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8 Articles in Volume 11, Issue #2
Preventive Therapies for Cluster Headaches
The Pain of Multiple Sclerosis: Is it Real and Is it Treatable?
Antidepressants in the Treatment of Chronic Pain
Genetic Screening for Defects in Opioid Metabolism: Historical Characteristics and Blood Levels
Post-operative Patient-controlled Analgesia in Pediatric Patients
Pharmacogenetics in Pain Care: Consideration of Economic Impediments and Ethical Imperatives
Are Opioids More Harmful Than NSAIDs for Elderly Patients?
How Genetics Can Complicate Pain Treatment

Pharmacogenetics in Pain Care: Consideration of Economic Impediments and Ethical Imperatives

“You can look at the menu, but you just can’t eat
You can feel the cushion, but you can’t have a seat
You can dip your foot in the pool, but you can't have a swim…”
—Howard Jones, “No One is to Blame”

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

Pharmacogenomics and Pharmacogenetics

Although information about the genetic basis of pain may be important to a conceptual understanding of patterns of variability and individual differences in pain experience and expression, genetic loci are not yet used as predictive indicators of clinical pain syndromes. Also, they cannot be directly targeted for the prevention and/or treatment of pain. Thus, I agree with Dr. Tennant that pharmacogenomic and pharmacogenetics—the identification of genomic and genetic variation in substrates and mechanisms involved in the pharmacokinetics and dynamics of analgesic drugs—may be more viable and valuable approaches in clinical pain care.

In humans, the cytochrome P-450 (CYP450) isoenzyme system consists of 21 currently described families and 20 subfamilies (that are coded by 57 genes). CYP450 isoforms 1, 2, and 3 are responsible for the majority of hepatic drug metabolism.29-31 Of these, CYP450 2C9 and 2D6 are involved in the biotransformation of several (non-opioid and opioid) agents used for pain control, and these isoforms have polymorphisms that show inter-individual difference that appears to subserve—at least to some extent—variations in patients’ response to these drugs, and the potential for drug-interaction effects.32

CYP2D6 polymorphisms affect the metabolism—and hence effectiveness and doses required—of opioids (eg, codeine), tramadol, N-Methyl-D-aspartic acid antagonists, and certain anti-depressants.33 The CYP3A subfamily is also responsible for the metabolic biotransformation of opioids (eg, buprenorphine, methadone, and fentanyl) and is susceptible to induction by the psychotropic drugs paroxetine and olanzapine. This could thereby incur overdose when such agents are combined with the aforementioned opioids.34

However, as Dr. Tennant notes, while these polymorphic variations can determine patients’ responses to particular analgesic drugs, assessing these genetic and/or phenotypic characteristics is not routine in clinical practice. This is primarily due to the cost of genotyping CYP450, which while not high, is not currently standard procedure. This is despite the potential of such methods to 1) reduce or prevent trial-and-error empiricism, 2) improve the time and cost efficiency of treatment, 3) reduce the risk of adverse effects, and most importantly 4) enhance the benefit of patient care.

Dr. Tennant’s approach—the development of a set of simple clinical questions to provide relatively reliable indications of possible pharmacokinetic and pharmacodynamic variations—is noteworthy in its attempt to compensate for economic constraints upon the use of diagnostic and therapeutic technologies and maintain clinical acumen in pain care.

Dr. Tennant’s efforts have highlighted two important issues: often the financial expense of specific treatments make their use unrealistic; second these financial pressures require that new affordable techniques be developed.

Ethical Issues

While genetics of pain could be very useful, there is considerable discussion as to the actual (predictive and clinical) value and utility of currently described genetic variables in pain syndromes. Moreover, predicting diatheses for pain can be wrought with difficulties and improprieties, including the potential for implicit, inadvertent, or in some cases purposive stigmatization, bias, and exclusion from employment, healthcare coverage, and treatment.

The incipience, and potential, of descriptive and predictive genetics prompts questions of if and how genetics can inform, support, and advance the biomedical accuracy, ethico-legal articulation of pain care. Dr. Tennant rightly views pharmacogenomics and pharmacogenetics as possible techniques and tools that can be employed toward these ends. Pharmacogenetic information could streamline opioid analgesic regimens, substantiate the need for and use of higher drug doses, and in this way validate physicians’ clinical judgment, and avoid possible medico-legal sanctions. In other words, such information could contribute to prudence in practice, and in this way, assume both intellectual and moral value by providing knowledge needed to intuit the nuances of personalized pain medicine. To paraphrase Aquinas’ interpretation of Aristotle’s construct of practical wisdom—it is the right knowledge, used in the right ways, to afford right actions for the right reasons.

Justice and Medical Economics

But, what is to be done when financial pressures hinder optimal clinical care? Dr. Tennant relates how economic and administrative factors impart considerable difficulty to using pharmacogenetic approaches to predict patterns of patient responses to analgesic drugs. This exposes the underlying ethical issue of just allocation of clinical resources and services (ie, “goods”). So, while ethics is characteristically concerned about discerning what “should be done” from the available options of what “can be done,” it is equally important to consider how various factors impact what actually “can be done” (given the restrictions upon the use and availability of resources, such as primary pharmacogenetic evaluation) from what we recognize should be done.

This illustrates the tension, if not conflict, that arises between commutative justice (ie, the differential provision of goods and resources based on the differing needs of patients) and distributive justice (ie, the systematized allocation of restricted goods and resources to patients). The economics of medicine seek to negotiate a balance of conceptually commutative construct of profession, and an unsentimental distribution of resources within the social, financial, and legal environment in which practice is enacted.

It would be naïve to maintain that such economics actually consist of the unlimited resources and rational actors described 2 centuries ago by Adam Smith. Indeed, Alejandro Canadas and I have recently argued that the precepts of neo-classical, Smithian economics are unrealistic, and miscognizant of biopsychosocial frameworks inherent to the human condition and its enterprises–inclusive of medicine.35 We have posited that the appropriation of resources and services should 1) reflect the conditions, agents, circumstances, and responsibilities, and 2) maximize the relative good (and defined “ends”) of the enterprise in which they are used.

The pain management field needs to be committed to providing the best care possible for patients in pain. This establishes a cooperative framework of pain medicine as an “estate” in which its multiple enterprises (ie, research, education, clinical practice, administration, and economics) are all oriented toward and participative in enabling practitioners to provide patients (as the defined subjects of therapeutic and moral regard and responsibility) the best care with the least side effects.36

Pharmacogenetic evaluation could be useful in pragmatic, ethical, and legal contexts. The use of these techniques could decrease over and under-use of particular therapeutic interventions, prevent prescription errors, and (medico-legally) validate the selection and dosing of opioids (and other analgesics). By doing so, pharmacogenetics would improve the overall quality of pain care, and fortify pain care—and, thus pain practitioners and patients—against economic constraint and legal castigation.

As Roland Benedikter, Mark Boswell, and I have claimed, pain medicine currently stands poised at the threshold of capabilities conferred by the Human Genome Project, Decade of the Brain, and Decade of Pain Control and Research that may cumulatively afford “…technological means of accurately diagnosing and treating pain in ways that are practical, sound, and ethically good for all pain patients.”37 This may represent an evolutionary step toward the deeper appreciation for, and implementation of, personalized care.

Maximizing the benefit of care to each patient while at the same time providing good care to many patients is a tall order. But if we are to make claims about the sophistication and benefits of personalized pain care, it will be critical to pay equal attention to, and uphold the technical, economic, ethical, and legal challenges posed. To confront these challenges, we have proposed a basic paradigm that involves “…evaluation and potential utility and uses for new technologies in more personalized therapeutic settings and regimes, and the development of healthcare coverage that enables the use of high technology as necessary and appropriate.”37 To date, however, such an insurance infrastructure has not been embraced or configured. To quote Jones’ lyrics, “…you can look at the menu, but you just can’t eat.”1 It is commendable that Dr. Tennant has developed methods that might compensate for inequities that keep such potentially beneficially technology from the palette of practical use. It’s just a shame that he’s had to do so.

Last updated on: March 7, 2011
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