pointes risk 2
• For chronic pain outside cancer/palliative care, avoid increasing to ≥90 MME/day without careful justification 2
• Reassess benefits and risks before reaching ≥50 MME/day 2

QT Interval Monitoring

Obtain baseline ECG before initiating methadone, with follow-up ECG for patients on doses >100 mg/day, those with cardiac disease, or those taking other QTc-prolonging medications (including tricyclic antidepressants). 2

ECG Monitoring Protocol

• Baseline ECG required for all patients 2
• Follow-up ECG indicated for:
  • Doses >100 mg/day 2
  • Pre-existing cardiac disease 2
  • Concomitant QTc-prolonging medications (TCAs, class I/III antiarrhythmics, some neuroleptics, calcium channel blockers) 2, 1

QTc Interpretation and Action

• QTc ≥500 msec: Switch to alternate opioid 2
• QTc 450-500 msec: Strongly consider alternate opioid while correcting reversible causes 2
• Correct hypokalemia, hypomagnesemia, or hypocalcemia 2
• Avoid CYP3A4 inhibitors that impair methadone metabolism 2
• Avoid other QTc-prolonging drugs 2

Evidence on Low-Dose Safety

• Recent research shows low-dose methadone for chronic pain (mean doses well below 100 mg) demonstrates small, transient QTc increases primarily during first month of therapy 3
• Even patients with baseline heart disease or prolonged QTc may safely receive methadone when started at low doses with careful medication adjustment 4

Dose Adjustments for Special Populations

Elderly Patients

Reduce initial dose in elderly patients due to smaller therapeutic window between safe dosages and respiratory depression/overdose. 2, 1

• Use additional caution with starting doses 2
• Consider formulations with lower opioid content (e.g., 2.5 mg preparations) 2
• Decreased drug clearance increases accumulation risk 2

Hepatic Impairment

Reduce initial dose in patients with severe hepatic impairment due to decreased methadone metabolism and prolonged elimination. 1

• Methadone undergoes hepatic metabolism with potential for slow release from liver stores 1
• Severe hepatic dysfunction dramatically prolongs methadone half-life—one case report showed precipitated withdrawal 11 days after last methadone dose in acute liver failure 5
• Use lower starting doses and slower titration 1

Renal Impairment

Exercise caution in renal insufficiency, though methadone is safer than morphine, hydromorphone, or codeine which accumulate renally-cleared neurotoxic metabolites. 2

• Reduce initial dose 1
• Methadone does not have renally-cleared active metabolites like morphine-6-glucuronide 2

Critical Drug Interactions

Avoid concomitant benzodiazepines—deaths have been reported with this combination. 1

• Additive CNS depression with alcohol, other opioids, CNS depressants 1
• CYP3A4 inhibitors increase methadone levels and QTc risk 2
• Avoid mixed agonist-antagonists (pentazocine, nalbuphine, butorphanol) which precipitate withdrawal 6, 1

Managing Acute Pain in Patients on Methadone Maintenance

Continue the patient's usual maintenance methadone dose without interruption and add scheduled short-acting opioids (morphine, hydromorphone, oxycodone) at higher doses and more frequent intervals (every 3-4 hours) than used for opioid-naïve patients. 6, 1

Acute Pain Protocol

• Maintain baseline methadone dose—it provides no analgesia for acute pain in tolerant patients 6, 1
• Add short-acting opioids at fixed intervals, not PRN 6
• Expect need for higher doses due to cross-tolerance 6, 1
• Consider splitting daily methadone into 6-8 hour intervals for analgesic effect, adding 5-10% to afternoon/evening doses (10-20% total daily increase) 6
• Use multimodal analgesia (NSAIDs, acetaminophen) 6
• Avoid fixed-dose acetaminophen combinations due to hepatotoxicity risk at high opioid doses 6
• Monitor consciousness and respiratory rate frequently with naloxone immediately available 6