Codeine and Tramadol CYP2D6 Conversion Interpreter

Codeine and tramadol are prodrugs activated by CYP2D6, so a fixed oral morphine equivalent factor is wrong in both tails — far too low in an ultrarapid metaboliser and far too high in a poor one. This page reads the published factor against the CPIC phenotype.

Why a fixed factor is wrong at both ends

CPIC’s positions, by drug and phenotype

The published conversion factors these phenotypes sit underneath

A conversion factor for a drug that is not the active drug

Codeine and tramadol are the two opioids a conversion table is most often asked about, and they are the two for which a fixed factor is least defensible. Neither is the active drug. CPIC’s guideline states that both “are O-demethylated by CYP2D6 to the more active metabolites morphine and O-desmethyltramadol, respectively”, so the dose written on the chart is a prodrug and the exposure that produces analgesia depends on an enzyme whose activity varies enormously between people.

The size of that variation dwarfs everything else in this category. At the top end, a CYP2D6 ultrarapid metaboliser converts more of the prodrug and CPIC’s implication is “Increased formation of morphine leading to higher risk of toxicity”, with a strong recommendation to “Avoid codeine use because of potential for serious toxicity”. At the bottom end, a poor metaboliser converts almost none: “Greatly reduced morphine formation leading to diminished analgesia”, and again a strong recommendation to avoid. The same milligram dose is therefore scored identically by every conversion table in the world and means two completely different exposures.

For this category the poor-metaboliser end is the more dangerous one, and in a way that is easy to miss. Converting such a patient off codeine or tramadol using the published factor credits them with an opioid history they never actually had — and the arithmetic then implies a tolerance that does not exist, which is exactly the situation the reduction for incomplete cross-tolerance exists to protect against and is not sized for. Tramadol adds a complication of its own: it also inhibits serotonin and noradrenaline reuptake, so a poor metaboliser may get a partial response that does not prove the CYP2D6 pathway is working at all, and that second mechanism brings a serotonergic hazard — see the Hunter criteria — that no opioid conversion factor represents.

Two further things keep a genotype from settling the question. A strong CYP2D6 inhibitor — paroxetine, fluoxetine, bupropion, quinidine or terbinafine — turns a genotypic normal metaboliser into a phenotypic poor one, and an activity score computed from alleles cannot see it. And the phenotype boundaries themselves moved: the 2019 to 2020 CPIC and Dutch Pharmacogenetics Working Group consensus made an activity score of exactly 1 — the score of the common CYP2D6 *1/*4 genotype — an intermediate metaboliser where it used to be a normal one. The activity score interpreter computes the score from the two allele values and reads it against the current bands. What no source read for this page publishes is a phenotype-adjusted conversion factor for any opioid, which is the real state of the field: the arithmetic and the pharmacogenomics are two literatures that have not yet met. Every published conversion factor on this page is a population approximation with wide interindividual variability. The factor that fits the average of a cohort can be out by twofold or more in one person, because opioid absorption, clearance, active-metabolite handling and receptor pharmacology all differ between individuals. The equianalgesic tables these factors descend from were largely derived from single-dose studies in opioid-naive or acute-pain patients, and they are applied in practice to chronic, repeated dosing in people who are already tolerant — a use the original studies were never designed to support. Published practice when changing from one opioid to another is to reduce the calculated equivalent, and the reduction is applied after the equivalence rather than instead of it. The reason is incomplete cross-tolerance: tolerance to one opioid does not transfer fully to another, so the arithmetic equivalent over-estimates what the patient already tolerates. The Faculty of Pain Medicine puts the cut at 25 to 50 per cent, and at least 50 per cent above about 500 mg of oral morphine equivalent a day or in the frail and elderly; the other five sources read for this page put the first cut between 25 and 50 per cent and none puts it at zero; and MSD’s table raises it to 75 to 90 per cent for methadone. The figure this page returns is an arithmetic equivalence and nothing else. It is not a dose, not a target and not a limit, and no part of this page says what any patient’s dose ought to be. Your own formulary, local conversion chart or specialist pain or palliative care service governs: where it differs from anything here, it wins. The factors themselves, and the sources that disagree about them, are on the oral morphine equivalent page.

Frequently asked questions

Related calculators

References

1. Crews KR, Monte AA, Huddart R, Caudle KE, Kharasch ED, Gaedigk A, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clin Pharmacol Ther. 2021. doi:10.1002/cpt.2149. Codeine and tramadol “are O-demethylated by CYP2D6 to the more active metabolites morphine and O-desmethyltramadol, respectively”. Ultrarapid metaboliser, activity score above 2.25: “Increased formation of morphine leading to higher risk of toxicity” and, graded strong, “Avoid codeine use because of potential for serious toxicity”. Poor metaboliser, score 0: “Greatly reduced morphine formation leading to diminished analgesia” and “Avoid codeine use because of possibility of diminished analgesia”. The tramadol table is the same shape. Hydrocodone, ultrarapid: “No recommendation for hydrocodone therapy because of minimal evidence regarding adverse events or analgesia”. Oxycodone and methadone: “There is insufficient evidence and confidence to provide a recommendation to guide clinical practice at this time”. OPRM1 and COMT: “There are no therapeutic recommendations for dosing opioids based on either OPRM1 or COMT genotype”.
2. Caudle KE, et al. Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci. 2020. doi:10.1111/cts.12692. The consensus that moved the intermediate-to-normal boundary, so that an activity score of exactly 1 — the score of the common CYP2D6 *1/*4 genotype — is now an intermediate metaboliser where it used to be a normal one. The current bands are 0, above 0 and below 1.25, 1.25 to 2.25 inclusive, and above 2.25.
3. Faculty of Pain Medicine of the Royal College of Anaesthetists. Opioids Aware: dose equivalents and changing opioids. Oral potencies, reviewed March 2023 against the BNF: codeine 0.1, dihydrocodeine 0.1, hydromorphone 5, morphine 1, oxycodone 1.5, tapentadol 0.4, tramadol 0.1, methadone “varies” with specialist advice required. Transdermal fentanyl 12, 25, 50, 75 and 100 micrograms an hour against 30, 60, 120, 180 and 240 mg of oral morphine a day. Conversion factors are an approximate guide only “because data are incomplete and individual variation is significant”; in most switches the calculated equivalent is cut by 25 to 50 per cent, and by at least 50 per cent above about 500 mg of oral morphine equivalent a day or in the elderly or frail; and “Opioid rotation is not recommended if a patient has responded to one opioid”.
4. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022. MMWR Recomm Rep. 2022;71(RR-3). Its conversion table, reproduced in CDC’s own 2022 Implementation Guide, reads: codeine 0.15, transdermal fentanyl 2.4 per microgram an hour, hydrocodone 1, hydromorphone 5, methadone 4.7, morphine 1, oxycodone 1.5, oxymorphone 3, tapentadol 0.4, tramadol 0.2. Of its seven cautions, the second is “Equianalgesic dose conversions are only estimates”, the third “Do not use the calculated dose in MMEs to determine the doses to use when converting one opioid to another”, and the seventh “These conversion factors should not be applied to dosage decisions related to the management of opioid use disorder”.
5. Severn Hospice. Opioid Conversion Table, version 07.19. Oral potencies of 0.1 for codeine and dihydrocodeine but 0.15 for tramadol, and oral oxycodone reached by dividing oral morphine by 2 — two figures that disagree with the Faculty of Pain Medicine’s 0.1 and 1.5 for the same drugs. Transdermal fentanyl “approx. 100 to 150 times more potent than oral morphine” with the table built at 100:1; buprenorphine 5 micrograms an hour matched to 12 mg of oral morphine a day. Puts the switching reduction at 25 to 30 per cent, and at 50 per cent when converting high doses, to avoid toxicity.
6. MSD Manuals Professional Version. Equianalgesic Doses of Opioid Analgesics. Parenteral against oral: morphine 10 to 30 mg, codeine 130 to 200, hydromorphone 1.5 to 7.5, methadone 10 to 20, oxycodone 15 to 20, oxymorphone 1 to 15. Its footnotes state that the equivalences come from single-dose studies and clinical experience and are approximations; that on changing opioid the equianalgesic dose is cut by 50 per cent, and by 75 to 90 per cent for methadone; and that the morphine-to-methadone ratio is non-linear, rising from about 2:1 below 30 mg of oral morphine equivalent a day to about 20:1 at 1000 mg a day and above. Its oral oxymorphone figure of 15 mg against 30 mg of morphine implies a potency of 2, where CDC publishes 3.

Not medical advice. For healthcare professionals and education. Reference intervals vary by laboratory and assay — always use your own laboratory's. Never base a dose or a treatment decision on this page alone. Full disclaimer at calcengines.com/disclaimer/