PROGRESS IN GENETIC PAIN STUDIES REGARDING ANALGESICS THERAPY-A Systemic Review PART I-GENETIC MODULATION OF PAIN from genotype-phenotype (original) (raw)
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A review of the role of genetic testing in pain medicine
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The pharmacogenomics of pain management: prospects for personalized medicine
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Pain is a common symptom that can be complex to treat. Analgesic medications are the mainstay treatment, but there is wide interindividual variability in analgesic response and adverse effects. Pharmacogenomics is the study of inherited genetic traits that result in these individual responses to drugs. This narrative review will attempt to cover the current understanding of the pharmacogenomics of pain, examining common genes affecting metabolism of analgesic medications, their distribution throughout the body, and end organ effects.
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The experience of chronic pain is one of the commonest reasons for seeking medical attention, being a major issue in clinical practice. While pain is a universal experience, only a small proportion of people who felt pain develop pain syndromes. In addition, painkillers are associated with wide inter-individual variability in the analgesic response. This may be partly explained by the presence of single nucleotide polymorphisms in genes encoding molecular entities involved in pharmacodynamics and pharmacokinetics. However, uptake of this information has been slow due in large part to the lack of robust evidences demonstrating clinical utility. Furthermore, novel therapies, including targeting of epigenetic changes and gene therapy-based approaches are further broadening future options for the treatment of chronic pain. The aim of this article is to review the evidences behind pharmacogenetics (PGx) to individualize therapy (boosting the efficacy and minimizing potential toxicity) an...
European Journal of Pharmacology, 2007
Neuropathic pain conditions can encompass a diverse constellation of signs and symptoms consisting of sensory deficits, allodynia and hyperalgesia. Animal models of neuropathic pain have enabled the identification of key pathophysiological changes occurring within nociceptive pathways as a result of injury, and serve an invaluable role for preclinical screening of novel analgesic candidates. We have produced the first systematic description of the development and maintenance, and the pharmacological sensitivity of nociceptive behaviours in four rat strains with different genetic background (outbred Sprague-Dawley and inbred Brown Norway, Lewis and Fischer 344 rats), using the spared nerve injury model of peripheral neuropathic pain. Hindpaw mechanical hypersensitivity was evident from 7 to 30 days post-injury in all four strains, developing most quickly and severely in Fischer 344 rats; Lewis rats were least affected. Morphine (6 but not 3 mg/kg, s.c.) and gabapentin (100 but not 50 mg/kg, s.c.) had significant antiallodynic and antihyperalgesic actions in all four strains after spared nerve injury, although marked differences in potency across strains were observed. Two strains (Fischer 344 rats and Lewis) were insensitive to the antihyperalgesic properties of gaboxadol (15 mg/kg) whereas gaboxadol (6 mg/kg) was equipotent to morphine (6 mg/kg) in two other strains (Sprague-Dawley and Brown Norway). The observed pharmacogenetic variations have important implications for the preclinical testing of drugs, and provide a basis for development of pharmacogenomics in neuropathic pain.
Genetic contributions to pain: a review of findings in humans
Oral Diseases, 2008
Pain represents the major motivating factor for which individuals seek healthcare, and pain responses are characterized by substantial inter-individual differences. Increasing evidence suggests that genetic factors contribute significantly to individual differences in responses to both clinical and experimental pain. The purpose of this review article was to summarize the current literature regarding genetic contributions to pain, highlighting findings relevant to oral pain where available. A brief discussion of methodologic considerations is followed by a review of findings regarding genetic influences on clinical pain. Next, the literature examining genetic contributions to experimental pain responses is presented, emphasizing genetic associations that have been replicated in multiple cohorts. It is hoped that an enhanced understanding of genetic contributions to pain responses will ultimately improve diagnosis and treatment of clinical pain conditions.
Current Oncology Reports, 2020
Purpose of Review Pain is multifactorial and complex, often with a genetic component. Pharmacogenomics is a relative new field, which allows for the development of a truly unique and personalized therapeutic approach in the treatment of pain. Recent Findings Until recently, drug mechanisms in humans were determined by testing that drug in a population and calculating response averages. However, some patients will inevitably fall outside of those averages, and it is nearly impossible to predict who those outliers might be. Pharmacogenetics considers a patient's unique genetic information and allows for anticipation of that individual's response to medication. Summary Pharmacogenomic testing is steadily making progress in the management of pain by being able to identify individual differences in the perception of pain and susceptibility and sensitivity to drugs based on genetic markers. This has a huge potential to increase efficacy and reduce the incidence of iatrogenic drug dependence and addiction. The streamlining of relevant polymorphisms of genes encoding receptors, transporters, and drug-metabolizing enzymes influencing the pain phenotype can be an important guide to develop safe new strategies and approaches to personalized pain management. Additionally, some challenges still prevail and preclude adoption of pharmacogenomic testing universally. These include lack of knowledge about pharmacogenomic testing, inadequate standardization of the process of data handling, questionable benefits about the clinical and financial aspects of pharmacogenomic testing-guided therapy, discrepancies in clinical evidence supporting these tests, and doubtful reimbursement of the tests by health insurance agencies.
Journal of Pharmacology and Experimental Therapeutics, 2003
The heritability of nociception and antinociception has been well established in the mouse. The pharmacogenetics of morphine analgesia are fairly well characterized, but far less is known about other analgesics. The purpose of this work was to begin the systematic genetic study of non-mu-opioid analgesics. We tested mice of 12 inbred mouse strains for baseline nociceptive sensitivity (49 degrees C tail-withdrawal assay) and subsequent antinociceptive sensitivity to systemic administration of (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate (U50,488; 10-150 mg/kg), a kappa-opioid receptor agonist; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55,212-2; 0.5-480 mg/kg), a synthetic cannabinoid receptor agonist; epibatidine (7.5-150 microg/kg), a nicotinic receptor agonist; clonidine (0.1-5 mg/kg), an alpha(2)-adrenergic receptor agonist; and, for purposes of comparison, the prototypic mu-opioid receptor agonist, morphine (5-200 mg/kg). Robust interstrain variability was observed in nociceptive sensitivity and in the antinociceptive effects of each of the drugs, with extreme-responding strains exhibiting antinociceptive potencies differing up to 37-fold. Unexpectedly, we observed moderate-to-high genetic correlations of strain sensitivities to the five drugs (r = 0.39-0.77). We also found moderate-to-high correlations between baseline nociceptive sensitivity and subsequent analgesic response to each drug (r = 0.33-0.68). The generalizability of these findings was established in follow-up experiments investigating morphine and clonidine inhibition of formalin test nociception. Despite the fact that each drug activates a unique receptor, our results suggest that the potency of each drug is affected by a common set of genes. However, the genes in question may affect antinociception indirectly, via a primary action on baseline nociceptive sensitivity.