Understanding What Drugs to Avoid for CYP2D6 Poor Metabolizer Status

October 14, 2025 •

4 min read

Approximately 5 to 10% of Caucasians are poor metabolizers of the CYP2D6 enzyme, a genetic variation that significantly impacts how their bodies process and respond to many common medications. Understanding what drugs to avoid for CYP2D6 poor metabolizer status is crucial for preventing adverse drug reactions and ensuring treatment effectiveness.

Quick Summary

A genetic variation can impair CYP2D6 enzyme function, affecting drug metabolism. Patients with this variant should avoid certain opioids, antidepressants, and other medications to prevent adverse effects or inadequate treatment.

Key Points

Genetic Variation: A CYP2D6 poor metabolizer has a genetic variation causing little or no functional enzyme activity, affecting drug metabolism.
Ineffective Pain Relief: Pro-drugs like codeine and tramadol are ineffective in poor metabolizers because they cannot be properly converted to their active analgesic forms.
Increased Side Effects: Drugs that are cleared from the body by CYP2D6, such as certain antidepressants and antipsychotics, can accumulate in poor metabolizers, leading to higher plasma concentrations and increased risk of toxicity.
Antidepressant Adjustments: Poor metabolizers may need lower starting doses or alternative SSRIs and TCAs, as standard doses can cause severe side effects.
Antipsychotic Considerations: Specific antipsychotics like aripiprazole, risperidone, and thioridazine require dose adjustments or avoidance in poor metabolizers to prevent severe adverse drug reactions.
Anti-cancer Treatment Risk: The breast cancer drug tamoxifen is a pro-drug whose efficacy is dependent on CYP2D6, meaning poor metabolizers may receive less benefit from the treatment.
Personalized Medicine: Pharmacogenetic testing can identify an individual's CYP2D6 status, enabling healthcare providers to tailor drug therapy for improved safety and efficacy.

The Role of CYP2D6 in Drug Metabolism

The CYP2D6 enzyme is part of the cytochrome P450 family, a group of enzymes primarily located in the liver. These enzymes are responsible for metabolizing (breaking down) a wide array of foreign substances, including approximately 25% of all prescription drugs. For many medications, CYP2D6 converts the parent drug into metabolites, which can be either inactive for elimination or pharmacologically active.

Genetic variations, or polymorphisms, can alter the function of the CYP2D6 enzyme, categorizing individuals into different metabolizer phenotypes, such as normal, intermediate, rapid, ultrarapid, and poor metabolizers. A CYP2D6 poor metabolizer (PM) has significantly reduced or absent enzyme activity due to inheriting two non-functional alleles of the gene. This lack of function can lead to two major types of problems, depending on how a specific drug is processed:

For pro-drugs, which must be converted to an active metabolite to work, a PM's body cannot perform this conversion effectively. This results in the drug having little to no therapeutic effect.
For active drugs that are metabolized by CYP2D6 for clearance from the body, a PM's system clears the drug more slowly. This can cause the drug to accumulate in the bloodstream, leading to higher-than-expected plasma concentrations and an increased risk of severe side effects or toxicity.

Drugs to Avoid for CYP2D6 Poor Metabolizers

The Clinical Pharmacogenetics Implementation Consortium (CPIC) and other authoritative bodies provide guidelines on prescribing for individuals with altered CYP2D6 metabolism. A significant number of drugs fall into categories that are problematic for PMs. Careful management and consideration of alternative medications are essential.

Opioid Pain Relievers

For CYP2D6 PMs, specific opioids that rely on the enzyme for activation should be avoided due to the high risk of inadequate pain relief.

Codeine: As a pro-drug, codeine requires conversion by CYP2D6 into its active form, morphine, to provide pain relief. PMs will have little or no analgesic effect from codeine and should use an alternative.
Tramadol: Similar to codeine, tramadol is a pro-drug whose analgesic effect is mediated by a metabolite produced by CYP2D6. PMs will likely experience suboptimal pain relief from tramadol.
Hydrocodone and Oxycodone: While some older research on hydrocodone and oxycodone has been mixed, newer evidence and guidelines suggest that PMs may experience inadequate pain relief from these opioids, which are also metabolized by CYP2D6. Alternative pain management strategies are recommended.

Antidepressants

Many common antidepressants are metabolized by CYP2D6. For PMs, this can lead to elevated plasma drug levels, increasing the risk of adverse effects.

Tricyclic Antidepressants (TCAs): Drugs like amitriptyline, nortriptyline, and imipramine are primarily metabolized by CYP2D6. Poor metabolizers may experience significantly increased blood levels, raising the risk of sedation, cardiovascular side effects, and anticholinergic effects. Lower doses or alternative medications are necessary.
SSRIs: Some selective serotonin reuptake inhibitors (SSRIs), notably fluoxetine and paroxetine, are potent CYP2D6 inhibitors themselves, but their own metabolism is also affected by the enzyme. In PMs, high plasma levels of paroxetine can increase the likelihood of side effects. Alternatives should be considered.
SNRIs: Certain serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, are also metabolized by CYP2D6. PMs can experience higher-than-normal plasma concentrations, increasing the risk of side effects.

Antipsychotics

CYP2D6 metabolizes several antipsychotic drugs, and PMs are at a higher risk of adverse reactions due to increased drug exposure.

Aripiprazole: The FDA advises that the dose of aripiprazole be reduced for CYP2D6 PMs. Increased concentrations may lead to side effects such as headache, dizziness, and restlessness.
Risperidone: Studies have shown that PMs of CYP2D6 have significantly higher risperidone plasma concentrations compared to normal metabolizers, increasing the risk of adverse effects like somnolence, headache, and dizziness.
Thioridazine: The use of thioridazine is contraindicated in individuals known to have reduced CYP2D6 activity due to an increased risk of potentially fatal side effects.

Other Drug Classes

Beta-blockers: Medications like metoprolol and carvedilol are metabolized by CYP2D6. Poor metabolizers have higher plasma concentrations, which can cause excessive slowing of the heart rate and other undesired side effects.
Anti-cancer drugs: Tamoxifen is a pro-drug that requires CYP2D6 activation to produce its active metabolites. Some breast cancer patients who are poor metabolizers may have reduced benefit from tamoxifen therapy and are more likely to experience cancer relapse.
Anti-emetics: The anti-nausea drug ondansetron is a substrate for CYP2D6, and poor metabolizers may experience altered effectiveness.

Comparison of Drugs for CYP2D6 Poor Metabolizers


Drug Category	Problematic Drugs for PMs	Reason	Safer Alternatives for PMs
Opioids	Codeine, Tramadol	Inadequate conversion to active form	Morphine, Hydromorphone, Fentanyl, Buprenorphine, non-opioid analgesics
Antidepressants	Amitriptyline, Paroxetine, Venlafaxine	Higher plasma concentrations, increased side effects	Citalopram, Escitalopram, Sertraline (with careful monitoring)
Antipsychotics	Aripiprazole, Risperidone, Thioridazine	Higher plasma concentrations, increased side effects	Quetiapine (Seroquel), Olanzapine (Zyprexa)
Cardiovascular	Metoprolol, Carvedilol	Higher plasma concentrations, excessive heart rate reduction	Atenolol, Bisoprolol
Anti-cancer	Tamoxifen	Inadequate conversion to active metabolites, reduced efficacy	Other cancer treatments not dependent on CYP2D6

Conclusion

Being a CYP2D6 poor metabolizer is a genetic reality for a significant portion of the population, with profound implications for drug therapy. The inability to properly metabolize a wide range of medications, from common pain relievers to life-saving anti-cancer drugs, can result in either treatment failure or an increased risk of severe adverse effects. Pharmacogenetic testing is a valuable tool that can identify an individual's CYP2D6 phenotype, allowing healthcare providers to personalize treatment plans. By understanding which medications are affected, physicians can make informed decisions to select safer and more effective therapeutic alternatives, optimizing patient care and minimizing risk. Always consult with a healthcare professional to determine the best course of action based on your individual genetic profile and medical history. The Clinical Pharmacogenetics Implementation Consortium (CPIC) is an excellent resource for detailed, evidence-based guidelines on this topic.

Frequently Asked Questions

A CYP2D6 poor metabolizer is an individual with a genetic variation resulting in little to no functional CYP2D6 enzyme activity. This reduces the body's ability to metabolize or activate certain medications, impacting their effectiveness and side effect profile.

Codeine is a pro-drug that needs to be converted by the CYP2D6 enzyme into its active form, morphine, to provide pain relief. A poor metabolizer cannot perform this conversion effectively, rendering codeine ineffective for pain.

For poor metabolizers, drugs like tricyclic antidepressants (amitriptyline) and some SSRIs (paroxetine) cannot be cleared efficiently. This leads to higher-than-normal drug concentrations in the body, increasing the risk of adverse side effects.

Yes, alternatives include non-opioid analgesics and opioids that are not primarily metabolized by CYP2D6, such as morphine, hydromorphone, and fentanyl.

Tamoxifen is a pro-drug that requires CYP2D6 to be converted into its active metabolites. For poor metabolizers, this conversion is impaired, potentially reducing the effectiveness of the cancer treatment and increasing the risk of relapse.

Phenoconversion occurs when an individual's CYP2D6 activity is altered by external factors, such as taking a strong CYP2D6 inhibitor drug (e.g., fluoxetine). This can cause a normal metabolizer to temporarily exhibit poor metabolizer characteristics, increasing the risk of drug accumulation and side effects.

No, not always. For some substrates, dose adjustments may be appropriate, and therapeutic drug monitoring may be used. However, drugs that rely on CYP2D6 for activation (like codeine) should typically be avoided entirely.