Pharmacogenetic Guidelines for Prescribing and Using Nonsteroidal Anti-inflammatory Drugs
The Clinical Pharmacogenetics Implementation Consortium (CPIC) has issued updated guidelines for the prescription is nonsteroidal anti-inflammatory drugs (NSAIDs) based on the CYP2C9 genetic polymorphism. The guidelines are published in Clinical Pharmacology & Therapeutics.1
Rating the evidence
An international group of experts performed a systematic review “to provide information for the interpretation of CYP2D9 genotype tests so that the results can guide dosing and/or use of NSAIDs,” including celecoxib, diclofenac, flurbiprofen, ibuprofen, indomethacin, lornoxicam, meloxicam, nabumetone, naproxen, piroxicam, tenoxicam, and sulindac. The experts rated the quality and strength of each evidence as weak, moderate, or high. For instance, high evidence described “well-designed and well-conducted studies.” In contrast, weak evidence implied that the outcomes could not be confidently linked to the genotype because of small sample sizes or flaws in the study design, among other reasons.
The CYP2C9 genotype is frequently reported as star (*) alleles, which the authors linked to the likely phenotype based on enzyme activity. For instance, CYP2C9*1/*1 genotype is classified as normal metabolizer, CYP2C9*2/*2 as intermediate metabolizer (IM), CYP2C9*2/*3 as poor metabolizer (PM), and CYP2C9*7/*10 is unknown or indeterminate. Also, a meta-analysis was used to assess the effects of the CYP2C9*2 and CYP2C9*3 alleles on the impact of each NSAID.
Guidelines by genotype
When prescribing or using Celecoxib, Flurbiprofen, Lornoxicam, and Ibuprofen, the CPIC guidelines recommend the following:
- Stratify patients based on the CYP2C9 genotype and risk.
- Normal metabolizers should take the lowest effective dose to achieve the desired therapeutic effect. (Evidence level: strong)
- IMs should take the lowest effective dose to achieve the desired therapeutic effect (Evidence level: moderate).
- IMs may report higher than average risk of adverse events, especially those with hepatic impairment. (Evidence level: moderate)
- For PMs, consider alternative therapies not metabolized by CYP2C9 such as aspirin, ketorolac, naproxen, and sulindac. (Evidence level: moderate)
- If medically necessary to use these NSAIDs in PMs, initiate therapy at 25-50% of the lowest recommended starting dose and titrate to achieve the desired clinical effect. (Evidence level: moderate)
- Upward titration should be delayed until a steady state is reached; about “8 days for celecoxib and five days for ibuprofen, flurbiprofen, and lornoxicam”. (Evidence level: moderate)
- Monitor blood pressure and renal function of intermediate and poor metabolizers during NSAID therapy. (Evidence level: moderate)
Meloxicam has a longer half-life than celecoxib and ibuprofen; thus, diminished metabolism may result in more severe adverse effects. The authors recommend the following:
- IMs may report a higher risk of adverse events than usual, thus initiate therapy at 50% of the recommended effective dose and titrate to desired clinical effect. (Evidence level: moderate)
- Upward titration of meloxicam in IMs should be deferred for at least seven days. (Evidence level: moderate)
- Avoid meloxicam in PMs and choose an alternate NSAID not metabolized by CYP2C9 enzyme. (Evidence level: moderate)
Piroxicam and tenoxicam have a longer half-life than meloxicam; thus, the risk of adverse events in IMs and PMs may be amplified:
- They recommend choosing an alternate NSAID not metabolized by CYP2C9 in IMs and PMs. (Evidence level: moderate)
While NSAIDs can be useful for the management of acute and chronic pain, clinicians should be aware of potential drug-drug interactions, especially in IMs and PMs. For instance, PMs and IMs may be at an increased risk for bleeding when prescribed NSAIDs and warfarin therapy. (Evidence level: moderate)
The pharmacokinetics of Aceclofenac, aspirin, diclofenac, indomethacin, lumiracoxib, metamizole, nabumetone, and naproxen are not significantly affected by CYP2C9 polymorphism.
In conclusion, the author cautions that “as with any diagnostic test, CYP2C9 genotype is just one factor that clinicians should consider when prescribing NSAIDs to an individual patient. Age, sex, race and ethnicity, liver dysfunction, comorbidities, concomitant medications, genetic linkage disequilibrium with CYP2C8, and other undiscovered genetic and environmental factors can all impact the likelihood that a patient will experience adverse events with NSAID therapy.”
- Theken KN, Lee CR, Gong L, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for cyp2c9 and nonsteroidal anti-inflammatory drugs. Clinical Pharmacology & Therapeutics. 2020. doi:10.1002/cpt.1830
Dr. Aroke is Assistant Professor of Nurse Anesthesia, and Pain & Genomics Researcher at the University of Alabama at Birmingham. He received his Ph.D. from the University of Massachusetts Medical School with distinction; earning the 2016 Chancellor’s Award for his academic excellence, and clinical/community leadership. In 2011, he completed his Nurse Anesthesia education at Duke University Nurse Anesthesia Program in Durham, NC. Dr. Aroke is an active member of the American Association of Nurse Anesthetists (AANA), The Nursing Honors Society-Sigma Theta Tau International, and Alabama Association of Nurse Anesthetists (ALANA), and serves on both the NBCRNA Evaluation and Research Advisory Committee and the NBCRNA Continued Professional Certification Assessment Committee. He has published several peer-reviewed articles, and presented nationally and internationally on pharmacogenomics, pain management, and anesthesia outcomes.