Genetic Testing in Pain Medicine—The Future Is Coming
Over 100 million adults in the United States suffer from chronic pain on a daily basis.1 In the past decade, physicians have increasingly turned to opioids as a standard approach to pain management. Americans constitute only 4.6% of the world’s population, yet they consume 80% of the global opioid supply and 99% of the global hydrocodone supply.2 This has led, unfortunately, to a rise in opioid abuse and deaths secondary to opioid overdose. In 2014, there were 18,893 overdose deaths related to prescription pain relievers alone.3
A patient’s response to pain and opioids is quite variable, making identifying patients who are good (risk-free) candidates for opioid therapy difficult. Clinicians have tried to attribute weight, age, sex, and medication blood levels to explain the wide variability of responses to opioids, but none of these factors predict a patient’s response to medications. In addition, physicians have limited tools when it comes to evaluating which patients could benefit from opioids versus nonopioids, which opioids to initiate, and/or which patients are more likely to become addicted to these opioids.
Genetic studies, however, have begun to shine light on some of these questions. This new field of medicine can potentially help physicians choose more effective treatments (similar to targeted cancer therapies), decrease iatrogenic addictions and overdoses by prescreening patients for genetic risks, and possibly even aid in the diagnosis of genetically based pain conditions.
Genetic testing can be used to explore the genes that encode the enzymes that metabolize opioid and nonopioid medications, the transporters, the receptors, and even the more cerebral aspects of perceiving and processing pain. This review covers topics at the forefront of genetics and pain medicine, including drug metabolism, addiction risk, and pain sensitivity testing.
Genetics of Drug Metabolism Leading to Personalized Medicine
Currently, the largest area of research in pain medicine and genetics has been in the field of drug metabolism. Individuals all process and metabolize drugs to differing degrees. While the practical effect of this variation can be as minimal as requiring a slightly larger dose of gabapentin, it can be quite profound when a patient has nontherapeutic levels of anticoagulation because of the way his or her body metabolizes warfarin.
Most opioid medications are metabolized by one or more of the cytochrome P450 (CYP450) isoenzymes.4 A patient’s ability to metabolize medications is largely based on the type and number of copies of alleles (alternative forms of genes) he or she inherits. On the one hand, the inhibition of a drug’s metabolism will result in an increase in the blood level of the parent drug and a decrease in its metabolite(s). On the other hand, induction of a drug’s metabolism results in a decreased blood level of the parent drug and an increase in its metabolite(s). People who are termed extensive metabolizers have 2 normal alleles; intermediate metabolizers have 1 normal and 1 reduced allele; and poor metabolizers have 2 mutant alleles with limited to no activity. Finally, ultrarapid metabolizers can have multiple copies of functioning alleles (Table 1).
A prime example of this in pain medicine is the metabolism of codeine. Codeine is metabolized by hepatic enzymes, specifically the CYP2D6 enzyme. Codeine itself is not analgesic; it becomes effective in treating pain only when it is metabolized into morphine. Some individuals completely lack the alleles needed to produce functioning CYP2D6, and they are considered poor metabolizers. These poor metabolizers may never achieve pain relief since they cannot form the active metabolite morphine. By contrast, individuals with multiple copies of CYP2D6, ultrarapid metabolizers, can have fatally high levels of the drug on standard doses.5 Other opioids that are partially dependent on CYP2D6 for metabolism include hydrocodone, meperidine, methadone, oxycodone, and tramadol.
How common is this polymorphism? Approximately 7% to 10% of Caucasians are CYP2D6 deficient, while approximately 1% of Asians are poor metabolizers—explaining the slower metabolism of antidepressants and neuroleptics observed in Asians compared with Caucasians (rates for African Americans and Hispanics were not provided).6 Although not all opioids depend wholly on a single enzyme for activation, their effectiveness in individuals can vary substantially based on an individual’s genetic makeup. Genetic polymorphisms contribute to the variable metabolism of different enzymes. Other isoenzymes involved in metabolism of opioids include CYP3A4 and CYP2B6. Opioids that do not rely on CYP450 isoenzyme metabolism include morphine, oxymorphone, and tapentadol.
Not only does variability of alleles account for changes in drug metabolism, differences of genetic transcription of enzymes involved in drug metabolism can have an effect on the expression of enzymes. The transcription of a number of different proteins, drug receptors, and transporters can help us accurately tailor medications on a patient-to-patient basis.
One example is the m-opioid receptor gene (OPRM1) that is responsible for encoding the m-opioid receptor. Liu and Wang examined the A118G polymorphism in OPRM1 in cancer patients who developed painful neuropathy following oxaliplatin chemotherapy and were treated with tramadol (Ultracet). They reported that different genotypes (AA, AG, and GG) were directly correlated with opioid requirements for pain relief 24 hours after surgery.7 Patients who had at least 1 G allele (genotypes AG or GG) required much higher doses of tramadol to achieve pain relief postoperatively—pretreatment and posttreatment visual analog scale (VAS) scores were 3.1 and 2.6, respectively—requiring rescue analgesia. However, patients with the AA genotype had a better analgesic effect—pretreatment and posttreatment VAS scores were 3.0 and 0.9, respectively.
Patient who use opioids may be at risk for addiction. Addiction involves loss of control, continuation despite significant negative consequences, and preoccupation with obtaining, using, and recovering from the effects of the drug.Opioids are used for acute and chronic painful conditions, from postoperative surgical pain to cancer pain to musculoskeletal pain. While there is a place for opioids in pain control, patients must be chosen with care. Certain patients will be prone to addiction when exposed to opioids. In such cases, the benefit of pain relief from opioids may be outweighed by the potential for addiction.