Codeine vs. Morphine: Pharmacogenomic Testing And Opiates

Genetic Testing Insights for Safer Opioid Prescribing

For UK clinicians seeking to personalise pain management with pharmacogenomics, the conversation around opioids is shifting. Not all opiates are created equal, and two of the most prescribed—codeine and morphine—offer a clear case study in why pharmacogenetic testing is entering mainstream prescribing practice.

Codeine: A Common Painkiller With Uncommon Risks

Although often described as a prodrug, codeine has some weak intrinsic activity at the µ-opioid receptor. However, its clinically meaningful pain relief depends largely on its conversion to morphine—a process governed by the liver enzyme CYP2D6.

Genetic differences in the CYP2D6 gene can dramatically alter this conversion:

• Poor metabolisers may struggle to convert codeine to morphine, resulting in little or no pain relief.

• Ultrarapid metabolisers may convert it too efficiently, producing high levels of morphine and increasing the risk of side effects such as sedation or respiratory depression.

This variability makes codeine a good candidate for pharmacogenetic testing, especially in patients who report poor response or heightened sensitivity.

Pharmacogenetic Testing and Codeine Side Effects

The pharmacogenetic variants of CYD2D6 directly affect the common 15mg dose of codeine, and in some patients, may result in serious respiratory depression or treatment failure. Despite codeine's reputation as a mild opioid, it is addictive, and does cause drowsiness, particularly in ultrarapid metabolisers or when taken in combination with alcohol or sedatives.

Because of these risks, CPIC guidelines increasingly recommend CYP2D6 genotyping before initiating long-term or repeat codeine therapy. In the UK, however, routine NHS access to this testing remains limited. Instead, clinicians and patients may pursue testing through private pharmacogenomics services or accredited at-home PGx providers offering comprehensive panels that include CYP2D6 analysis.

Morphine: The Benchmark Opioid, With Different Variables

Unlike codeine, morphine is a pharmacologically active compound that does not require metabolic activation to exert its analgesic effects. It bypasses the CYP450 system, including CYP2D6, and is instead primarily metabolised via glucuronidation in the liver, producing two main metabolites:

• Morphine-6-glucuronide (M6G) – An active metabolite that contributes to analgesia.

• Morphine-3-glucuronide (M3G) – An inactive metabolite for pain relief, but one that may be associated with neurotoxic effects such as agitation, confusion, or myoclonus.

Although there is emerging research into genetic variation in the OPRM1 gene and its potential influence on morphine sensitivity, there are currently no clinical PGx guidelines recommending dosing adjustments for morphine based on genetics.

Practical Implications: Testing Where It Matters

Although not yet standard across the NHS, pharmacogenomic testing is increasingly recognised as good clinical practice—particularly when prescribing codeine, where CYP2D6 variation can dramatically affect both efficacy and safety. Testing may be especially useful in patients who:

• Have experienced side effects from opioids

• Are starting chronic or repeated opioid therapy

• Report inadequate response to standard 15 mg codeine doses

In such cases, CYP2D6 genotyping can help determine whether codeine is likely to be an appropriate choice—or whether alternatives should be considered.

For morphine, pharmacogenomic guidance is more limited. While there is ongoing research into genes like OPRM1, current clinical guidelines do not recommend genotype-based dosing. However, pharmacological testing may still play a role in optimising morphine use—particularly in assessing renal function, drug–drug interactions, or broader opioid sensitivity.

In contrast, for other opioids such as tramadol, there is clearer PGx relevance, with CPIC and DPWG guidelines offering actionable recommendations based on CYP2D6 metabolism. This makes PGx testing a valuable tool for selecting the right opioid in complex or refractory cases.

Takeaway for Clinicians

Not all opioids demand the same PGx scrutiny. Codeine's reliance on CYP2D6 metabolism means that pharmacogenomic testing can directly improve safety and efficacy. Morphine, in contrast, is less variable from a genetic standpoint but still complex due to its metabolites and CNS effects.

If you're prescribing codeine or morphine and want to avoid the guesswork, consider integrating pharmacogenetic testing into your workflow. Our AttoDiagnostics pharmacogenetic report includes CYP2D6 analysis and clear commentary on which opioids may be better suited to your patient's genetic profile.

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