Impact of genetic variation on response to therapy
Tramadol is metabolised to its active metabolite, O-demethyl tramadol (also known as O-desmethyltramadol), by the liver enzyme CYP2D6. The activity of this enzyme can be highly variable due to genetic variants in the CYP2D6 gene. Poor metabolisers convert very little tramadol into O-demethyl tramadol and therefore have little or no pain relief from tramadol. In ultra-rapid metabolisers, there is an increased risk of opioid toxicity including life-threatening respiratory depression even at commonly prescribed doses, as rapid conversion to O-demethyl tramadol results in higher-than-expected serum levels.
The SmPCs for tramadol and tramadol‑containing medicinal products include a special warning and precaution in use, stating that if a patient has a CYP2D6 deficiency, an adequate analgesic effect may not be obtained; and if the patient is a CYP2D6 ultra-rapid metaboliser, there is a risk of developing side effects of opioid toxicity, even at commonly prescribed doses.
Testing recommendations
At the time of publication, there are no UK recommendations for CYP2D6 genotype testing to guide the use of tramadol.
Therapeutic recommendations
CYP2D6 metaboliser status unknown
- Use standard age-specific or weight-specific starting dose
CYP2D6 Ultra-rapid metabolisers: Activity score >2.25
Some examples of CYP2D6 genotypes include (see note): *1/*1xN, *1/*2xN
- Increased formation of O-demethyl tramadol leading to higher risk of toxicity.
- Avoid tramadol due to the increased risk of serious toxicity even at commonly prescribed doses.
- Consider alternative analgesic therapy without major CYP2D6 metabolism. Do not select codeine as this is also metabolised by CYP2D6.
CYP2D6 Normal metabolisers: Activity score ≥1.25 – ≤2.25
Some examples of CYP2D6 genotypes include (see note): *1/*1, *1/*2, *2/*2
- Expected levels of O-demethyl tramadol formation.
- Use standard dose.
- Monitor treatment response and offer alternative analgesic if warranted.
CYP2D6 Intermediate metabolisers: Activity score >0 – <1.25
Some examples of CYP2D6 genotypes include (see note): *1/*4, *1/*5, *1/*4xN
- Reduced levels of O-demethyl tramadol formation compared to normal metabolisers.
- Increased risk of treatment failure due to reduced efficacy.
- Initiate treatment with standard dose and monitor for efficacy.
- If no response, consider a dose increase if the maximum licensed dose has not already been reached, or consider alternative analgesic therapy without major CYP2D6 metabolism. Do not select codeine as this is also metabolised by CYP2D6.
CYP2D6 Poor metabolisers: Activity score 0
Some examples of CYP2D6 genotypes include (see note): *4/*4, *4/*4xN, *3/*4, *5/*5
- Greatly reduced O-demethyl tramadol formation compared to normal metabolisers.
- Avoid tramadol due to significantly increased risk of treatment failure due to reduced efficacy.
- Consider alternative analgesic therapy without major CYP2D6 metabolism. Do not select codeine as this is also metabolised by CYP2D6.
Note: This is a limited list of examples of CYP2D6 genotypes. N represents the number of additional copies of the gene.
Further information
Drug metabolism and interactions
Both CYP2D6 and CYP3A4 are involved in the biotransformation of tramadol and its metabolites. CYP2D6 inducers or inhibitors may also affect the clinical response to tramadol. CYP3A4 inhibitors may inhibit both the metabolism of tramadol and possibly also the metabolism of the active O-demethylated metabolites. Consult the SmPC for further information on drug interactions.
Other genes associated with clinical response to opioids
Other genes have been associated with opioid clinical efficacy and risk of adverse events, including OPRM1 and COMT. However, there is limited data on OPRM1 and COMT for clinical use. To date, no standardised genotype to phenotype groupings have been proposed for OPRM1 or COMT and there is limited data for their clinical use.
Alternative analgesics without major CYP2D6 metabolism
Morphine is not metabolised by CYP2D6. Other analgesics without major CYP2D6 metabolism include non-steroidal anti-inflammatory drugs (NSAIDs). Oxycodone is metabolised by CYP2D6 to a limited extent, and does not require dose adjustment in CYP2D6 poor, ultrarapid or intermediate metabolisers.
References
Ethypharm UK Ltd (2024). Maxitram SR 100 mg prolonged-release capsule SmPC. Available at: https://www.medicines.org.uk/emc/product/6989/smpc Accessed online 16th February 2026.
Clinical Pharmacogenetics Implementation Consortium CPIC® (2021) Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Available at: https://www.clinpgx.org/guideline/PA166251454 Accessed online 16th February 2026.
Matic M et al. Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between CYP2D6 and opioids (codeine, tramadol and oxycodone). Eur J Hum Genet. 2022 Oct 30(10):1105-1113. doi: 10.1038/s41431-021-00920-y. Erratum in: Eur J Hum Genet. 2022 Oct 30(10):1196. doi: 10.1038/s41431-021-00969-9.
