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Personalized Medicine for Patients with Chronic Pain

Faculty Perspectives in Chronic Pain:Utilizing Pharmacogenomics When Selecting Personalized Medicine for Patients with Chronic Pain
Ofer M. Wellisch, MD, MPH

The new millennium has brought about the promise of genomics for the understanding of disease and the advancement of therapeutic approaches.1 The scientific community has continued to establish the genetic basis of phenotypic variability among individuals and ethnic groups in terms of susceptibility to disease as well as response to therapy.2 As pointed out in the main article in this publication, the pharmacogenetic basis to interpatient variability in drug response and toxicity may be broadly classified into factors affecting drug pharmacokinetics and factors affecting pharmacodynamics.3 The relationship between drug dose and steady-state serum drug concentration is indeed subject to variability in drug metabolism, elimination, and/or transport. Therefore, interindividual variability in drug response is governed, at least partially, by a genetic blueprint and mainly involves genes encoding cytochrome P450 (CYP) enzymes, glucuronidation, and drug transporter proteins.4 Pharmacodynamic factors are known to affect various aspects of the nervous system, including ion channels, target receptors, and signal transduction pathways.4

The International Association for the Study of Pain has defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”5 The sensory and emotional components of pain are derived from peripheral and central components of the nervous system, respectively. Nociception, signal transduction, and perception of pain are complex processes that rely on many factors in the way of small molecules, proteins, and neural networks.6 Therefore, many variations in gene products along these complex pathways stand to affect the pain experience and treatment thereof. In the general population, the specific genetic variations along these pathways often “balance out” and result in only minor phenotypic changes. Frequently, the clinically relevant variations are observed in adverse effect profiles of certain drug classes.7-9 Notably, rare mutations, such as those resulting in aberrant ion channel function (ie, Nav1.9), lead to substantive abnormalities in nociception and pain perception.10

The CYP family of enzymes represents perhaps the most important class of drug-metabolizing enzymes for analgesics.11 As noted in the main article, genetic alterations have been described in several CYP enzymes; predominant among these are those involving CYP2D6 and CYP3A4 enymes. These genetic variations result in 4 phenotypes that have been identified in humans: extensive metabolizers, poor metabolizers, intermediate metabolizers (IMs), and ultrarapid metabolizers (UMs).12 The most clinically relevant data are on PMs that demonstrate low plasma concentration of an active metabolite of a popular mu-opioid agonist prodrug, which directly correlates with suboptimal analgesic effect in these individuals.13 Conversely, in UMs, the analgesic effect of the same opioid was more pronounced, with a higher incidence of side effects.12 Perhaps most troubling are data demonstrating an increased risk for overdose in breast-fed neonates of mothers using the mu-agonist prodrug and carrying the UM phenotype.14 Children of these mothers likely received much greater concentrations of active metabolite in the breast milk, conferring an increased risk for potentially life-threatening central nervous system depression. Nevertheless, other analgesics were not found to be significantly modulated by genetic alterations in CYP2D6 activity.15 Therefore, there is insufficient evidence as to the clinical relevance of CYP2D6 when it comes to opioids as a drug family, beyond the aforementioned data on the mu-opioid prodrug.

Notably, tricyclic antidepressants (TCAs) commonly used in pain management are primarily metabolized through CYP2D6. Antagonists of CYP2D6, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors, often used in patients with chronic pain and comorbid depression, may result in TCA toxicity and serotonin syndrome when used concomitantly with a TCA. Although drug–drug interactions are always of concern, providers must be ultravigilant in treating PMs, in whom TCA serum concentrations are generally higher at baseline.16-18

Genetic variants in the CYP2C family of CYP enzymes have also been shown to have clinical relevance in the metabolism and clearance of nonsteroidal anti-inflammatory drugs (NSAIDs). Importantly, variations in the CYP2C family have been shown to modulate risk for developing acute gastrointestinal bleeding with the use of NSAIDs that are substrates of CYP2C8/9 enzymes.8,9

CYP3A4 is known to play an important role in the metabolism of some opioids, including a long-acting opioid developed in Germany in the late 1930s. Still, evidence is lacking as to the clinical significance of CYP3A4 genetic variations in the modulation of opioid metabolism or activity.2 It should be noted that the aforementioned long-acting opioid carries the highest risk for overdose among all opioids, and this phenomenon is at least partially owed to CYP3A4 metabolism and modulation thereof. PMs are certainly at increased risk for overdose, through decreased tolerance of higher or escalating dosing regimens and drug–drug interactions affecting CYP3A4.19 Several commonly used drugs such as macrolide antibiotics, benzodiazepines, SSRIs, and antifungals serve as strong antagonists to CYP3A4 metabolic activity and may further increase overdose risk in PMs.20

Regarding susceptibility to adverse reactions, genetic variations in the transported P-glycoprotein were found to be strong determinants of less pronounced adverse drug reactions and increased analgesic effect. As noted in the main article, in individuals receiving spinal analgesia with a specific opioid, presence of the C3435T allele was associated with increased suppression of respiratory rate and need for oxygen; these findings were corroborated with experimental evidence demonstrating the same.21

Genetic research has also focused on the µ-opioid receptor, as it is thought to be the primary target of opioid analgesics currently on the market. The opioid receptor mu 1 gene, which encodes this receptor, is subject to 1 prominent polymorphism (A118G), which occurs with an allelic frequency of about 8% to 17% in Caucasians and nearly 50% in Asians.6 It is thought that this is at least partially responsible for opioid sensitivity in the Asian population, as well as susceptibility to alcohol addiction.22,23 However, data have been conflicted as to the modulatory effect of this polymorphism in the clinic.23-25 As noted, a meta-analysis found no consistent association between the A118G polymorphism and opioid dose requirement, and only a weak association for lower incidence of nausea.26

The author of the main article also states that catechol-O-methyltransferase is a key enzyme involved in the inactivation of catecholamine neurotransmitters, including dopamine, norepinephrine, and epinephrine, and also an important modulator of opioid efficacy. However, as noted, results from a large genetic association study did not find any significant association with opioid dosing.27

In summary, despite promising initial data on genetic variability in key candidate genes, evidence is lacking as to the utility of a pharmacogenomics-based approach to personalized medicine for patients with chronic pain. Nevertheless, providers should consider obtaining genetic data when caring for individuals demonstrating unresponsiveness or profound sensitivity to agents commonly used in the clinic. The medical field is certainly in need of continued research in pharmaco­genomics, including large, well-designed prospective studies focused on pain pathways.

References

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Last modified: February 4, 2016
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