Pharmacogenetics in Pain Care: Consideration of Economic Impediments and Ethical Imperatives
In his song, “No One is to Blame,” singer Howard Jones laments that “…insecurity is the thing that won’t get lost”.1 Given the ambiguities of illness and often tenuous technical and economic landscape of medical practice, many patients and physicians are faced with insecurity. A critical step in medicine involves the discernment of what is wrong with a patient: This impression is essential in overcoming insecurity and uncertainty, and determining the type(s), scope, and appropriateness of care.2 Indeed, this discrimination is vital to resolve clinical equipoise, and in this way, assumes technical and moral importance.3,4
Recall the adage that describes medicine as navigating a ship of probabilities on a sea of uncertainty. Pain medicine is notably problematic in this regard, given the subjectivity of pain, and physiological variations in the peripheral and central nociceptive and analgesic neuraxes, which can manifest in psychological and social domains that contribute to unique experiences of some patients’ pain.5
Thus, as Dr. Forest Tennant explains in this issue, genetic variation in many substrates and mechanisms may be linked to phenotypic distinctions in pain and response to analgesic pharmacotherapeutic agents.6 Understanding these mechanisms and patterns of variability could provide insights that reduce uncertainties related to both pain and its pharmacologic care. This individual variation can make prescribing and maintaining safe and effective regimens of opioids and adjunctive analgesics complicated, at the very least—problematic and precarious at worst.
Problems can occur from:
- inaccurate assessment and/or diagnosis of the type and nature of the pain-related pathology
- providing the wrong drug, dose, or schedule
- adverse primary and/or side effects
- drug-drug and drug-food interactions.
This fosters ethical concerns about the availability and translation of research findings to diagnostic and therapeutic aspects of clinical care; physicians’ stewarding (viz-obtaining and using) this knowledge and capability in ways that are in each patient’s best interest; and engaging intellectual stewardship within the contemporary view of pain treatments, given an increasing call for personalized medicine.6
The potential medico-legal ramifications that can occur when physicians are required to justify interpretation of baseline protocols for use of certain pharmacologic and/or technological interventions so as to afford each patient maximum benefit should be considered.7
Genomics, Genetics, and Personalized Medicine: Implications for Pain Care
The Human Genome Project was instrumental to establishing a sustained interest in translating population-wide genomic data into informational resource(s) that could be accessed and applied to develop and enable patient-specific care. This established genomics (the study of the spectrum of genes present in a group or individual relevant to patterns of physiological and/or behavioral functions or conditions) and genetics (study of individual and inter-individual expressions of inheritance) as viable clinical approaches—and set the stage for the formalization and momentum of personalized medicine. The Decade of the Brain Project channeled genomics into clinical genetics of neurology and psychiatry, and these techniques and technologies were engaged in studies of pain and analgesic drug effects during the Decade of Pain Control and Research.
Pain and Pain Disorders
Given the variability of neural mechanisms, subjectivity of pain, and each individual’s pain, it is clear that pain care would strive toward a personalized approach that is executable in biological, psychological, and social domains.8 Although genetics has been viewed as a potentially important resource in pain care, the applicability of genetic analyses may be limited by many factors.9
The first limitation is that genetic patterns do not directly express phenotype(s), and thus, single genes rarely code for single effects (but more commonly produce a multiplicity of phenotypic expressions). Multiple genes are characteristically responsible for a particular (phenotypic) effect.10 This makes direct genotype-to-phenotype predictions difficult, particularly for pain, which involves multi-factorial inheritance, and heterogeneous patho-etiologies and substrates.11
Animal studies have provided significant information about the identification and influence of specific genes that operate in conjunction with environmental variables upon several phenotypic factors that are involved in pain sensitivity and expression.12 However, identifying quantitative trait loci is most effective when specific genetic strains can be identified and controlled (eg, in research animals), and thus may be of limited value and when attempting to evaluate heritability of pain in humans.13
Yet, there is mounting evidence to suggest candidate genes that code for 1) receptors of algogenic substances and ion channels that affect nociceptor sensitivity; 2) opioid, glutamate, and other neurochemical receptors; and 3) synthetic and degrading enzymes for a variety of neurotransmitter and neuromodulatory substances involved in peripheral and central nociception and anti-nociception in humans.14-16
Moreover, genetic influences and predispositions have been implicated in a number of disease states that elicit pain as a key symptom, including migraines and headaches,17 osteoarthritis,18 rheumatological conditions (eg, fibromyalgia),19 complex regional pain syndrome,20 and abdominal21 and menstrual pain syndromes.22 There also appears to be genetic predispositions to psychiatric conditions (eg, depression, anxiety, and certain forms of substance abuse) that co-manifest with chronic pain.23 These findings have strengthened the hypothesis that pain is a multi-faceted.24-26
Still, the extent to which genetic factors establish a basis for pain sensation, perception and behaviors remains to be determined. Certainly, there appears to be patterns of certain types of pain-related disorders and types of pain. However, the expression of physiologic and behavioral phenotypes also largely depends on environmental variables, and thus are likely to be complex (gene-phenotype-environment) interactions, that involve reciprocal effects on a variety of levels.27, 28