Chronic pain affects approximately 100 million U.S. adults at a cost of up to $635 billion annually in direct medical costs and lost productivity. As clinicians attempt to reduce pain and improve functionality in patients with chronic pain, pharmacotherapy remains a cornerstone of treatment. Typically, several medications with different mechanisms of action are employed to target different physiological pain pathways. Thus, polypharmacy is common in patients with chronic pain, exposing patients to increased risk of drug-drug interactions. Another challenge clinicians face is wide inter-patient variability in responses to prescribed medications.
Due to these variables, clinicians must consider multiple factors when determining optimal pharmacotherapy for patients, including the pharmacokinetics/pharmacodynamics of a medication and the patient’s comorbid medical conditions, age, and concomitant medications.
Pharmacogenetics is the study of how genes affect the response to medications. Pharmacogenetic information may be used to predict a patient’s genetically driven response to a specific medication. Genetic variances account for 20% to 40% of inter-individual differences in metabolism and responses to medications and can exacerbate drug-drug interactions, hinder a pro-drug from bio-activation, or induce metabolism through alternative, potentially deleterious pathways.3 The goal of pharmacogenetics is to deliver improved pharmacotherapeutic treatment for an individual by distinguishing between patients who may be more or less likely to respond to a specific drug and identifying patients who may be at higher risk for adverse events and certain drug interactions.3
The human body breaks down or metabolizes medications in order to eliminate them. Many medications commonly used in the treatment of chronic pain are broken down in the liver via hepatic enzyme metabolism. The cytochrome P450 (CYP450) enzymes are responsible for the metabolism of the majority of medications and associated with genetic variations (i.e., polymorphisms) that can affect an individual’s response. During the past several years, the ability to test for polymorphisms in these hepatic metabolic enzymes has become more convenient, more commercially available, and reimbursable by third-party payers, leading to increased clinical use. The ability to identify polymorphisms in an individual’s genotype can now be used to predict a phenotype for these hepatic metabolic enzymes. The phenotype is the observable trait encoded by the genotype, which in this case describes how a patient metabolizes medications that are processed by the enzyme that is tested. The test for a particular hepatic enzyme is referred to as a pharmacogenetic test.
When patients undergo pharmacogenetic testing, they are categorized into one of four phenotypes: ultra-rapid metabolizer (UM), extensive metabolizer (EM), intermediate metabolizer (IM), or poor metabolizer (PM). Extensive metabolizers are considered to have normal enzyme activity and metabolism through the enzyme pathway tested and, based on pharmacogenetics alone, would be expected to have a typical response on standard medication doses. Ultra-rapid metabolizers will metabolize medications faster through the enzymatic pathway tested compared to an extensive (normal) metabolizer. Intermediate metabolizers have a decreased capacity to metabolize medications through the enzymatic pathway tested, and poor metabolizers have very little to no ability to metabolize medications through the enzymatic pathway tested.5
The clinical consequence of each phenotype will depend on whether the medication is inactivated by metabolism or needs metabolism to produce an active metabolite (i.e., a prodrug). For example, a poor metabolizer, unable to metabolize certain medications, is at risk for accumulation of the active parent compound and increased toxicity, or lack of conversion of a prodrug into an active metabolite and decreased efficacy.
When deciding which patients may benefit from pharmacogenetic testing, considerations include the clinical consequences of a genetic polymorphism, whether the medication(s) prescribed or to be prescribed are metabolized by the enzyme(s) tested, and salient information from the patient’s medical history (response to medications, personal or family history of adverse events to medications, response to anesthesia, response to alcohol and history of genetic diseases).4 If a genetic variant is identified, the predicted clinical consequences should be assessed and clinical adjustments, such as modifying the dose, modifying the dosing schedule, or changing the medication should be considered. In some cases, the genetic variant may support the dosing regimen or drug choice(s), and no change is required.3
Chronic pain is a major burden to the healthcare system, and it lacks many objective tests available to help guide treatment. Pharmacogenetic testing is a tool that is available today that, when applied to patient care, may lead to improved selection of medication(s) for the individual and optimal pharmacotherapy. Benefits of using pharmacogenetic testing may include fewer medication-related side effects, avoidance of drug-drug interactions, and a reduced number of opioid rotations by avoiding the use of medications that repeat negative outcomes due to a genetic variant. Testing may also provide documentation to support a decision to change or continue a medication regimen.7 Pharmacogenetic testing brings us one step closer to the ideal treatment: personalized medicine.
- Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education and research. 2011. http://www.iom.edu/Reports/2011/Relieving-Pain-in-America-A-Blueprint-for-transforming-Prevention-Care-Education-Research.aspx. Accessed December 21, 2013. Jacubeit T, Drisch D, Weber E. Risk factors as reflected by an intensive drug monitoring system. Agents Actions Suppl. 1990;29:117-125.
- Brennan M. The clinical implications of cytochrome P450 interactions with opioids and strategies for pain management. J Pain Symp Man. 2012;44(6S):S15-S22.
- Fishbain DA, Fishbain D, Lewis J, et al. Genetic testing for enzymes of drug metabolism: does it have clinical utility for pain medicine at the present time? a structured review. Pain Med. 2004;5(1):81-93.
- Tennant F. Cytochrome P450 testing in high-dose opioid patients. Pract Pain Man. 2012. http://www.practicalpainmanagement.com/treatments/pharmacological/opioids/cytochrome-p450-testing-high-dose-opioid-patients. Accessed December 21, 2013.
- Gudin J. Opioid therapies and cytochrome P450 interactions. J Pain Symp Man. 2012;44(6S): S4-S14.
- Tennant F. Making practical sense of cytochrome P450. Pract Pain Man. 2010. http://www.practicalpainmanagement.com/treatments/pharmacological/opioids/making-practical-sense-cytochrome-p450. Accessed December 21, 2013.