Abstract: | Summary
While it is well established that the principal ascending pathways for pain originate in the dorsal horn of the spinal cord and in the medulla, the control and sensitivity to pain may reside in additional neurological loci, especially in the mesolimbic system of the brain (i.e., a reward center), and a number of genes and associated polymorphisms may indeed impact pain tolerance and or sensitivity. It is hypothesized that these polymorphisms associate with a predisposition to intolerance or tolerance to pain. It is further hypothesized that identification of certain gene polymorphisms provides a unique therapeutic target to assist in the treatment of pain. It is hereby proposed that pharmacogenetic testing of certain candidate genes (i.e., mu receptors, PENK etc.) will result in pharmacogenomic solutions personalized to the individual patient, with potential improvement in clinical outcomes.
Background
It is well known that individuals respond differently to medications and certain nutraceuticals, in terms of both toxicity and treatment efficacy [1]. Potential causes for such variability in drug (nutrient) effects include the pathogenesis and severity of the disease being treated: drug (nutrient) interactions; the individual’s age; nutritional status; kidney and liver function; and concomitant illnesses. Despite the potential importance of these clinical variables in determining drug/nutrient effects, it is now recognized that inherited differences in the metabolism and disposition of drugs/nutrients, and genetic variants (polymorphisms) in the targets of drug/nutrient therapy (such as receptors like the dopamine D2 receptor), can have even greater influence on the efficacy and toxicity of medications and of nutraceuticals [2] B. Meshkin, T.J.H. Chen, A.L.C. Chen, T.J.H. Prihoda, H. Morrisette and E.R. Braverman et al., Health economics of nutrigenomics in weight management, Gene Ther Mol Biol 12 (2008), pp. 25–30. View Record in Scopus | Cited By in Scopus (3)[2].
Clinical observations of such inherited differences in drug effects were first documented in the 1950s, exemplified by the prolonged muscle relaxation after the drug became known as suxamethonium (an inhibitor of the breakdown of acetylcholine) and by an inherited deficiency in the genes that encode the enzyme responsible for the breakdown of this drug as marked by plasma cholinesterase (the enzyme which breaks down acetylcholine) [3]. The second gene-based drug response was observed when researchers found that certain patients bled to death after they were treated with an anti-malarial therapy, because they carried a gene variant that lowered their blood cell glucose 6-phosphate dehydrogenase activity [4]. Such observations gave rise to the field of ‘pharmacogenetics’, the antecedent to pharmacogenomics, the current topic. However, we now know that individual differences in response to drugs and/or nutrients are not due to single gene variants; rather, they are determined by the interplay of several genes encoding proteins (enzymes, receptors, and transporters) involved in multiple pathways of drug/nutrient metabolism, disposition, and effects [5]. We are embarking on new era where efficacy of any substance is governed by an individual’s inherited genotype to a greater degree than even other non-genetic factors. Understanding structure/function normal physiology, as well as certain observable dysfunctions, may indeed lead to promising nutrient-based targets. However, without the knowledge afforded by accurate DNA-based prescreening (genotyping), subsequent supplementation may be hit-or-miss. Similar to the pharmaceutical industry, the nutraceutical industry can become an equal opportunity player, and begin to initiate ongoing research and development by incorporating these genome-based doctrines as described herein.
Out of the three million unshared DNA bases, individuals could carry gene variants (polymorphisms) that might lead to either an increase or a decrease of certain important drug/nutrient response-related proteins such as receptors, enzymes, cell cycle control, chemical messenger synthesis or catabolism (breakdown), or many other cellular events. As stated earlier, while there is a paucity of molecular studies involving genome-based response in the nutrition field (see below), a plethora of molecular studies have revealed that many genes encoding drug targets exhibit genetic polymorphisms, which in many cases alter their sensitivity to specific medications and/or offer specific targeted therapy.
Pharmacogenetics is the study of the role of genetics in inter-individual variability to drug response and therapy. In this regard, we found more than 200 PubMed reports concerning pharmacogenetic studies for opioid drugs. Opioid analgesics are widely used clinically for pain management, and inter-patient variability with opioid therapy is often reported [6]. Information on genetic polymorphisms in enzymes, receptors, and transporters related to opioid disposition (pharmacokinetics) and pharmacology (pharmacodynamics) is documented [7]. Pharmacogenetics of enzymes, including the cytochrome P450s and uridine diphosphoglucuronosyltransferases, opioid receptors and the ABC family of transporters, are a few examples. |