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10 Articles in Volume 10, Issue #1
An Overview of CRPS
Balancing Evidence, Efficacy and Stakeholder Values in Practical Pain Care
Biopsychosocial Approach to Management of Total Joint Arthroplasty Patients
Dextrose Prolotherapy Injections for Chronic Ankle Pain
Genetic Influences on Pain Perception and Treatment
Headache in Children and Adolescents
Hormone Replacements and Treatments in Chronic Pain: Update 2010
Opioid Treatment 10-year Longevity Survey Final Report
Therapeutic Laser in the Treatment of Herpes Zoster
Use and Effectiveness of Spinal Cord Stimulation

Genetic Influences on Pain Perception and Treatment

Genomic variations influence basal pain sensitivity and the likelihood of developing chronic pain so it is logical that the future of medicine is to provide more focused treatment based on a person's genetic code.
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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.

Table 1. Pain Conditions Influenced by Genetic Factors
  • Catecholamine-induced Musculoskeletal Pain
  • Chronic Fatigue/Fibromyalgia Syndrome
  • Low Back Pain

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.

Last updated on: February 25, 2011