Opioid pharmacology, MME and opioid conversion

Know which opioids are prodrugs, which leave toxic renal metabolites, and what the label means by opioid tolerant. Use MME to gauge risk, not to convert doses one-for-one between drugs.

1. MME estimates risk, not exact equivalence. CDC 2022 factors include 1.5 for oxycodone (mg/day) and 2.4 for transdermal fentanyl (mcg/h). They do not account for incomplete cross-tolerance and should not be used to convert directly from one opioid to another ¹.
2. Opioid tolerant has a precise label meaning. For at least one week: oral morphine ≥60 mg/day, transdermal fentanyl ≥25 mcg/h, oral oxycodone ≥30 mg/day, oral hydromorphone ≥8 mg/day, or an equianalgesic dose of another opioid ²³.
3. Fentanyl patches and transmucosal fentanyl need tolerance. Both are restricted to opioid-tolerant patients because use in opioid-naive patients can cause fatal respiratory depression, even at the lowest strength ²³.
4. Codeine and tramadol are CYP2D6 prodrugs. CPIC advises avoiding both in CYP2D6 poor metabolizers and in ultrarapid metabolizers, and recommends an opioid not metabolized by CYP2D6, such as morphine or hydromorphone, or a nonopioid ⁴.
5. Renal failure changes the choice. Morphine and codeine leave renally cleared active metabolites and are best avoided in dialysis; hydromorphone can be used cautiously, starting at one-quarter to one-half the usual dose ⁵⁶.
6. Some opioids are simply poor choices. Beers advises avoiding meperidine in older adults: it is an ineffective oral analgesic at usual doses and carries neurotoxicity, including delirium ⁷.

Never start a fentanyl patch to "simplify" therapy in a patient on low-dose oral opioids; below the tolerance thresholds even 12 mcg/h risks life-threatening respiratory depression ².

• Tolerance requires both the dose threshold and at least 1 week at that dose ²³.
• CPIC makes no CYP2D6-based recommendation for oxycodone, and for hydrocodone in poor metabolizers advises standard label dosing, because evidence is insufficient ⁴.
• CPIC finds insufficient evidence for overcoming poor metabolism by raising the codeine dose ⁴.
• On the WHO ladder, codeine and tramadol are step II; strong opioids such as morphine form the top rung ⁸.
• Beers gives the avoid-meperidine recommendation moderate-quality evidence and a strong rating, and notes safer alternatives exist ⁷.
• Fentanyl and methadone appear safer than morphine in dialysis in Dean's review, while hydromorphone and oxycodone need caution and close monitoring ⁵.

• Using MME factors as an equianalgesic table for rotation; CDC warns they ignore incomplete cross-tolerance ¹.
• Assuming oxycodone is a clean non-CYP2D6 choice; it is partly converted to oxymorphone by CYP2D6 ⁴.
• Raising codeine in a poor metabolizer instead of switching to a non-CYP2D6 opioid ⁴.
• Counting a high dose taken for only a few days as opioid tolerance ³.