Codeine phosphate

Impact of genetic variation on response to therapy

Codeine is metabolised to its active metabolite, morphine, 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 codeine into morphine and therefore have little or no pain relief from codeine.  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 morphine results in higher-than-expected serum morphine levels. 

The MHRA and the SmPCs for codeine and medicinal products containing codeine state that codeine is contraindicated in patients for whom it is known they are CYP2D6 ultra-rapid metabolisers. 

Testing recommendations

At the time of publication, there are no UK recommendations for CYP2D6 genotype testing to guide the use of codeine. 

Therapeutic recommendations

CYP2D6 metaboliser status unknown 

• Use standard dose.
• Monitor treatment response and offer alternative analgesic if warranted.  

CYP2D6 Ultra-rapid metabolisers: Activity score >2.25

Some examples of CYP2D6 genotypes include (see note): *1/*1xN, *1/*2xN   

• Increased formation of morphine leading to higher risk of toxicity. 
• Avoid codeine. Codeine is contraindicated due to the increased risk of serious toxicity even at commonly prescribed doses. 
• Consider alternative analgesic therapy without major CYP2D6 metabolism. Do not select tramadol 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 morphine 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 morphine 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 tramadol 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 morphine formation compared to normal metabolisers. 
• Avoid codeine due to increased risk of treatment failure due to reduced efficacy. 
• Consider alternative analgesic therapy without major CYP2D6 metabolism. Do not select tramadol 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

Variability in codeine response in CYP2D6 normal metabolisers 

The association between CYP2D6 metaboliser phenotype and clinical response to codeine is well defined. However, there is a degree of response variability and unpredictable risk of side effects within patients classed as CYP2D6 normal metabolisers, and some patients may develop symptoms of opioid toxicity similar to ultra-rapid metabolisers.  Information should be given to patients on how to recognise the signs of morphine toxicity, and what to do if these signs or symptoms occur.  

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

Aurobindo Pharma – Milpharm Ltd (2023). Codeine phosphate 15mg tablets SmPC.  Availabe at: https://www.medicines.org.uk/emc/product/11268/smpc Accessed online 21st November 2025. 

Clinical Pharmacogenetics Implementation Consortium CPIC® (2021) Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Available at: https://cpicpgx.org/guidelines/guideline-for-codeine-and-cyp2d6/ Accessed online 04^th February 2026. 

Medicines and Healthcare products Regulatory Agency (2014). Codeine for analgesia: restricted use in children because of reports of morphine toxicity. Drug Safety Update. Available at: https://www.gov.uk/drug-safety-update/codeine-for-analgesia-restricted-use-in-children-because-of-reports-of-morphine-toxicity. Accessed online 04^th 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.  Accessed online 04^th February 2026.