What is the recommended initial dose and titration strategy for methadone (opioid agonist) induction in an adult patient with a history of opioid use disorder or chronic pain?

Methadone Dosing for Induction

For opioid use disorder, start with 20-30 mg as a single supervised dose (maximum 30 mg on day 1), and do not exceed 40 mg total on the first day; for chronic pain, initiate at much lower doses of 2.5-5 mg every 8 hours (5-10 mg total daily) with slow upward titration over 5-7 days. 1, 2

Opioid Use Disorder Induction

Initial Dosing Protocol

• Administer the first dose only when the patient shows objective withdrawal symptoms and has no signs of sedation or intoxication 1
• Start with 20-30 mg as a single supervised dose; the initial dose must not exceed 30 mg 1
• If same-day adjustment is needed, wait 2-4 hours for peak levels, then provide an additional 5-10 mg if withdrawal symptoms persist 1
• The total daily dose on day 1 should not ordinarily exceed 40 mg 1

Titration Strategy

• Make dose adjustments over the first week based on withdrawal control at expected peak activity (2-4 hours post-dose) 1
• Titrate cautiously—deaths have occurred in early treatment due to cumulative effects over the first several days as methadone accumulates in tissues before reaching steady-state at 3-5 days 2, 1
• For maintenance treatment, titrate to 80-120 mg/day, which is the typical range for achieving clinical stability (preventing withdrawal for 24 hours, reducing cravings, and blocking euphoric effects of other opioids) 1

Critical Safety Consideration

• Patients with low expected tolerance (no opioid use for >5 days) require lower initial doses 1
• Never determine initial doses based on previous treatment episodes or reported illicit drug spending 1

Chronic Pain Induction

Initial Dosing Protocol

• Start at 2.5-5 mg every 8 hours or 5-10 mg total daily dose 2
• The analgesic effect lasts only 6-8 hours despite methadone's 30+ hour half-life, requiring dosing every 6-8 hours for pain control (not once daily) 2
• Deaths have occurred during early treatment due to cumulative effects, as methadone accumulates before reaching steady-state at 3-5 days 2

Titration Strategy

• Titrate slowly upward every 5-7 days, typically by 5-10 mg per dose 3
• Provide adequate short-acting breakthrough pain medications during the titration period 3
• Avoid rapid titration, as it can lead to iatrogenic overdose 2

Dosing Frequency

• Split-dosing (dividing total daily dose into 3-4 administrations every 6-8 hours) is strongly recommended to maintain continuous pain control 2
• Once-daily dosing is appropriate only for opioid use disorder treatment, not pain management 2

Mandatory Cardiac Monitoring

ECG Requirements

• Obtain baseline ECG before initiating methadone in all patients 2, 4
• Follow-up ECG is required for doses >100 mg daily, patients with cardiac disease, or those on QTc-prolonging medications (including tricyclic antidepressants, macrolides, certain fluoroquinolones, azole antifungals) 3, 2
• QTc ≥450 ms indicates need to reduce or discontinue methadone 3, 2
• High doses (≥120 mg) significantly increase risk of torsades de pointes and sudden cardiac death 3, 2

Additional Monitoring

• Check for hypomagnesemia and hypokalemia, which can impact QTc interval 3
• Consider follow-up ECG as early as 2-4 weeks for high-risk patients and when reaching 100 mg/day 3

Prescriber Requirements and Precautions

Expertise Requirements

• Methadone should be initiated only by physicians with experience and expertise in its use 3
• Consult a pain management specialist if unfamiliar with methadone prescribing or if rapid switching is needed 3, 2

Critical Pitfalls to Avoid

• Never use standard equianalgesic tables—the morphine-to-methadone ratio is not fixed and becomes increasingly favorable to methadone at higher morphine doses 2
• Methadone's complex, non-linear conversion ratios and high interpatient variability in pharmacokinetics make conversions from other opioids particularly dangerous 2, 1
• Incomplete cross-tolerance between opioids makes dosing during conversion complex 1
• A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose 1

Patient Education

• Remind patients that the dose will "hold" for a longer period as tissue stores accumulate 1
• Educate patients and families about methadone's analgesic utility, as some may only be familiar with its use for addiction maintenance 3

Special Populations

Renal Impairment

• Use methadone with caution in patients with fluctuating renal function, though it is generally safer than morphine or hydromorphone in this population 3

Drug Interactions

• Investigate potential drug-drug interactions before initiating methadone, as it is associated with several significant interactions 3
• Be aware of CYP3A4 interactions and medications that prolong QTc 3