Genetics of chronic pain states

Best Practice & Research Clinical Rheumatology Vol. 21, No. 3, pp. 535–547, 2007 doi:10.1016/j.berh.2007.02.011 available online at http://www.sciencedirect.com

9 Genetics of chronic pain states Dan Buskila *

MD

Professor Department of Medicine H, Soroka Medical Center and Faculty of Health Sciences, Ben Gurion University, Beer Sheva, P.O.B 151, Israel 84101

Chronic pain states are common in the general population. Genetic factors can explain a significant amount of the variability in the perception of pain. Fibromyalgia syndrome (FMS) and related conditions are syndromes characterized by generalized pain sensitivity as well as a constellation of other symptoms. Family studies show a strong familial aggregation of FMS and related conditions, suggesting the importance of genetic factors in the development of these conditions. Recent evidence suggests a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the pathogenesis of FMS and related conditions. Environmental factors may trigger the development of these disorders in genetically predisposed individuals. Future large well-designed studies are needed to further clarify the role of genetic factors in FMS and related conditions. The knowledge of these gene polymorphisms may help with better subgrouping of FMS patients and in designing a more specific pharmacologic treatment approach. Key words: chronic pain; fibromyalgia; chronic widespread pain; genetics; gene polymorphisms; familial aggregation; functional somatic syndrome; affective spectrum disorder.

GENES AND PAIN Pain is an unpleasant sensory and emotional experience, determined in terms of systems and regions involved, degree of intensity, time since onset and aetiology. Perception of pain is a complex process that implies multiple biochemical pathways together with processes of cortical integration. Chronic pain syndromes affect a significant portion of the general population. Population-based studies of chronic widespread pain (CWP) have suggested that approximately 10–11% of the population has this symptom at any given time, and chronic regional pain is found in 20–25% of the population.1 * Tel.: þ972-507883360; Fax: þ972-86403201. E-mail address: [email protected]. 1521-6942/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.

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Pain perception is a complex process that may be influenced by a variety of environmental and genetic factors.2 It has been suggested that genetic factors can explain a significant amount of the variance in the perception of pain, sensitivity to painful stimuli and development of chronic pain.3 Kim et al evaluated genetic influences on variability in human pain sensitivity associated with gender, ethnicity and temperament.4 Pain sensitivity in response to experimental painful thermal and cold stimuli was measured with visual analogue scale ratings, and temperament dimensions of personality were evaluated. Loci in the vanilloid receptor subtype 1 gene (TRPV1), d-opioid receptor subtype 1 gene (OPRD1) and catechol-O-methyltransferase gene (COMT) were genotyped using 50 nuclease assays. Female European Americans with the TRPV1 Val(585)Val allele and males with low harm avoidance showed longer cold withdrawal times based on the classification and regression tree (CART) analysis. CART identified gender, an OPRD1 polymorphism, and temperament dimensions of personality as the primary determinants of heat pain sensitivity at 49 C. It was suggested that these observations demonstrate that gender, ethnicity and temperament contribute to individual variation in thermal and cold pain sensitivity by interactions with TRPV1 and OPRD1 single-nucleotide polymorphisms (SNPs).4 A study by Fillingim et al investigated whether the A118G SNP of the m-opioid receptor gene (OPRM1) was associated with responses to three different experimental pain modalities.5 Genotyping of OPRM1 revealed that the rare A118G allele occurred in 25% of the females and 17% of the males. Statistical analysis indicates that subjects with a rare allele had significantly higher pressure pain thresholds than those homozygous for the common allele. Also, a sex-by-genotype interaction emerged for heat pain ratings at 49 C such that the rare allele was associated with lower pain ratings among men but higher pain ratings among women. It was concluded that these data indicate an association of a common SNP of OPRM1 with mechanical pain responses, and this genotype may be associated with heat pain perception in a sex-dependent manner, and the rare allele is associated with higher pressure pain thresholds.5 Catechol-O-methyltransferase (COMT) is one of the enzymes that metabolize catecholamines, thereby acting as a key modulator of dopaminergic neurotransmission. There is a cannon functional polymorphism of the COMT gene that codes the substitution of valine (val) by methionine (met) at codon 158 (val158met).6 Zubieta and colleagues examined the influence of a common functional genetic polymorphism affecting the metabolism of catecholamines on the modulation of responses to sustained pain in humans.7 Individuals homozygous for the Met158 allele of the COMT polymorphism (Val158Met) show diminished regional m-opioid system responses to pain compared with heterozygotes. These effects were accompanied by higher sensory and affective ratings of pain and a more negative internal affective state. It was concluded that the COMT Val158Met polymorphism influences the human experience of pain and may underlie inter-individual differences in the adaptation and responses to pain and other stimuli.7 Diatchenko et al identified three genetic variants (haplotypes) of the gene encoding COMT that they designated as low pain sensitivity (LPS), average pain sensitivity (APS), and high pain sensitivity (HPS).8 They showed that these haplotypes encompass 96% of the human population, and five combinations of these haplotypes are strongly associated with variation in the sensitivity to experimental pain. The presence of even a single LPS haplotype diminished by as much as 2.3 times the risk of developing myogenous temporomandibular joint disorder (TMD). The LPS haplotype produces much higher levels of COMT enzymatic activity when compared with the APS or HPS haplotypes.

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Inhibition of COMT in the rat results in a profound increase in pain sensitivity. It was concluded that COMT activity substantially influences pain sensitivity, and that the three major haplotypes determine COMT activity in humans, inversely correlating with pain sensitivity and the risk of developing TMD.8 The influence from the COMT Val158Met polymorphism on the efficacy of morphine in patients suffering from cancer pain was recently analysed by Rakvag et al.9 They genotyped 207 Caucasian cancer patients on morphine treatment with respect to the Val158Met polymorphism and compared the morphine doses and serum concentrations of morphine and morphine metabolites between the genotype groups. Patients with the Val/Val genotype needed more morphine when compared to the Val/Met and the Met/Met genotype groups. The difference was not explained by other factors such as duration of morphine treatment, performance status, time since diagnosis, perceived pain intensity, adverse symptoms, or time until death. It was suggested that genetic variation in the COMT gene may contribute to variability in the efficacy of morphine in cancer pain treatment.9 However, it should be noted that a Spanish study which examined the COMT Val158Met polymorphism in neuropathic pain found no evidence for such an association.10 Linkage studies have allowed the associations of TRKA gene mutations with the syndrome of congenital insensitivity to pain with anhydrosis11 and CACNL1A4 gene mutations with familial hemiplegics migraine.12 GENETIC FACTORS IN FIBROMYALGIA Fibromyalgia syndrome (FMS) is a commonly encountered disorder characterized by chronic widespread musculoskeletal pain and related symptoms (fatigue, disturbed sleep, etc) along with multiple painful tender points. In the past decade, tremendous progress has been made in our understanding of FMS, which is now recognized as one of many ‘central’ pain syndromes that are common in the general population.13 Recent evidence suggests that genetic factors appear to play a role in the pathogenesis of FMS in combination with environmental stimuli. The evidence for the role of genetics in the development of FMS comes from studies demonstrating familial aggregation in FMS and the recognition that specific genes might confer an increased risk of developing FMS.14–16 Family studies Two studies have suggested that FMS segregates within families in an autosomal dominant mode of inheritance.17,18 One of them17, based on clinical diagnostic criteria modified from Yunus and colleagues19, showed a female preponderance and postulated the existence of a latent or precursor stage of the disease. However, this study showed a rate of 70% of affected offspring of fibromyalgia patients, a rate considerably exceeding that expected from autosomal dominant inheritance (50%), and actually suggests over-diagnosis. The second study18 was based on data retrieved from questionnaires regarding fibromyalgia symptoms in family members of index patients. About two thirds reported family clustering. Unfortunately, the results of this study actually depended on the reliability of patients reporting the FMS symptoms in their relatives. Roizenblatt and colleagues reported a significant predominance of mothers with FMS in a group of children with fibromyalgia (71%) compared with children with diffuse pain (30%) and asymptomatic childrean (0%).20

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Buskila et al studied the familial occurrence of FMS to determine a possible role for genetic and familial factors in this syndrome21; 58 offspring aged 5–46 years (35 males and 23 females) from 20 complete nuclear families ascertained through affected mothers with FMS were clinically evaluated for FMS. Sixteen offspring (28%) were found to have FMS. The male/female ratio among those affected was 0.8 compared with 1.5 in the whole study group. Offspring with and without FMS did not differ in anxiety, depression, global well-being, quality of life, and physical functioning. In this study a high prevalence of FMS was observed among offspring of FMS mothers. Because psychological and familial factors were not different in children with and without FMS, it was suggested that the high familial occurrence of this syndrome may be attributable to genetic factors. We further expanded our observations on the prevalence of FMS in relatives of FMS patients, and studied 30 FMS female patients and 117 of their close relatives (parents, brothers, sisters, children, husbands).22 The prevalence of FMS among blood relatives of patients with FMS was 26% and among their husbands 19%. FMS prevalence in male relatives was 14% and in female relatives 41%. The mean tender point counts of male and female young relatives was significantly higher than that of controls: 6.1 versus 0.2 (P < 0.01), and 4.4 versus 0.4 (P < 0.01) respectively. Similarly, adult relatives had considerably higher mean tender point counts than controls: 4.0 versus 0.04 (P < 0.01) and 10.3 versus 0.28 (P < 0.01) respectively, for males and females. It was concluded that relatives of patients with FMS have a higher prevalence of FMS and are more tender than the general population, as reported and shown in a healthy control group. It was suggested that this findings can be attributed to genetic and environmental factors. The quality of life and physical functioning of relatives with FMS were found to be impaired, especially in female relatives and those with undiagnosed FMS.23 Arnold et al provided a family study of fibromyalgia, the aim of which was to assess familial aggregation of FMS and measures of tenderness and pain, and for familial coaggregation of FMS and major mood disorder.24 Information was collected for 533 relatives of 78 probands with FMS and 272 relatives of 40 probands with rheumatoid arthritis (RA). FMS aggregated strongly in families: the odds ratio (OR) measuring the odds of FMS in a relative of a proband with FMS versus the odds of FMS in a relative of a proband with RA was 8.5. The number of tender points was significantly higher, and the total myalgic score was significantly lower in the relatives of probands with FMS compared with the relatives of probands with RA. FMS coaggregated significantly with major mood disorder: the OR measuring the odds of major mood disorder in a relative of a proband with FMS versus the odds of major mood disorder in a relative of a proband with RA was 1.8. It was concluded that FMS and reduced pressure pain thresholds aggregate in families, and FMS coaggregates with major mood disorder in families. It was suggested that these findings have important clinical and theoretical implications, including the possibility that genetic factors are involved in the aetiology of FMS and in pain sensitivity. In addition, mood disorders and FMS may share some of these inherited factors.24 Genetic markers The compelling evidence regarding a genetic basis of FMS has led researchers to attempt to identify specific target genes involved in the pathogenesis. The assumption is that identifying such candidate genes may shed further light on the pathophysiology

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involved, possibly leading the way towards novel therapeutic venues and helping in the subgrouping of FMS patients. Few studies have addressed the possible linkage of FMS to HLA antigens. One early study found an excess representation of DR4: 64% as opposed to a frequency of 30% among healthy controls.25 In a multicase 40-family study, Yunus et al confirmed the existence of a possible gene for FMS that is linked with the HLA region (a weak association).26 The authors stress that these results should be regarded as preliminary, and their independent confirmation by other studies is warranted.26 Lowe et al have hypothesized that in euthyroid fibromyalgia, a mutant C-erbA-b1 gene or alternately the C-erbA-a1 gene results in low-affinity thyroid hormone receptors that prevent normal thyroid hormone regulation of transcription.27 As in hypothyroidism, this would cause a shift toward a-adrenergic dominance and increases in both cyclic adenosine 30 ,50 -phosphate phosphodiesterase and inhibitory Gi proteins. The result would be tissue-specific hypothyroid-like symptoms despite normal circulating thyroid hormone levels.27 Research done in recent years demonstrated a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the pathogenesis of FMS. Offenbaecher et al analysed the genotypes of the promoter region of the serotonin transporter gene (5-HTT) in patients with FMS.28 A higher frequency of the S/S genotype of 5-HTT was found in FMS patients compared with healthy controls. The S/S subgroup exhibited higher mean levels of depression and psychological distress. It was suggested that these results support the notion of altered serotonin metabolism in at least a subgroup of patients with FMS. Bondy et al have investigated a silent polymorphism (T102C) in the 5-HT2A receptor gene, located on the long arm of chromosome 13 in 168 FMS patients and 115 healthy controls.29 Their results showed a significantly different genotype distribution in FMS patients with a decrease in T/T and an increase in both T/C and C/C genotypes as compared to the control population. However, the increase in allele-C102 frequency felt short of significance. The pain score was significantly higher in patients of the T/T genotype. It was suggested that the T102 allele might be involved in the complex circuits of nociception.29 We performed genotyping in a group of 99 female FMS patients from two Israeli ethnic groups.30 Additionally, we assessed each patient with the tridimensional personality questionnaire (TPQ), a self-report instrument consisting of 100 yes/no questions. In this study we confirmed the observation by the German group28 that the 5-HTTLPR polymorphism is associated with FMS. There was also a significant association between 5-HTTLRR genotype and the TPQ harm-avoidance trait, which is consistent with the initial report by Lesch et al that the short allele of this polymorphism is associated with anxiety-related traits.31 It was suggested that the relationship between FMS and the serotonin transporter may be indirect and mediated by anxiety-related traits. Most important, these findings support the idea that a genetic approach to a complex trait such as FMS will help elucidate the biological underpinnings of this disease and allow a more rational approach to drug development and treatment paradigms. Recently both serotonin receptor subunit genes, HTR3A and HTR3B, have been investigated for sequence variations in FMS patients.32 HTR3A mutational analysis revealed one novel as well as five known sequence variations. HTR3B mutational analysis revealed seven formerly described mutations and one novel sequence. It was suggested that these mutations represent the basis for future studies on their pharmacogenetic relevance.32 However, the association of the 5-HTT gene polymorphism on FMS was not found in Turkish patients

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with fibromyalgia.33 Gursoy and colleagues have reported on the involvement of COMT gene polymorphism in patients with FMS.34 It was concluded that COMT gene polymorphism is of potential pharmacological importance regarding individual differences in the metabolism of catechol drugs, and may also be involved in the pathogenesis and treatment of fibromyalgia through adrenergic mechanism as well as genetic predisposition to fibromyalgia.34 Recently, Buskila and colleagues have reported on an association between fibromyalgia and the D4 dopamine receptor exon III repeat polymorphism and relationship to novelty-seeking personality traits.35 Interestingly, it was shown that dopaminergic rather than serotoninergic neurotransmission is altered in fibromyalgia, suggesting increased sensitivity or density of D2 dopamine receptors in fibromyalgia patients.36 It was suggested that fibromyalgia is related to anxiety and associated with disturbance in the stress response systems. Altogether, recent evidence suggests an involvement of both serotoninergic and dopaminergic neurotransmitter pathways in fibromyalgia, probably mediated by personality traits. GENETIC FACTORS IN FIBROMYALGIA-RELATED DISORDERS Fibromyalgia is but one of a number of overlapping systemic and regional disorders that share common clinical features.37 These include chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), temporomandibular disorder (TMD), and more. These related conditions have been referred to by different terms, including functional somatic syndromes and affective spectrum disorder (ASD).38,39 Patients with these FMS-related conditions express somatic hyperalgesia as reported in fibromyalgia.40,41 Since these syndromes share many clinical features, including generalized pain sensitivity, it is postulated that they share common pathogenetic mechanisms. Hudson et al provided a family study of affective spectrum disorder (ASD).39 ASD represents a group of psychiatric and medical conditions including major depressive disorder (MDD), dysthymic disorder, FMS, IBS, migraine, post-traumatic stress disorder (PTSD) and more. In 178 interviewed relatives of 64 probands with MDD and 152 relatives of 58 probands without MDD, the estimated odds ratio for the familial aggregation of ASD as a whole was 2.5, and for the familial coaggregation of MDD with at least one other form of ASD was 1.9. It was concluded that ASD aggregates strongly in families, and MDD displays a significant familial coaggregation with other forms of ASD taken collectively. It was suggested that forms of ASD may share heritable pathophysiological features.39 Another family study of FMS and ASD found that the estimated odds ratio for the familial aggregation of ASD was 1.8, and the increase in number of forms of ASD in a relative for each additional form of ASD in a proband was 0.076.42 The odds ratio for other forms of ASD was 2/0. It was concluded that these findings support familial aggregation of ASD collectively, and familial coaggregation of FMS with other forms of ASD.42 Walsh et al assessed 25 CFS cases and 36 medical control subjects for life-time psychiatric symptoms.43 Informant family history was obtained regarding first-degree relatives. There were significantly higher rates of CFS in the relatives of CFS cases compared with the relatives of control subjects. The rate of depression in the CFS cases was similar to that in previous studies, but did not appear to reflect a greater familial loading for depression when compared with control subjects. It was suggested that familial factors are important in the aetiology of chronic fatigue syndrome.43

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The role of genetic and environmental factors was assessed in unexplained chronic fatigue.44 A classic twin study was conducted using 146 female–female twin pairs, of whom at least one member reported at least 6 months of fatigue. The concordance rate was higher in monozygotic than dizygotic twins for each definition of chronic pain. The results of this study provided evidence supporting the familial aggregation of fatigue and suggested that genes may play a role in the aetiology of CFS.44 IBS prevalence was found in 17% of patients’ relatives versus 7% in spouses’ relatives.45 It was concluded that familial aggregation of IBS occurs, supporting a genetic or intra-familial environment component, but this may be explained in part by familial aggregation of somatization. Central sensitizations and allodynia described in FMS has been reported in migraine.46 Recently we have reported on a high incidence of FMS among female migraine patients but not in males.47 It has been shown that migraine, as well as other comorbid conditions, aggregates in families.39 Previous studies have demonstrated an association between PTSD and FMS.41,48 A twin study of Vietnam veterans has shown a significant genetic contribution to PTSD.49 In a twin study assessing genetic and environmental influences on trauma exposure and posttraumatic stress disorder symptoms, Stein et al have concluded that genetic factors can influence the risk of exposure to some forms of trauma, perhaps through individual differences in personality that influence environmental choices.50 Genetic studies have provided evidence for the role of polymorphism of genes in the serotoninergic, dopaminergic and catecholaminergic systems not only in FMS but also in comorbid conditions. Narita et al examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT, in 78 CFS patients.51 A significant increase of longer (L and XL) allelic variants was found in the CFS patients compared to the controls, both by the genotype-wise and the allele-wise analyses. It was suggested that attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS. Smith et al evaluated polymorphisms in 11 candidate genes related to both hypothalamic pituitary adrenal (HPA) axis function and mood-related neurotransmitter systems by comparing each of five ill classes of fatigued subjects with subjects defined as well.52 Of the five classes of subjects with unexplained fatigue, three classes were distinguished by gene polymorphisms involved in either HPA axis function or neurotransmitter systems, including proopiomelanocortin (POMC), nuclear receptor subfamily 3, group C, member 1 (NR3C1), monoamine oxidase A (MAOA), monoamine oxidase B (MAOB), and tryptophan hydroxylase 2 (TPH2). It was suggested that these data support the hypothesis that medically unexplained chronic fatigue is heterogeneous and presents preliminary evidence of the genetic mechanisms underlying some of the putative conditions. Goertzel et al assessed combinations of SNPs in neuroendocrine effector and receptor genes in chronic fatigue syndrome.53 The top three genes containing the SNPs accounting for the highest accumulated importances were neuronal tryptophan hydroxylase (TPH2), catechol-O-methyltransferase (COMT), and nuclear receptor subfamily 3, group C, member 1 glucocorticoid receptor (NR3C1). It was concluded that the fact that only 28 out of several million possible SNPs predict whether a person has CFS with 76% accuracy indicates that CFS has a genetic component that may help to explain some aspects of the illness.53 These papers52,53 were two out of 14 papers published in Pharmacogenomics in April 2006 addressing the issue of genetics and CFS. These studies have been criticized for their methodology and conclusions.54

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Carlo-Stella et al reported on a positive association of TNF-857 and IFNg-874 rare alleles in CFS.55 It was hypothesized that CFS patients can have a genetic predisposition to an immunomodulatory response of an inflammatory nature, probably secondary to one or more environmental insults of unknown nature. Genetic polymorphisms at the SERT (5-HT transporter protein) promoter was found to influence the response to a 5-HT3 antagonist in diarrhoea-predominant IBS and may influence the benefit/risk ratio with this class of compounds.56 Another study suggested that patients with homozygote C allele of the 102 T/C polymorphisms or homozygote A allele of the 1438 G/A polymorphism of the 5-HT2A receptor gene have a high risk of IBS.57 On the other hand, T/T genotype of 102 T/C polymorphism may be associated with more severe pain in patients with IBS.57 Kim et al found that functionally distinct a2A- and a2C-adrenoceptor and serotonin transporter polymorphisms are associated with constipation and high somatic symptoms in patients with lower functional gastrointestinal disorders, although the strength of the genetic contribution to the phenotype is unclear.58 However, Pata el al could not demonstrate a relationship between IBS and serotonin transporter gene polymorphism.59 The possible relationship between the T102C polymorphism of 5-HT2A receptor gene and temporomandibular dysfunction was assessed.60 It was found that the T102C polymorphism may be involved in the aetiology of temporomandibular dysfunction. The overrepresentation of the C/C variant of 5-HT2A receptor gene in temporomandibular dysfunction suggested a possible role of the serotoninergic system in this disease, particularly at the receptor level.60 Segman et al reported on an association between the dopamine transporter gene and PTSD.61 It was suggested that genetically determined changes in dopaminergic reactivity may contribute to the occurrence of PTSD among trauma survivors. This association was further expanded upon in PTSD by a subsequent study demonstrating the association between the efficacy of paroxetine treatment in PTSD and the presence of a D2 dopamine receptor gene polymorphism.62 Thus both the susceptibility to develop PTSD following combat-like trauma and the response to treatment may be determined genetically through genes affecting dopaminergic transmission. A recent study by Lee at al has further stressed that serotonin transporter promoter gene polymorphism is one of the genetic factors for susceptibility to PTSD.63 Juhasz et al have suggested that the genetic susceptibility of migraine may be associated with a locus at or near the 5-HTT.64 Functional serotonin 5-HTTLPR polymorphism was found to be a risk factor for migraine with aura.65 Finally, migraine patients without aura, but not migraine patients with aura, showed significant genetic association with D4 dopamine receptor gene.66 Altogether, recent evidence suggests a role for polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems in the pathogenesis of FMS and FMS-related conditions. As with other illnesses that may have a genetic underpinning, environmental factors may play a prominent role in triggering the development of FMS and related conditions.37 Environmental factors found to be associated with the development of FMS and related conditions include physical trauma, emotional stress, and certain infections. It is believed that these conditions may be expressed when a person who is genetically predisposed comes into contact with the aforementioned environmental factors.37 It should be emphasized that the gene polymorphisms found in FMS and related conditions are not specific to these syndromes, and have been reported in other disorders, including major depression67 and ischaemic heart disease.68,69

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CLINICAL IMPLICATIONS OF MOLECULAR GENETIC FINDINGS IN CHRONIC PAIN STATES Fibromyalgia and related conditions are syndromes characterized by generalized pain sensitivity as well as a constellation of other symptoms. The gene polymorphisms reported in the serotoninergic and dopaminergic systems may help to better understand the pathogenesis of these ‘central’ pain syndromes. Notably these polymorphisms all affect the metabolism or transport of monoamine compounds that have a critical role in both sensory processing and the human stress response.13 Knowledge of the patient’s genotype may help in better subclassification of FMS patients. Given the biopsychosocial nature of FMS, attempts have been made to identify subsets of FMS patients that might present differently or respond differentially to treatment.70 Turk et al classified FMS patients into three subgroups based on psychosocial and behavioural characteristics.70 These subgroups showed substantial differences in clinical presentation of their symptoms. Giesecke et al also reported on distinct subgroups of patients with FMS.71 There was a group of FMS patients who exhibited extreme tenderness but lacked any associated psychological cognitive factors, an intermediate group who displayed moderate tenderness and had normal mood, and a group in whom mood and cognitive factors could have been significantly influencing the symptom report.71 Analysing the genetic characteristics of FMS and related syndromes may help in better determining clinical subsets and may prove considerably more rewarding than looking at vastly heterogeneous patient populations falling within the broad net of the current ACR classification criteria.72 Finally, the current genetic discoveries may be used in order to fine-tune the pharmacological treatment of FMS. Thus patients carrying the short 5-HTTLPR allele may be more suitable candidates for antidepressant medication, while patients lacking the 7DRD4 allele may be better candidates for dopaminergic medication, such as pramipexole. SUMMARY Chronic pain conditions are prevalent in the general population. Pain sensitivity varies substantially among humans and is dependent on cultural, psychological and physiological factors. There is increasing evidence for the role of genetic factors in individual variations in pain perception and the development of chronic pain conditions. FMS is a chronic widespread pain disorder which is now recognized as one of many central pain syndromes. Increasing evidence supports a role for genetic factors in the development of FMS. A strong familial aggregation of FMS was reported in FMS patients. Polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems have been suggested to play a role in the aetiopathogenesis of FMS. These polymorphisms are not specific for FMS and are associated with other FMS-related syndromes, the affective spectrum disorder or functional somatic disorder. The mode of inheritance of FMS is unknown, but it is most probably polygenic. Environmental factors may trigger the development of FMS in genetically predisposed individuals. Recognition of these gene polymorphisms may help to better subgroup FMS patients and to treat them in a more rational pharmacological approach.

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Practice points  recent studies suggest that genetic factors can explain a significant amount of the variance in the perception of pain and the development of chronic pain  a strong familial aggregation is reports in FMS and related conditions (the functional somatic syndrome or affective spectrum disorder)  polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems have been reported in these chronic pain states, and may play a role in its pathogenesis  genetic and environmental factors may both play a role in the development of FMS and relates syndromes  the mode of inheritance of FMS is unknown but it is moat probably polygenic.

Research agenda  more robust studies, conducted in larger numbers of patients and wellmatched controls, are needed to better clarify the role of genetic factors in FMS and related conditions  newer genetic methodologies – including haplotype analysis gene expression studies and proteomics – hould be applied in future studies  the recognition of polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems may help better subclassify FMS patients, and plan a more rational pharmacologic treatment

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