What is the recommended starting dose and titration schedule for oral liquid methadone for opioid dependence induction and chronic pain management in an adult, including adjustments for elderly patients, hepatic impairment, and CYP3A4/CYP2D6 inhibitors?

Methadone Liquid Dosing

For Opioid Dependence (Maintenance Therapy)

Start methadone at 60-100 mg daily as the target maintenance dose for opioid use disorder, with doses above 100 mg considered for patients who continue illicit opioid use despite adequate trials within this range. 1

Initial Dosing Strategy

• Begin with lower starting doses (typically 20-40 mg) and titrate upward over 1-2 weeks to reach the 60-100 mg target range 1
• The consensus maintenance dose of 60-100 mg daily provides optimal outcomes for most patients 1
• For patients with persistent illicit opioid use on 60-100 mg daily, consider escalation above 100 mg, though this requires careful risk-benefit assessment 1

Critical Cardiac Monitoring

• Obtain baseline ECG before initiating methadone and follow-up ECGs for doses >100 mg/day or in patients with cardiac disease 2
• Methadone doses ≥120 mg carry increased risk of QTc prolongation and torsades de pointes 2
• Switch to alternative opioid if QTc >500 msec; strongly consider switching if QTc 450-500 msec 2
• Correct hypokalemia, hypomagnesemia, and hypocalcemia before and during treatment 2

Drug Interaction Management

• Avoid CYP3A4 inhibitors (e.g., azole antifungals, macrolides, protease inhibitors) as they can increase methadone levels and prolong QTc 2
• CYP2B6, not CYP3A4, is the principal determinant of methadone metabolism and clearance in humans 3
• CYP2B6 genetic variants significantly affect methadone disposition: CYP2B66 carriers have reduced clearance (requiring lower doses), while CYP2B64 carriers have increased clearance (potentially requiring higher doses) 3
• Avoid concurrent medications that prolong QTc, including tricyclic antidepressants 2

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For Chronic Pain Management

Methadone for chronic pain should only be initiated by or in consultation with an experienced pain or palliative care specialist due to its complex pharmacokinetics, long half-life (8-120 hours), and high interindividual variability. 2

Conversion from Other Opioids to Methadone

Step 1: Calculate Total Daily Morphine Equivalent

• Determine the patient's current total daily oral morphine dose (or convert other opioids to morphine equivalents) 2

Step 2: Apply Dose-Dependent Conversion Ratios

The conversion ratio from morphine to methadone varies based on baseline morphine dose 2:

• 30-90 mg/day oral morphine: use 4:1 ratio (morphine:methadone) 2
• 91-300 mg/day oral morphine: use 8:1 ratio 2
• >300 mg/day oral morphine: use 12:1 ratio 2
• >800 mg/day oral morphine: requires even higher ratios and cross-titration is recommended 2

Step 3: Reduce for Safety

• Reduce the calculated equianalgesic methadone dose by 25-50% to account for incomplete cross-tolerance, dosing ratio variability, and patient variability 2

Step 4: Divide into Multiple Daily Doses

• Divide the total daily methadone dose into 3-4 doses per day (every 6-8 hours) 2
• Methadone is available in 5 mg and 10 mg tablets, and as oral solution 2

Titration Schedule

• Titrate methadone upward every 5-7 days, typically by 5-10 mg per dose 2
• Monitor intensively for drug accumulation and adverse effects over the first 4-7 days 2
• Steady state may not be reached for several days to 2 weeks due to methadone's long and variable half-life 2
• Provide adequate short-acting breakthrough opioid medications during the titration period 2

Practical Dosing Example

For a patient on 180 mg/day oral morphine 2:

1. Use 8:1 conversion ratio: 180 ÷ 8 = 22.5 mg/day methadone
2. Reduce by 25%: 22.5 × 0.75 = 16.875 mg ≈ 15 mg/day methadone
3. Divide into 3 doses: 5 mg every 8 hours

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Special Populations

Elderly Patients

• Use lower starting doses with slower titration (increase every 5-7 days rather than more frequently) 4
• Methadone can be used safely in elderly cancer patients when doses are kept low initially and carefully titrated 4
• No correlation exists between age and methadone-related adverse effects when doses are individually titrated 4

Hepatic Impairment

• Exercise extreme caution in acute liver failure, as hepatic metabolism of methadone is severely impaired 5
• Methadone half-life becomes unpredictable and dramatically prolonged in acute liver dysfunction 5
• Consider dose reduction and extended monitoring intervals 5
• In severe hepatic impairment, consider alternative opioids or buprenorphine 5

CYP2B6 Inhibitors

• CYP2B6 inhibitors (not CYP3A4) will significantly increase methadone levels and risk of toxicity 3
• Reduce methadone dose when initiating CYP2B6 inhibitors 3
• Monitor closely for sedation and respiratory depression 3

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Mandatory Concurrent Management

Constipation Prevention

• Prescribe stimulant laxative (senna/docusate) starting at 2 tablets every morning from day one of methadone therapy 2
• Increase laxative dose when escalating methadone dose 2
• Opioid-induced constipation does not improve with tolerance and requires ongoing prophylaxis 2
• Maintain adequate hydration and nutrition 2

Acute Pain Management in Methadone Maintenance Patients

• Continue the usual methadone maintenance dose without modification 6
• Methadone maintenance provides minimal to no analgesia for acute pain 6
• Treat breakthrough pain aggressively with additional short-acting opioids (e.g., morphine every 3-4 hours) 6
• Higher opioid doses will be required due to cross-tolerance 6
• Prescribe scheduled doses rather than as-needed for severe pain 6
• Avoid mixed agonist-antagonist opioids (e.g., nalbuphine, butorphanol) as they can precipitate withdrawal 6

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Critical Warnings

Never Use Standard Conversion Ratios in Reverse

• Do NOT use the morphine-to-methadone conversion ratios when converting FROM methadone TO other opioids 2
• When discontinuing methadone, use a conservative 1:1 ratio (methadone:morphine) on day 1, then adjust daily as methadone clears over several days 2
• Methadone's long elimination half-life means residual drug persists for days after discontinuation 2

QTc Monitoring is Non-Negotiable

• Baseline ECG is mandatory before starting methadone 2
• Follow-up ECG required for doses >100 mg/day, cardiac disease, or concurrent QTc-prolonging medications 2
• This monitoring should be discussed within the patient's goals of care and risk-benefit context 2