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8 Articles in Volume 16, Issue #8
Genetic Testing in Pain Medicine—The Future Is Coming
Genetic Factors in Fibromyalgia and Chronic Widespread Pain
IV Treatment of Centralized Pain and Headache
Low Back Pain and Osteopathic Manipulative Medicine: A Trend in Pain Management
Clinician as Patient: What I Learned About the Role of Physical Therapy in Pain Management
Mental Health & Vocational Rehabilitation: Information for Pain Management
Neuroinflammation and Peripheral Inflammation—A Big Difference
Letters to the Editor: Genetic Testing

Genetic Factors in Fibromyalgia and Chronic Widespread Pain

Chronic widespread pain, including fibromyalgia, is a pain disorder with genetic links. Learn what genes may influence a person's perception and sensitivity to pain.

Pain is influenced equally by genetic and environmental factors, working in concert to control how humans process it. Pain sensitivity falls on a bell-shaped curve in the general population. The higher the volume control setting, the more pain a person will experience, irrespective of nociceptive input (see Figure 1).

During the past decade pain research has focused on single nucleotide polymorphisms (SNPs) to help decipher which genes may be involved in pain generation. In fact, similar genetic factors have been identified among patients with fibromyalgia and chronic widespread pain (CWP). Investigations have looked for altered DNA sequence variations of a single nucleotide (A, T, C, or G). Other genetic advances in pain research include genome-wide association studies (GWAS) and epigenetics.

This review will highlight the latest clinical data on genetic factors that influence chronic pain conditions.

Chronic Widespread Pain

Genetic factors are associated with every chronic pain disorder, including CWP and fibromyalgia.1,2 Approximately 40% of the CWP heritability estimates were attributable to genetic effects. In a study from Norway, researchers found a 20% to 40% increased odds of chronic musculoskeletal pain (CMP) in adult sons and daughters of parents with CWP.3 “Both sons and daughters had an odds ratio of 1.6 (95% CI 1.4 to 1.9) when both parents reported CMP, compared to when none of the parents had CMP,” noted the authors. Interestingly, genetic risk does not always mean clinical disability. For example, in the Norway study, the odds of inheriting CWP were not influenced by whether the parent had limited ability to work or enjoy leisure time.3

Clinical cohort studies have also demonstrated that fibromyalgia clusters among families and that fibromyalgia co-aggregates with major mood disorders. In a study from 2004, Arnold and co-workers found an 8.5-fold greater risk of fibromyalgia in relatives of a patient (proband) with fibromyalgia compared to relatives of a patient with rheumatoid arthritis (RA) (see Figure 2).2 They also found a greater number of tender points in the relatives of probands with fibromyalgia compared to those with RA. Fibromyalgia also correlated with the presence of major mood disorder (major depressive disorder or bipolar disorder). The comorbidity of fibromyalgia with depression impacts diagnostic and therapeutic decisions. Treating clinicians must always screen for mood disturbances in any patient with CWP. Optimal pharmacologic and nonpharmacologic therapy should improve depression as well as chronic pain.  

In 2013, Arnold et al performed the first genome-wide linkage scan and confirmed that fibromyalgia aggregates in families.4 They reported an estimated sibling recurrence risk ratio of 13.6, consistent with values reported for other complex disorders to which multiple genetic and environmental factors likely contribute. One major locus for fibromyalgia was found on the chromosome 17p11.2–q11.2 region.

Twin studies have been instrumental in linking chronic pain to genetic factors.5,6 In a study of more than 15,000 twins, the prevalence of CWP was 4.1%, and the ratio of women to men was 3.3 to 1.6 There were modest genetic influences for both women and men. These investigators also found considerable co-occurrences in CWP cases with chronic fatigue, joint pain, depressive symptoms, and irritable bowel syndrome (IBS).7 This led the investigators to conclude that associations between CWP and most comorbidities were mediated by unmeasured genetic and family environmental factors in the general population.7

A person’s response to pain has also been linked to genetics. A landmark twin study revealed a 22% to 55% genetic component for pain sensitivity.8 To measure pain response, the researchers produced a variety of painful stimuli, including heat pain threshold (HPT), the pain rating during induction of a thermal burn, the secondary areas of punctate hyperalgesia and brush-evoked allodynia following the induction of a 45°C thermal burn, and the pain ratings during the iontophoresis of adenosine triphosphate (ATP) and acid.8 The authors concluded that “our study demonstrates the importance of genetic factors in determining human experimental pain sensitivity.”

A later study also found a significantly increased likelihood of multisite CWP among monozygotic twins as compared to dizygotic twins when reporting pain.9 The clinical features of fatigue and depression, as well as levels of dehydroepiandrosterone (DHEAS), were interrelated in a multivariate twin design of 463 British female twin pairs.10 The researchers reported a strong genetic relationship between DHEAS levels and CWP and depression. Lastly, in a large twin study, CWP was found in 15% of the population, and there was a correlation of CWP with neuropathic pain as well as age, elevated body mass index, female gender, and smoking.11

Role of COMT in Pain Perception

The first gene that was closely linked to increased pain sensitivity in patients with fibromyalgia and chronic pain was catechol-O-methyltransferase (COMT).12 COMT is one of several enzymes that degrade dopamine, noradrenaline, and adrenaline, which play major roles in pain perception. Three genetic variants (haplotypes) of the gene encoding COMT were designated as low pain sensitivity (LPS), average pain sensitivity (APS), and high pain sensitivity (HPS), respectively. These haplotypes encompass more than 90% of the human population, and 5 combinations of these haplotypes were strongly associated with variation in the sensitivity to experimental pain.

Certain personality traits, including anxiety, have also been associated with polymorphic variants of the dopamine system that heighten pain response. Heightened anxiety, where a patient focuses and magnifies painful sensations, is called catastrophizing. Researchers have discovered an association between COMT genetic variants and pain intensity during episodes of catastrophizing.13 Experimental pain studies have demonstrated that the COMT polymorphism affects pain processing. For example, the carriers of the Met/Met genotype of the COMT gene demonstrated stronger pain-related signals seen on functional magnetic resonance imaging (fMRI) studies than did carriers of the Val/Val genotype.14

In another study involving motor vehicle accident (MVA) patients, researchers discovered an association between the COMT haplotype and developing pain after the accident.15 This study evaluated the association between COMT genotype and acute neck pain intensity and other patient characteristics in 89 Caucasian individuals presenting to the emergency department after an MVA. Individuals with a COMT pain-vulnerable genotype were more likely to report moderate to severe musculoskeletal neck pain, moderate or severe headache, and moderate or severe dizziness, noted the researchers. These subjects also took a longer time to recover following the MVA.

In a survey of more than 100 women with fibromyalgia, the frequency of genetic variations associated with low COMT enzyme activity (ie, increased pain sensitivity) was significantly higher than in healthy volunteers.16 The fibromyalgia patients were more sensitive to experimental pain than healthy controls, and those patients with the Met/Met genotype (Val158Met) or the HPS-APS haplotypes demonstrated the greatest sensitivity to thermal and pressure pain stimuli compared to other fibromyalgia patients.

Another study found that the Val158Met COMT polymorphism modulated some psychological variables—anxiety and depression—but not pressure pain sensitivity in women with fibromyalgia.17 The women with fibromyalgia who carried this haplotype also had greater disability. A second report confirmed the association between COMT Val158Met genotype and specific psychological profiles, including greater mood disturbances and poorer function.18 These findings were further confirmed in a large Turkish study of 379 fibromyalgia patients. In this study, the Met/Met genotype was found to be significantly higher in the fibromyalgia patients than in 290 healthy controls.19 The pain sensitivity, measured by algometry, was also higher in patients with Met/Met genotype.

Using samples from the 1958 British Birth Cohort Study, researchers found that functional variants in beta(2)-adrenergic receptor (beta2 adrenoceptor), also known as beta2AR, was involved in pain, but they could not find an association with COMT and chronic pain.20 A laboratory study, however, found differences in intracellular cAMP responses of fibromyalgia blood cells after beta2AR stimulation.21 The authors suggested that this demonstrates a relationship between beta2AR polymorphism and fibromyalgia.

A systematic evaluation of 17 candidate genes and over 35 different polymorphisms demonstrated an association of serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor polymorphism with fibromyalgia, but not the 5-HTTLPR (serotonin-transporter-linked polymorphic region) S/L allele and COMT Val158Met haplotype in studies on fibromyalgia susceptibility.22 Another systematic review also could not confirm the association of the COMT polymorphism with fibromyalgia.23 However, a subsequent meta-analysis did report an association between fibromyalgia risk and the COMT Val158Met polymorphism as well as the FIQ score in fibromyalgia patients.24

The interaction of genetic polymorphism and fibromyalgia requires much more investigation, as witnessed by the number of contradictory studies. Additional studies have reported that:

  • Neither the serotonin transporter gene nor its polymorphism were associated with fibromyalgia.25
  • However, a more comprehensive study, including a subsequent meta-analysis, did report an association of HTR2A polymorphisms with CWP.26
  • Associations were noted between SNPs in the HTR2A gene and the serotonin biosynthesis gene (tryptophan hydroxylase, TPH2) with regards to the number of somatic symptoms.27
  • Adrenergic receptor gene polymorphisms were related to the risk of developing fibromyalgia and to symptom severity.28 These varied with ethnicity.
  • A comprehensive review suggested that there is evidence to support genetic susceptibility as well as physiological alteration for COMT genes, the glucocorticoid, and the related mineralocorticoid receptors (NR3C1, NR3C2), as well as the purinergic 2X4 (P2X4) ion channel in fibromyalgia and CWP.29  

Other Genetic Variants And Chronic Pain

Genes strongly associated with pain include mutations in the sodium channel gene SCN9A and the serotonin transporter gene 5-HTTLPR. A deletion of the SCN9A gene produces a complete absence of pain, inherited as an autosomal recessive trait, whereas allele variations of the gene have been linked to a number of chronic pain syndromes, including temporomandibular joint disorder (TMJD), fibromyalgia syndrome, IBS, chronic headaches, interstitial cystitis, chronic pelvic pain, and whiplash-associated disorders. A severe form of fibromyalgia was associated with a particular SCN9A sodium channel gene variant.30 Such findings indicate that a single gene deletion causes congenital absence of pain sensation whereas different mutations of the same gene may enhance pain sensitivity.

Heat pain thresholds have been associated with 5-HTTLPR genotypes, categorized as high, intermediate, or low expressors of the serotonin transporter gene.31 In a study by Hooten et al, 277 chronic pain patients were tested for the genotypes. The distribution of the high-, intermediate-, and low-expressing genotypes was 61 (22%), 149 (54%), and 67 (24%), respectively. The authors reported that the heat pain thresholds were significantly greater in the intermediate-expressing group compared with the high-expressing subjects.31

Genetic variations in the m-opioid receptor gene (OPRM1) have been associated with variation in opioid requirement and in chronic pain conditions. For example, a single polymorphism of OPRM1 was associated with responses to 3 different experimental pain modalities in healthy subjects.32 A similar study reported polymorphism in the OPRM1, with the 118G allele frequency significantly lower in fibromyalgia patients compared to controls.33 (For more on OPRM1 and addiction risk, click here)

Polymorphisms in the guanosine triphosphate cyclohydrolase 1 (GCH1) gene, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin and an essential cofactor in nitric oxide (NO), have been implicated in pain sensitivity. In patients with fibromyalgia, the CCTA haplotype of GCH1 was associated with significantly lower pain sensitivity.34

Fibromyalgia patients had shorter telomere length than controls, and higher levels of pain were associated with shorter telomere length.35 This was most striking when pain and depression were concurrent. A subset of patients had brain imaging, and the reduced telomere length correlated with reduced gray matter volume in regions associated with pain transmission.

The Genome and Fibromyalgia

Smith et al performed the largest candidate gene association study of fibromyalgia to date, involving 496 patients with fibromyalgia and 348 individuals with no chronic pain.36 They evaluated more than 350 genes known to be involved in nociception, inflammation, and affect. They found significant differences in allele frequencies between cases and controls for several novel genes: GABRB3 (in the promoter region), TAAR1, GBP1, RGS4, CNR1, and GRIA4. Three of these genes, TAAR1, RGS4, and CNR1, play roles in the modulation of analgesic pathways.

A genome-wide analysis of 313 fibromyalgia cases having low comorbidities found no SNP that reached an association threshold, but 21 of the most associated SNPs were chosen for a replication study in 952 cases and 644 controls.37 In the replication study, rs11127292 (MYT1L) was found to be associated with fibromyalgia. The researchers also reported an association of fibromyalgia with a deletion in NRXN3.  

Complete exome sequencing, sequencing all the expressed genes in a genome, reported 2 nonsense mutations to be associated with transmission to affected patients with fibromyalgia.38 A nonsense mutation, such as those identified for cystic fibrosis and beta thalassemia, is a point mutation in a single DNA sequence. There was an association of more than one variant with young age of onset of fibromyalgia symptoms.

Exploratory factor analysis on 34 candidate genes was used to determine whether independent candidate genes can be grouped into meaningful biologic factors, and whether these factors are associated with the diagnosis of chronic fatigue syndrome (CFS) and fibromyalgia syndrome.39 Four potential biologic factors were reported, including purinergic and cellular modulators, neuronal growth and immune function, nociception and stress mediators, and energy and mitochondrial function. This model revealed that some of these factors were associated with CFS and others with depression and fibromyalgia.

Conclusion

Genetic factors are associated with fibromyalgia and CWP. No single factor has been identified, and it is likely that multiple genetic traits interact with environmental factors to influence chronic pain. The identification of specific genetic factors, already the most exciting area of research in oncology and many other fields, will likely prove instrumental in better understanding and treating chronic pain in the near future. 

Last updated on: October 13, 2016
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IV Treatment of Centralized Pain and Headache

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