What is the recommended rate for up-titrating (increasing the dose of) methadone in opioid withdrawal treatment?

Methadone Up-Titration Rate

For opioid use disorder treatment, methadone may be titrated up every 5-7 days, typically by 5-10 mg per dose, after an initial dose not exceeding 30 mg on day one. 1, 2

Initial Dosing 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 2
• The first day's total dose must not exceed 40 mg 2
• If same-day adjustment is needed, wait 2-4 hours for peak levels, then provide an additional 5-10 mg if withdrawal persists 2

Standard Titration Schedule (Outpatient/Maintenance)

• Dose adjustments should occur over the first week based on withdrawal control at expected peak activity (2-4 hours post-dose) 2
• After initial stabilization, increase doses every 5-7 days by 5-10 mg per dose 1
• Target maintenance doses typically range from 80-120 mg/day for adequate opioid blockade and withdrawal suppression 2, 3
• Doses between 60-120 mg/day achieve clinical stability by preventing withdrawal for 24 hours, reducing cravings, and blocking euphoric effects of illicit opioids 2

Critical Safety Considerations During Titration

• Deaths have occurred during early treatment due to cumulative effects from the first several days of dosing 2
• Methadone's elimination half-life (8-59 hours) is substantially longer than its analgesic duration (4-8 hours), causing delayed peak respiratory depression 2
• Steady-state plasma concentrations are not reached until 3-5 days of dosing, requiring cautious early titration 2
• Patients must be reminded that tissue stores accumulate and the dose will "hold" longer as treatment progresses 2

Accelerated Inpatient Titration

• In monitored hospital settings, more rapid titration is feasible: 30 mg initial dose with 10 mg daily increases until reaching 60 mg 4
• This accelerated approach showed no major adverse events, overdoses, or deaths in hospitalized patients with close monitoring 4
• The fentanyl era may necessitate faster titration due to increased opioid tolerance 4

Dose-Response Relationship

• Only doses ≥60 mg/day provide complete opioid receptor blockade 3
• Lower doses (30-60 mg) suppress withdrawal adequately but fail to block heroin effects completely, potentially explaining continued illicit use 3
• High-dose methadone (120 mg) produces superior opioid blockade compared to lower doses while maintaining comparable withdrawal suppression 3

Common Pitfalls to Avoid

• Never use conversion ratios in reverse when switching from methadone to other opioids due to methadone's long half-life and accumulation risk 1, 5
• Consider loss of tolerance in any patient who has not taken opioids for more than 5 days—initial doses should be lower 2
• Do not determine initial doses based on previous treatment episodes or reported daily drug expenditure 2
• Obtain baseline and follow-up ECG for doses >100 mg/day or in patients with cardiac disease due to QTc prolongation risk 1

Monitoring Requirements

• Assess for withdrawal symptoms at expected peak methadone activity (2-4 hours post-dose) 2
• Evaluate for oversedation, particularly during the first week when tissue stores are accumulating 2
• Monitor for drug-drug interactions, as methadone metabolism involves CYP3A4 and CYP2D6 1, 6
• Rifampin, phenobarbital, phenytoin, carbamazepine, nevirapine, and efavirenz can precipitate severe withdrawal by inducing CYP3A4 6