How can an adult opioid‑tolerant patient on 1200 mg daily Kadian (extended‑release oral morphine) be safely converted to methadone?

Converting 1200 mg Daily Kadian to Methadone

For a patient on 1200 mg daily oral morphine (Kadian), cross-titration with methadone is strongly recommended rather than direct conversion, with an initial methadone dose not exceeding 30 mg daily divided into 3-4 doses, while gradually tapering the morphine. 1

Why Cross-Titration is Critical at This Dose

• At morphine doses ≥800 mg daily, the NCCN guidelines explicitly state that "higher dose ratio is necessary and cross titration is recommended" rather than using standard conversion ratios 1
• The conversion ratio becomes increasingly unpredictable at very high morphine doses—methadone becomes disproportionately more potent as baseline opioid doses increase 1, 2
• Deaths have been reported during conversion from chronic high-dose opioid therapy to methadone, even in opioid-tolerant patients 3

Recommended Cross-Titration Protocol

Initial Methadone Dosing

• Start methadone at 30 mg daily maximum, divided into 3-4 doses (e.g., 10 mg every 8 hours or 7.5 mg every 6 hours) 1, 2
• This conservative starting dose is supported by research showing that a fixed maximum of 30 mg/day methadone produced meaningful pain improvement in patients on >1200 mg morphine equivalent daily without adverse effects 2
• Do NOT calculate a theoretical equianalgesic dose at this morphine level—the standard conversion tables stop at 800 mg for safety reasons 1

Morphine Tapering Strategy

• Continue the full 1200 mg Kadian dose initially while starting methadone 1
• After 3-5 days (allowing methadone tissue stores to accumulate), begin reducing Kadian by 25-50% every 3-5 days while monitoring pain control 1, 3
• Provide immediate-release morphine 10-15% of remaining daily Kadian dose for breakthrough pain during the transition 1

Titration Timeline

• Methadone may be titrated upward every 5-7 days by 5-10 mg per dose based on pain control after morphine is fully discontinued 1
• Methadone's long and variable half-life (24-36 hours) means steady-state is not reached for 5-7 days after each dose change 1, 3
• Most patients stabilize between 80-120 mg/day methadone for maintenance, though this varies considerably 3

Mandatory Safety Monitoring

Cardiac Screening

• Obtain baseline ECG before initiating methadone and repeat ECG when methadone dose exceeds 100 mg/day 1, 3
• Methadone causes QTc prolongation and life-threatening arrhythmias, particularly at higher doses 1, 3
• Screen for risk factors: cardiac disease, hypokalemia, hypomagnesemia, concomitant QTc-prolonging medications (including tricyclic antidepressants), diuretic use 1, 3
• If QTc >450 ms develops, evaluate for modifiable risk factors and consider alternative opioids 3

Drug Interaction Assessment

• Investigate potential drug-drug interactions before initiating methadone—methadone is metabolized by CYP3A4 and CYP2B6 1
• Inhibitors (e.g., azole antifungals, macrolides, protease inhibitors) increase methadone levels and toxicity risk 1
• Inducers (e.g., rifampin, phenytoin, carbamazepine) decrease methadone efficacy 1

Respiratory Monitoring

• Monitor closely for respiratory depression, especially during the first 3-5 days when methadone is accumulating 3
• Peak respiratory depressant effects occur later and persist longer than peak analgesic effects 3
• High opioid tolerance does NOT eliminate methadone overdose risk 3

Concurrent Bowel Management

• Prescribe stimulant laxative (senna/docusate) starting at 2 tablets every morning from day one 1, 4, 5
• Increase laxative dose when escalating methadone—opioid-induced constipation does not improve with tolerance 1, 4, 5
• Maintain adequate hydration 1, 4

Common Pitfalls to Avoid

• Never use standard conversion ratios for morphine >800 mg daily—this leads to methadone overdosing 1
• Never make same-day methadone dose increases—wait at least 5-7 days between adjustments 1, 3
• Never abruptly discontinue the 1200 mg Kadian—cross-titration is essential at this dose level 1
• Never assume complete cross-tolerance—incomplete cross-tolerance between opioids is particularly dangerous with methadone 3

Alternative Approach: Inpatient Titration Method

• If inpatient specialist palliative care is available, some centers use a "10% rule": calculate 10% of morphine equivalent dose (120 mg in this case), but cap initial methadone at 40 mg daily maximum, given every 3 hours as needed 6
• Once daily requirements stabilize (typically 2-18 days), divide into 2-3 regular doses 6
• This method requires intensive monitoring in a specialist unit and is NOT appropriate for outpatient conversion at this dose level 6

When to Consult Pain Specialist

• Strongly consider pain specialist consultation for any patient on >800 mg morphine daily given the complexity and mortality risk of methadone conversion 1, 7
• Mandatory consultation if patient has cardiac conduction disease, QTc >450 ms, or complex medication regimen 1, 3