Elsevier

Metabolism

Volume 59, Supplement 1, October 2010, Pages S5-S8
Metabolism

Genetics of pain, opioids, and opioid responsiveness

https://doi.org/10.1016/j.metabol.2010.07.015Get rights and content

Abstract

Pain is an integral part of the defense mechanisms required for survival. Several hereditary syndromes of complete or almost complete insensitivity to pain have been identified and include channelopathy-associated pain insensitivity, of which the most likely candidate gene is the α-subunit of the voltage-gated sodium channel known as Na(v)1.7. Five hereditary sensory and autonomic neuropathy syndromes have been described. Variable pain sensitivity in the general population has been linked to common variants of the μ-opioid receptor and of the catecholamine-O-methyltransferase genes potentially leading to increased opioid tonus. Variants of the guanosine triphosphate cyclohydrolase 1/dopa-responsive dystonia gene appear to regulate nociception. Other candidate genes are the transient receptor potential cation channel, subfamily 5 member 1, gene and the melanocortin-1 receptor gene. Candidate genes for predicting opioid efficacy are drug-metabolizing enzymes and transporters—including cytochrome P450, uridine 5′-diphosphate-glucuronosyltransferases, and adenosine triphosphate–binding cassette transporters—that are involved in opioid metabolism. Most current knowledge on the genetic regulation of pain has been derived from animal models developed mainly in mice. Genomics has the potential to contribute to therapeutic advances with the promising approach of using small interfering RNA in the control of neuropathic pain. Knowledge of the genetic factors that affect opioid efficacy, metabolism, and adverse effects has the potential for personalizing both acute and chronic pain management, and for designing more useful opiate pain medications with lower adverse event profiles.

Introduction

The ability to sense pain (nociception) is variable in human populations as well as in animals; its heritability, genetic correlations, and linkage point to the importance of its genetic determinants [1]. Pain perception is a defense mechanism that alerts us to injury-producing events. The severity of pain is controlled by several genetic variants affecting the expression or function of nociceptive sensory system components. Migraine is among the first of painful diseases to be associated with a genetic component, and several of its variants have been identified [2], [3]. Pain is a common symptom of cancer and its treatment, and several genetic polymorphisms have been discovered to be associated with both cancer risk and cancer-induced pain [4]. Other pain syndromes are also under genetic control. Our understanding of the neurobiology of pain pathways has grown in the last decade, and several membrane receptors and channels that respond to pain-provoking stimuli have been found and characterized. This review will focus on the genetics of sensitivity to pain and opioid responses as well as its importance in the development of better pain therapies.

Section snippets

Rare hereditary syndromes of complete insensitivity to pain

The complete inability to sense pain is a very rare phenotype. Several hereditary syndromes that involve complete or almost complete insensitivity to pain have been discovered and are listed in the Online Mendelian Inheritance in Man database. They include channelopathy-associated insensitivity to pain syndrome, of which the most likely candidate gene is the α-subunit of the voltage-gated sodium channel Na(v)1.7, encoded by the gene SCN9A at locus 2q24.3. The gene is preferentially expressed in

The genetics of variable pain sensitivity in the general population

Abnormal responses to tissue injury are common in 1 of 6 adults suffering from a chronic pain condition [7]. Several genetic variants have been shown to modulate the generation, transmission, and processing of nociceptive information or the local availability of active analgesics and their pharmacodynamic effects. Each of them, however, has only a modest impact on the pain phenotype. Variable pain sensitivity in the general population has been associated with common variants of the μ-opioid

Pharmacogenomics of pain therapy

Genetic polymorphisms have been shown to contribute in part to interindividual variability in pain therapy. Opioids and other analgesic drugs are widely used to control moderate to severe pain. However, interindividual sensitivity and their severe adverse effects, such as dependence, tolerance, and respiratory depression, often hamper effective pain management. The MOP receptor is a preferred target of morphine, playing a crucial role in mediating the major clinical outcomes of morphine,

Studies in animal models

Most current knowledge on the genetic regulation of pain has been derived from monogenetic addition and subtraction models developed mainly in mice. The genetic control of pain has also been demonstrated in polygenic mouse models by quantitative sensory trait approaches [13]; and it has been noted that nociceptive responses behave as a continuous trait in 11 different inbred mouse strains, underlying its polygenic character. A behavioral quantitative trait locus-mapping strategy has recently

Personalized medicine in pain management

Knowledge of the genetic factors that affect opioid efficacy, metabolism, and adverse effects has the potential for personalizing both acute and chronic pain management, and for designing more useful opiate pain medications with lower adverse event profiles. For instance, it has long been recognized that genetic factors (specifically CYP2D6 whose absence makes codeine almost completely inefficient) predict individual responses to codeine administration [19], [20] or postoperative morphine

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    Publication of this article was supported by the Collège International de Recherche Servier (CIRS).

    STATEMENT OF CONFLICT OF INTEREST: The authors have nothing to disclose.

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