Optimizing Opioid Therapy Through Pharmacogenomics

Pain management remains one of the most challenging areas of medication management, as variability in patient response to analgesics can significantly impact treatment efficacy and safety. In 2023, data from the National Health Interview Survey revealed that 24.3% of adults had chronic pain, and 8.5% of adults had chronic pain that frequently limited daily activities in the past 3 months.¹

Despite the wide availability of opioid and non-opioid analgesics, many patients experience inadequate pain relief, while others develop severe adverse effects such as sedation, respiratory depression, or gastrointestinal complications. Increasing evidence suggests that genetic differences in cytochrome P450 and other metabolism enzymes are a major contributor to this variability. This concept is known as pharmacogenomics (PGx).

Pharmacogenomics is the study of how genetic variability, known as polymorphism, may influence a patient’s response to medications. It has emerged as a promising tool to optimize analgesic agents, particularly opioids. Among the most clinically significant genes are those encoding cytochrome P450 (CYP450) enzymes, which are responsible for the metabolism of 75% percent of drugs. Among these CYP enzymes, CYP3A4 and CYP2D6 are particularly significant, metabolizing over 50% of drugs.²

A specific gene encodes each CYP450 enzyme. Every person inherits one genetic allele from each parent. Alleles are referred to as “wild type” or “variant,” with wild type occurring most commonly in the general population. An “extensive metabolizer,” also known as a normal metabolizer (NM), inherited two copies of wild-type alleles. Polymorphism occurs when a variant allele replaces one or both wild-type alleles. Variant alleles usually encode a CYP450 enzyme with little to no activity. People with two copies of variant alleles are “poor metabolizers” (PM),, whereas those with one wild type and one variant have reduced enzyme activity, also known as “intermediate metabolizers” (IM). Lastly, those who inherit multiple copies of wild-type alleles, resulting in excess enzyme activity, are called “ultrarapid metabolizers (UM)”. Theoretically, poor metabolizers should have a higher steady state concentration of the parent drug, followed by intermediate, extensive, and then ultrarapid metabolizers.

CYP2D6 has shown to be highly polymorphic in the general population. Polymorphisms and their correlation to steady state drug concentrations, therapeutic efficacy, and toxicity has been investigated for various opioids; however, the strongest evidence for such correlations are found with tramadol and codeine.³

Tramadol

Tramadol is metabolized by the liver via demethylation mediated by CYP3A4 and CYP2D6, glucuronidation, and sulfonation. Most importantly, the pharmacologically active metabolite O-desmethyltramadol is formed by CYP2D6. Tramadol and its active metabolite bind to μ opioid receptors in the central nervous system, thereby inhibiting ascending pain pathways and altering the perception and response to pain.⁴ The caveat is that O-desmethyltramadol has a 200-fold greater affinity for μ opioid receptors compared to the parent drug. In a study with Stamer UM, et al., significantly higher levels of O-desmethyltramadol 90 and 180 minutes after tramadol administration were found in UM, NM, and IM individuals compared to PMs (P<0.001).⁵ This and other prospective studies have shown that, compared to CYP2D6 ultrarapid, normal, and intermediate metabolizers, poor metabolizers more often fail to experience analgesia in response to tramadol. Ultrarapid metabolizers not only have greater analgesia, but also stronger miosis and a higher incidence of nausea versus normal and poor metabolizers. Cases have been reported of near-fatal tramadol cardiotoxicity and respiratory depression in UM phenotypes.^6,7

Codeine

Codeine is metabolized by the liver via UGT2B7 and UGT2B4 to codeine-6-glucuronide and via CYP2D6 to morphine, the active metabolite. The analgesic effect of codeine is closely related to the CYP2D6 enzyme’s ability to convert the drug into morphine. Morphine is further metabolized via glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide, the active metabolite.⁸ Pharmacokinetic studies in healthy individuals receiving codeine show that poor metabolizers had a 96% lower mean morphine peak plasma concentration (Cmax) compared with normal and intermediate metabolizers.⁹ In regard to analgesic effect, studies have shown that following the administration of codeine, analgesia was observed in NMs, but not in PMs. In contrast to the phenotype-related differences in analgesic effects, no significant differences in adverse effects between the phenotypes were observed. Nonetheless, the prevalence of PMs in the Caucasian population is 7% to 10%. This means that this PM population is unlikely to experience the drug’s analgesic effects, whereas UMs may be at a high risk of toxicity due to their proportionally higher morphine concentrations.

Table 2. Codeine Therapy Recommendations Based on CYP2D6 Phenotype³

Hydrocodone and Oxycodone

If opioid therapy is warranted, alternative analgesics might include hydrocodone or oxycodone. Hydrocodone is metabolized predominantly by CYP2D6 to hydromorphone (major, active metabolite with up to 33-fold higher binding affinity for μ-opioid receptors than hydrocodone).¹⁰ The relationship between plasma concentration of the active metabolite, hydromorphone, and analgesia is unclear. Most evidence lies in the altered pharmacokinetics of hydrocodone in CYP2D6 ultrarapid metabolizers. Studies have shown that the Cmax of hydromorphone was 5 times lower in PMs than in NMs; however, it remains unclear whether this translates into reduced analgesia or adverse effects in poor metabolizers.

Eleven percent (11%) of oxycodone is converted to oxymorphone by CYP2D6, and 45% is converted to noroxycodone by CYP3A4.¹¹ Based on the results of a cross-sectional study of 450 Caucasian patients from the European Pharmacogenetic Opioid Study, CYP2D6 PMs had lower oxymorphone serum concentrations in comparison with EMs and UMs (P<0.001).¹² Additionally, noroxycodone has weak analgesic activity, while oxymorphone has analgesic activity but low plasma concentrations (<15%) in most individuals. Theoretically, CYP2D6 PMs would have little to no analgesia; however, the evidence is lacking. Therefore, there have not been established therapeutic guideline recommendations for oxycodone or hydrocodone.

Morphine

Morphine is metabolized by the liver via conjugation with glucuronic acid primarily to morphine-6-glucuronide (M6G), the active analgesic, and morphine-3-glucuronide (M3G), which is inactive as an analgesic but may contribute to central nervous system stimulation. A study that evaluated intrathecal morphine in low back pain concluded that the presence of the COMT Met allele is more responsive to morphine analgesia compared to the COMT Val/Val wild-type genotype.¹³ Other studies have also evaluated morphine analgesic response in Italian cancer patients using OPRM1 and ABCB1 genotypes and concluded that individuals with the OPRM1 A/A or ABCB1 T/T genotype will mount a strong response. On the other hand, the OPRM1 G/G or A/G or ABCB1 C/C or C/T genotype correlates with no response to morphine.¹⁴

Fentanyl

Few studies have analyzed the role of CYP3A4 and CYP3A5 polymorphisms on treatment outcomes with fentanyl in chronic cancer pain patients. They found that the absorption rate of fentanyl was significantly higher in CYP3A5 *3/*3 homozygous carriers as opposed to the heterozygote or wild-type carriers (P=0.048 and 0.021, respectively).¹⁵ There was also a correlation between a higher fentanyl absorption rate and a greater incidence of central adverse effects in homozygotes. These results suggest that CYP3A4 polymorphisms may have a role in predicting transdermal fentanyl analgesia response and risk of toxicity.¹⁵

What Is the Pharmacist’s Role in Using PGx in Opioid Therapy Management?

Incorporating PGx testing into clinical practice may enable more precise and timely drug selection, thus improving both safety and efficacy. Pharmacists can identify patients who may benefit from testing, particularly those with inadequate pain control, unexpected adverse effects, or a history of opioid misuse. Interpretation of test results allows pharmacists to recommend appropriate opioid selections, dosing adjustments, or non-opioid alternatives based on predicted metabolism. This individualized approach can reduce trial-and-error therapy and aligns with opioid stewardship initiatives.

Some barriers to utilization may include cost-effectiveness, genotyping error, and lack of evidence. Although there is evidence of associations between polymorphisms and serum concentrations, large prospective clinical trials are still needed to determine whether routine genotyping in clinical practice is cost-effective and improves clinical outcomes. As evidence continues to evolve, pharmacists can serve as educators to bridge the gap between genetic science and real-world clinical outcomes – ultimately improving pain control, enhancing medication safety, and advancing personalized care.

REFERENCES

1. Chronic Pain and High-impact Chronic Pain in U.S. Adults, 2023. CDC/National Center for Health Statistics. November 21, 2024. Accessed September 20, 2025.

2. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76(3):391-396.

3. Crews, K.R., Monte, A.A., Huddart, R., Caudle, K.E., et al. (2021), Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy. Clin. Pharmacol. Ther., 110: 888-896. https://doi.org/10.1002/cpt.2149.

4. Lexicomp. Tramadol. Lexi-Drugs. Wolters Kluwer Health; 2025. Accessed October 1, 2025. https://online.lexi.com.

5. Stamer UM, Musshoff F, Kobilay M, Madea B, Hoeft A, Stuber F. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther. 2007;82(1):41-47. doi:10.1038/sj.clpt.6100152

6. Elkalioubie A, Allorge D, Robriquet L, et al. Near-fatal tramadol cardiotoxicity in a CYP2D6 ultrarapid metabolizer. Eur J Clin Pharmacol. 2011;67(8):855-858. doi:10.1007/s00228-011-1080-x

7. Stamer UM, Stüber F, Muders T, Musshoff F. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesth Analg. 2008;107(3):926-929. doi:10.1213/ane.0b013e31817b796e

8. Lexicomp. Codeine. Lexi-Drugs. Wolters Kluwer Health; 2025. Accessed October 1, 2025. https://online.lexi.com.

9. Eckhardt, Klaus; Li, Shuxia; Ammon, Susanne; Schänzle, Gerhard; Mikus, Gerd; Eichelbaum, Michel. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 76(1):p 27-33, May 1998. | DOI: 10.1016/S0304-3959(98)00021-9

10. Lexicomp. Hydrocodone. Lexi-Drugs. Wolters Kluwer Health; 2025. Accessed October 1, 2025. https://online.lexi.com.

11. Lexicomp. Oxycodone. Lexi-Drugs. Wolters Kluwer Health; 2025. Accessed October 1, 2025. https://online.lexi.com.

12. Klepstad P, Fladvad T, Skorpen F, et al. Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain. 2011;152(5):1139-1145. doi:10.1016/j.pain.2011.01.040

13. Cargnin S, Magnani F, Viana M, et al. An opposite-direction modulation of the COMT Val158Met polymorphism on the clinical response to intrathecal morphine and triptans. J Pain. 2013;14(10):1097-1106. doi:10.1016/j.jpain.2013.04.006

14. Campa D, Gioia A, Tomei A, Poli P, Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008;83(4):559-566. doi:10.1038/sj.clpt.6100385

15. Takashina Y, Naito T, Mino Y, Yagi T, Ohnishi K, Kawakami J. Impact of CYP3A5 and ABCB1 gene polymorphisms on fentanyl pharmacokinetics and clinical responses in cancer patients undergoing conversion to a transdermal system. Drug Metab Pharmacokinet. 2012;27(4):414-421. doi:10.2133/dmpk.dmpk-11-rg-134