Poor Metabolizers of Codeine Have Severely Reduced to Absent Analgesic Benefit
Yes, poor metabolizers of codeine (CYP2D6 poor metabolizers) obtain reduced or no analgesic effects from codeine administration and should not be prescribed this medication. 1
Why Codeine Fails in Poor Metabolizers
Codeine is a prodrug with little to no direct analgesic effect—it must be metabolized to morphine via the CYP2D6 enzyme to provide pain relief 1
CYP2D6 poor metabolizers (approximately 5-10% of European Caucasians, lower in Asians) lack functional CYP2D6 enzyme activity and therefore cannot convert codeine to morphine 1
Poor metabolizers form only trace amounts of morphine (0.17% of the codeine dose converted versus 3.9% in normal metabolizers), resulting in morphine plasma concentrations of only 2 nmol/L compared to 38 nmol/L in extensive metabolizers 2
Clinical studies using the cold pressor test demonstrated that poor metabolizers experienced no significant analgesia from 170 mg codeine compared to placebo, while extensive metabolizers showed significant pain relief 2
The Critical Clinical Problem: Side Effects Without Benefit
Poor metabolizers still experience the full burden of codeine's adverse effects (nausea, vomiting, constipation, sedation) despite receiving no analgesic benefit 2
A randomized controlled trial found identical frequency and intensity of adverse events in both poor and extensive metabolizers after codeine administration 2
This means 7-10% of Caucasian patients are exposed to opioid side effects without any therapeutic benefit when prescribed codeine 2
Alternative Explanations (Minority View)
One older study from 2000 proposed that codeine-6-glucuronide (not morphine) provides the analgesic effect, suggesting poor metabolizers might still experience pain relief 3
However, this hypothesis contradicts multiple high-quality clinical trials and current guideline consensus, which consistently demonstrate that poor metabolizers lack codeine analgesia 1, 2
The weight of evidence strongly supports that morphine formation via CYP2D6 is essential for codeine's analgesic effect 4, 2
Practical Clinical Recommendations
Avoid codeine entirely in favor of alternative analgesics that do not depend on CYP2D6 metabolism: 1
For mild-to-moderate pain, use dihydrocodeine instead—its analgesic effect comes from the parent compound, not metabolites, so CYP2D6 poor metabolizer status does not reduce efficacy 1
Alternatively, use tramadol (though it also has reduced efficacy in poor metabolizers), NSAIDs, or acetaminophen for mild pain 1
For moderate-to-severe pain requiring opioids, skip directly to morphine, hydromorphone, oxycodone, or fentanyl—these do not require CYP2D6 activation 1
Drug Interactions That Create "Phenocopies"
Patients taking CYP2D6 inhibitors become functional poor metabolizers even if genetically normal: 4
Potent CYP2D6 inhibitors include quinidine, selective serotonin reuptake inhibitors (SSRIs like fluoxetine, paroxetine), and some antipsychotics 4
Even less potent inhibitors like tricyclic antidepressants will reduce codeine's pain-relieving effect due to codeine's low affinity for CYP2D6 4
Check medication lists before prescribing codeine—concurrent CYP2D6 inhibitors render codeine ineffective 4
Ethnic Considerations
Poor metabolizer prevalence varies by ethnicity: 5-10% in European Caucasians, lower in Asian populations 1
Conversely, ultrarapid metabolizers (up to 28% in Middle Eastern/North African populations, 10% in Caucasians, 1% in Asians) experience excessive morphine formation and potential toxicity from standard codeine doses 1, 5