Genetic Influences on Pain Perception and Treatment

On a daily basis, pain practitioners encounter a curious clinical phenomenon. Patents with seemingly the same painful condition may report a wide difference in pain severity. Their response to equal treatment may also vary widely. This frustrating situation is now being at least partially explained by new genetic research. Presented here are some clinical pain problems and their relationship to genetic makeup that helps to explain the wide variations in pain perception and treatment response.

Background

The completion of the human genome project in 2003 has provided a better understanding of why patients may experience pain syndromes. A genome is defined as all the deoxyribonucleic acid (DNA) in an organism, including its genes. DNA is defined as a molecule that carries all of our genetic information in all cell types except the red blood cell. DNA is like an instruction manual; it tells the body how to put something together. Genes located in the DNA carry information for making all the proteins required by each organism; genes are the words in the instruction manual. This information is encoded by four chemical nucleotides: adenosine, cytosine, guanine, and thymine (A, C, G, and T), which are the letters in the words of the instruction manual. The sequence of these letters determines which proteins (i.e., enzymes) are made. The proteins—the “building blocks” of an organism—determine, among other things, how the organism looks, metabolizes food, or fights infection, and sometimes even how it behaves. Knowledge about the effects of DNA variations among individuals can lead to revolutionary new ways to diagnose, treat and, hopefully someday, prevent the disorders that plague mankind.

Pain Is Genetically Influenced

Substantial evidence from preclinical models suggests that basal nociceptive sensitivity—neural processes of encoding and noxious stimuli—as well as antinociceptive responses to drugs show significant heritability. Evidence of genetic influences on pain sensitivity in humans has yet to be clinically applied. Polymorphisms—the normal differences in DNA sequences among individuals in a population—of receptors, transporters, metabolizing enzymes, and targets of pharmacotherapy are under investigation. To refer to the instruction manual analogy, polymorphisms are viewed as the different languages in which the instruction manual is written. It has the same information, but in a different form. Identifying a genetic predisposition to pain will allow pain to be treated with a genetic mindset and individualize treatment to each patient’s pain situation. It is estimated that about 10% of the general population experiences chronic pain at any given time.¹ This paper explores the genetic influences on specific human musculoskeletal pain perception.

From a Darwinian perspective, nociceptive pain is impossible to eliminate nor is it desirable to do so. Nociception is essential for survival and, if a variation in a pain mechanism gene alters the function of a nociception-related molecule, the survival rate would be diminished. For instance, without pain mechanisms, people would not recognize the danger of leaving their hand on a hot stove. Mutations leading to decreased pain sensitivity occur in well under 1% of the population and lead to frequent injuries and inadvertent self-mutilation, which are incompatible with longevity or transmission to offspring.² The limited number of individuals who have this mutation makes it difficult to produce a strong study, as that would require a large number of participants. While it is necessary to perceive pain from a survival standpoint, we must strive to manage pain pathways when they go awry and fire in the absence of noxious stimuli.

The Quantitative Trail Locus Concept

Men and women experience pain differently. Quantitative trait locus (QTL) refers to the inheritance of an observable trait—a phenotype—that varies in degree and is attributable to the interactions between two or more genes and their environment. When looking at a pillow, it is the pillowcase covering the pillow that is seen, not the pillow itself. However, you can deduce the size and shape of the pillow based on the pillow case you can see. It is the same with QTLs. Although not genes themselves, QTLs are stretches of DNA that are closely linked to the genes that underlie the trait in question. The identification of QTLs can help map regions of the genome that contain genes involved in specifying a trait. There have been two findings of gender-specific QTLs. The first concerns how the body processes painful stimuli. The second is a female-specific QTL for non-opioid stress-induced analgesia. This demonstrates the gender/genotype interactions of relevance to the process of pain perception. The gender-specific QTLs on autosomes—non-sex chromosomes—do not imply that each gender possesses or expresses different genes, but rather that the different genes are associated with trait variability in each gender. The existence of gender-specific QTLs does, however, imply that males and females possess at least partially independent physiological mechanisms underlying the traits in question.³

Disease-Specific Genetic Variants

In addition to gender specific QTL’s, there are also disease susceptibility variants that exhibit parental-origin-specific effects. For instance, a person’s risk of developing type II diabetes increases by 30 percent if genetic material is inherited form the father but decreases by 10 percent if inherited from the mother.⁴ Sequence variants that can provide risk and protection depending on parental origin may promote diversity and balanced selection. Even when associated with parental-origin-specific variants of established traits, it is underestimated. As this author speculates, this may be influenced by the fact the sequenced human genome is a compilation from different people—including male and female—or by the fact that it has missing sections. In an effort for anonymity in the sequenced genome, we may have blindfolded ourselves to useful information.

A single-nucleotide polymorphism (SNP) is a variation in the DNA sequence when a single nucleotide in the genome differs between members of a species or between paired chromosomes in an single individual. For example, two DNA fragment sequences from different individuals, AACA to AATA, contain a difference in a single nucleotide. In this case, we say that there are two alleles: C and T. A study on the AII8G SNP of the mu-opioid receptor gene (OPRME) was also linked to gender differences in the perception of pain. Genotyping of OPRMI showed that the rare AII8G allele had significantly higher indices of pressure-pain threshold that those with two alleles—homozygous—for the common allele. This allele occurred in 25 percent of females and 17 percent of men studied. The conclusion was that this genotype may be associated with pain perception in a sex-dependent manner and this rare allele is associated with higher indices of pressure-pain thresholds.¹

Pain Conditions Influenced by Genetic Factors

So far, data from certain studies indicate genetic influence in certain pain conditions (summarized in Table 1). These conditions include catecholamine-induced musculoskeletal pain, chronic fatigue/fibromyalgia syndrome, and low back pain. The following sections will discuss each of these conditions with respect to genetic factors that may be involved.

Catecholamine Musculoskeletal Pain

Catecholamine-sympathomimetic hor-mones—mainly epinephrine, norepinephrine, and dopamine—are released from the adrenal gland in response to stress, including that of severe pain. A sustained elevation in catecholamines is also associated with chronic musculoskeletal pain conditions. In fact, pain caused by an injury in one part of the body can cause musculoskeletal pain in another via the catecholamine system. Pain is mediated through both supraspinally-organized descending pathways and spinal mechanisms. Abnormalities in catecholamine physiology are associated with diminished activity of catechol-O-methyltransferase (COMT), an enzyme that acts centrally and peripherally to metabolize catecholamines. Studies have shown that elevated catecholamine levels promote persistent pain states.⁵ COMT inhibition showed increased pain sensitivity to hyperalgesia (increased sensitivity to pain) and allodynia (non-painful stimuli that causes pain).

The COMT gene is on the long arm of chromosome 22 at 22q11.2 and spans 27kb. The COMT gene codes for the COMT protein. The DNA that codes for COMT has two different promoters—regions of DNA that facilitate the interpretation of a particular gene. Each promoter produces a distinct transcript: 1.5kb and 1.3kb. The 1.3kb interpretation or transcript codes for a soluble form of the enzyme, S-COMT, whereas the 1.5kb transcript may code for both S-COMT and a membrane bound (MB-COMT) form. Both transcripts are expressed in the liver, kidney, and adrenal gland. However, the 1.5kb transcript is found in the brain, particularly in the prefrontal cortex. Alcohol is known to enhance the effect of neurotransmitters in the prefrontal cortex. One can hypothesize that consuming large amounts of alcohol is a coping mechanism for people experiencing chronic pain, allowing them to “self-medicate” to control their pain.

COMT contains a common functional coding polymorphism, known as COMT Va1158Met (G472A), which substitutes the amino acid valine for methionine at amino acid position 158. An amino acid substitution is the naturally occurring or experimentally-induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. In this case, the substitution makes a person three to four times more sensitive to pain. Individuals with homozygous Mer158 genotype, a mutation, reported greater sensory and affective ratings of pain. In this mutation, opioid receptor suppression is unregulated.⁶ This again demonstrates that a decrease in COMT leads to greater pain perception. It has also been found that COMT has three haplotypes—combinations of alleles at multiple loci that are transmitted together on the same chromosome. The three genetic haplotypes associated with pain sensitivity are low pain sensitivity (LPS), average pain sensitivity (APS), and high pain sensitivity (HPS).³ These haplotypes account for 121% of variability in pain perception.⁷

COMT inhibition increases pain behavior via p2 and p3 adrenergic receptors (ß2AR and ß3AR). ß2AR are located on vascular, uterine, and airway smooth muscle. ß2AR is also found in monomuclear leukocytes in the periphery and neurons and glial cells in the cerebellar and thalamic areas in the central nervous system. Moderate expression is found in adipocytes and spinal dorsal horn neurons. ß2AR promotes the release IL-6, TNF-α, and IL-1ß, all of which are fundamental in the production of inflammation and pain.

ß3AR is expressed in brown and white adipose tissue. It regulates norepinephrine-induced changes in energy metabolism and thermogenesis. Like ß2AR, ß3AR stimulates IL-6 transcription thus promoting inflammation but, unlike ß2AR, it does not undergo desensitization. The effects on ß2AR and ß3AR will attenuate pain by reducing the activity of catecholamines that engage peripheral and/or central processes to promote mechanical allodynia and thermal hyperalgesia. Elevated levels of norepinephrine and epinephrine, resulting from depressed COMT, activate ß2 and ß3 agonists to produce heighted pain sensitivity and inflammation.⁵ It can be hypothesized that overweight individuals are more susceptible to experiencing pain since they have an increase in adipocytes and therefore ß2AR and ß3AR.

“A serotonin transporter gene that affects the transcription efficiency of 5-HTT was found to have longer allelic variants in those with chronic fatigue syndrome compared to controls—both by genotype and allele analysis.¹”

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS), with or without fibromyalgia, is classified as a pain disorder affecting one million Americans. It is defined as a debilitating disorder demonstrated by persistent fatigue unrelated to exercise and not substantially relieved by rest and is accompanied by other nonparticular specific symptoms for a minimum of six months. Symptoms include muscle weakness, muscle and joint pain, cognitive difficulties, and chronic mental and physical exhaustion in a previously healthy and active person. The treatment of choice is graded physical exercise. Two genes of interest in the study of CFS are the neuronal tryptophan hydroxylase (TH2) gene and the 5-hydroxtryptamine-transporter (HTT) gene. TH2 is involved in tryptophan breakdown and serotonin production. HTT is involved in transporting serotonin metabolites out of the cell. A serotonin transporter gene that affects the transcription efficiency of 5-HTT was found to have longer allelic variants in those with chronic fatigue syndrome compared to controls—both by genotype and allele analysis.¹ This study suggested that attenuated concentration of extracellular serotonin due to longer variants might increase the susceptibility for CFS.

The 2003 Narita study⁸ found increased rates of mutation in the serotonin transporter gene that results in increased serotonin uptake. By reducing serotonin levels in the synapses of the nerves, this mutation could also lead to reduced serotonin activity in CFS. This reduction in serotonin receptor activity could cause disturbances in sleep, pain, motivation, anxiety, depression, and sexual activity. Low serotonin levels contribute to decreased gastric emptying in CFS. Serotonin also affects the distribution of body fat and is being investigated for its link to the increased waist/height ratio found in CFS. This further supports the hypothesis that there is a direct correlation between the number of adipocytes and the amount of perceived pain.

Low Back Pain

Low back pain (LBP) is second only to the common cold as a problem that brings a patient to their primary care provider. LBP is the number one cause of disability in the industrialized world.⁹ Back pain has a substantial impact on lifestyle and quality of life. A 2006 U.S. survey found that 72 percent of those who sought treatment for back pain gave up on exercising or sports-related activities. Sixty percent said they were unable to perform some daily activities, and 46 percent said they had given up sex because of their back condition.¹⁰ LBP is a complex entity of pathophysiological, mechanical, psychological, and social factors. Epidemiological evidence suggests the following risk factors for LBP: disc degeneration, physical and psycho-social stress, increased weight, and smoking. Several studies have demonstrated familial predisposition for LBP.⁹

Several recent findings suggest a possible contribution of the IL-1 gene polymorphisms to low back pain. In chronic back pain, a SNP of the endogenous IL-1 receptor antagonist (IL-1Ra) from G to A at nucleotide position 1812 is associated with the occurrence of pain, the number of days with pain, and the number of days with limitation of daily activities. A SNP of IL-1-beta (IL-1ß) at nucleotide 3954 from C to T is associated with the number of days with pain. Furthermore, a C to T substitution at nucleotide 889 has been linked to pain intensity.

IL-1ß has a number of pro-inflammatory properties relevant to the pathogenesis of LBP. IL-1ß causes pain directly or through increasing sensitivity to other pain producing substances, such as bradykinin-a neuropeptide linked to pain mechanisms. The study by Kang et al11 showed pro-inflammatory exaggerated release of nitric oxide, IL-6, and prostaglandin ß2, which promotes inflammation from herniated discs upon stimulation with IL-1ß.⁹ It has been recently shown that peripheral inflammation causes an induction of cyclooxygenase-2 (cox-2), leading to the release of prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity. IL-1ß is observed to be a major inducer of central cox-2 upregulation by neurons in the brain and spinal cord as well as synthesis of prostaglandin E2 within the brain.⁹ Thus, in addition to the local regulatory function in inflammatory processes, IL-1 may be involved in the regulation of the pain response.

IL-1 is produced in the degenerate invertebral disc (IVD). It is normally produced by the native chondrocyte-like cells but, in the non-degenerate IVD, there is a balance between IL-1 and inhibitor, IL-1Ra, ensuring that matrix homeostasis is maintained. In a study where IVD cells were given IL-1, the normal balance of catabolic and anabolic events are disturbed. The degrading enzymes were increased, and the gene expression for matrix proteins was decreased. In addition, this study demonstrated that although numbers of cells with immunopositivity for the IL-1 agonists increased with degeneration, no such increase was seen in the numbers of cells with immunopositivity for IL-1Ra.¹² This finding suggests that the normal inhibitory mechanism fails in disc degeneration, with a loss in the balance of IL-1 agonists to antagonists, allowing IL-1 to elicit and perpetuate a response. IL-1 causes cells from degenerate IVD’s to synthesize more IL-1, with the potential to induce accelerating degeneration. IL-1, a naturally occurring cytokine within the IVD could, through an imbalance between it and its inhibitor, play a role in the pathogenesis of IVD degeneration and therefore be an important therapeutic target for preventing and reversing disc degeneration.

Summary

Pain has diverse etiologies, mechanisms, and characteristics, and causes variable responses that are interpreted differently among individuals. Genomic variations influencing basal pain sensitivity and the likelihood of developing chronic pain diseases have been noted and continue to be studied. When treating pain, there are several factors to address. Think of pain as a tower of cards. The bottom layer is environmental and psychosocial factors. The second layer are the variations in nociception. The third is variations in the transmission of these signals. The fourth is the response that the pain transmission produces. The fifth is the chain reaction of system that has gone awry and causes chronic pain. The sixth is the interpretation of an individual’s pain. The top is the clinicians’ treatment of pain and is contingent upon understanding the underlying structure since without it treatment of the patient’s pain will limited, at best.

Genomics is developing a more granular understanding at each level and will ultimately lead to individualized pain management therapies. Suppose two people walk into a clinician’s office, both complaining of non-radiating low back pain. A clinician is apt to treat them the same. What if the clinician knew that one patient lacked IL-1Ra or had faulty ß2 receptors and the other did not? In this situation, the patients would more likely be treated differently, as the therapeutic agent that provides the most relief would be different. The future of medicine is providing more focused treatment based on a person’s genetic code. This understanding will allow clinicians to hone in on optimal treatment earlier in the individual’s quest for pain relief.