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Genetic Variability in the Activity of Monoamines: A Window into the Complexity of Pain

Flood, Pamela MD, MA; Clark, David MD, PhD

doi: 10.1213/ANE.0000000000000447
Editorials: Editorial

From the Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Palo Alto, California.

Accepted for publication July 29, 2014.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Pamela Flood, MD, MA, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Dr., Palo Alto, CA 94305. Address e-mail to

The physiology that underlies pain perception is complex and clearly influenced by both genetic and environmental factors. This issue of Anesthesia & Analgesia includes 2 articles that identify relationships between single nucleotide polymorphisms (SNPs) in the gene for Catechol-O-methyltransferase (COMT) and manifestations of acute1 and recurrent pain.2 It is one of the most highly investigated genes in pain research. The COMT enzyme breaks down catecholamines, plays a role in estrogen metabolism, and has been variably implicated in experimentally induced pain in a gender- and modality-specific manner.3 This work is important because the clinical expression of both acute and more persistent types of pain is highly variable, even in the setting of a monogenetic etiology such as sickle cell disease or after similar injuries such as a relatively standardized surgical procedure. The consequences of either under- or overtreatment of pain are severe. Both reports illustrate some of the promises as well as the substantial pitfalls associated with genetic research in pain.

The most commonly studied COMT SNP with respect to pain is rs4680: A > G, which results in amino acid substitution Val158Met (Fig. 1). This variant, considered alone, is associated with reduced activity of the COMT enzyme. However, 3 other synonymous variants that do not result in coding changes, rs6269: A > G in the promoter region for S-COMT, rs4633: C > T, and rs4818: C > G in the coding region for both S (soluble) and MB (membrane bound) forms of COMT contribute to haplotypes (groups of linked SNPs) that are present in 92% of the Caucasian population.4 These haplotypes are referred to as low pain sensitivity (LPS:G_C_G_G), average pain sensitivity (APS:A_T_C_A), and high pain sensitivity (HPS:A_C_C_G) and are associated with normal, 3-fold, and 20-fold reduced COMT enzyme activity. It is important to consider that while expression of rs4680 A > G has been associated with reduced enzyme function and increased pain sensitivity when considered alone, it contributes to both the LPS and HPS haplotypes that are associated normal and enhanced pain sensitivity respecitively.5

Figure 1

Figure 1

The finding of association between low COMT enzyme activity and pain sensitivity is biologically plausible and has been supported by preclinical5 and volunteer studies.3 Low activity of COMT would be expected to result in excess of synaptic and extrasynaptic norepinephrine, epinephrine, and dopamine. Norepinephrine and epinephrine modulate pain principally through the activation of α(1/2) and β(2/3) adrenergic receptors.6 Activation of α2 receptors with selective agonists such as dexmedetomidine results in analgesia. However activation of α1 and/or β receptors can either increase or decrease pain sensitivity.6 The effect of adrenergic activity is also regionally variable; increasing adrenergic activity in the spinal cord is associated with decreased pain sensitivity. In contrast, increased adrenergic activity in the peripheral nervous system is associated with increased pain sensitivity. Given these considerations, it is not obvious whether decreased COMT activity leading to excess catecholamine would be expected to result in pain reduction or exacerbation. The balance of positive and negative modulation is likely important, and the most relevant sites controlling pain and analgesic responses have not been defined. With these complexities in mind, we turn to the findings of the current studies.

Candiotti et al.1 assessed the association between 2 common COMT SNPs with morphine consumption after nephrectomy, a procedure associated with significant postoperative pain. They found that in the first 24 hours after surgery, patients homozygous for the expression of G at rs4680 (resulting in expression of less efficient COMT enzyme) used 36% more opioid than those who were homozygous for A. The difference persisted to the 48-hour assessment. In addition, patients homozygous for G at rs4818 SNP used more morphine than heterozygotes during the first 6 hours. These data seem reasonable as lower rates of catecholamine degradation have been linked to more pain or higher analgesic requirements in other studies, and there appears to be an allelic “dose-response.” Pain reports, however, were not different. Homozygotes for the C allele at rs4818 used more antiemetic than homozygotes for G, though the significance of the observation is somewhat unclear as differences in opioid consumption did not seem to provide an explanation. While the aforementioned findings are interesting, it is surprising that the authors did not evaluate genotype at rs6269 and rs4633 so that the contribution of the LPS, APS, and HPS haplotypes, suggested to be important by other investigators, could then be considered.

The relationship between acute pain and individual COMT SNPs and haplotypes has been assessed after other types of injuries, procedures and surgeries including lumbar discectomy, tonsillectomy, major abdominal and urological procedures, chest tube removal after cardiac surgery, labor pain, breast cancer surgery, oral surgery, and pain after motor vehicle accident with highly variable results (Table 1).7–17 Some studies found more pain and/or analgesic use associated with genotypes for which reduced enzyme activity is predicted. Other studies found no association. Some even found the reverse relationship. Indeed our years of study of COMT variants have not provided a clear and consistent picture of the impact of genetic variation of this gene on pain. Moreover, the cohort studied by Candotti et al. had mixed gender. Experimental studies have suggested that the effect is both gender- and modality-dependent with an effect found more reliably in female animals and women.4 A gender difference is intriguing as COMT metabolized catechol-estrogens in addition to catecholamines neurotransmitters. However, no effect was identified in a study of 22 COMT SNPs and acute pain after breast cancer surgery in 1000 women.12

Table 1

Table 1

The relationship between the likelihood of utilizing emergency room resources in patients with sickle cell disease and the COMT rs4680 A > G SNP as well as the rs6380 variant in the gene for the dopamine D3 receptor (DRD3) receptor, that results in a Ser9Gly substitution, was reported by Wang et al. in this issue of the journal.2 Though the findings were preliminary in nature, sickle cell patients who expressed the G allele at rs4680 in COMT that results in reduced enzyme activity were twice as likely to utilize emergency room resources for acute pain crisis. Interestingly, patients who were heterozygous at DRD3 were less likely to have an acute pain crisis.

The consideration of variability in a pain phenotype with both COMT and a dopamine receptor is interesting in that dopamine, like all catecholamines, is a substrate for COMT and receptor binding potential has been associated with variability in pain phenotypes.18–22 DRD3 Gly9Gly receptor activation induces a greater increase in cAMP than the wild type receptor and has been associated with higher pain thresholds in fibromyalgia.18 It is unfortunate that the authors did not assess the interaction between the 2 polymorphisms and pain behavior, though perhaps the sample did not provide adequate power for that exercise. Interpretation is made more difficult by the fact that expression of fetal hemoglobin and other variants such as β-thalassemia are known to alter the pain phenotype in sickle cell disease.23 These and other factors not evaluated as covariates might have changed the results.

The manifestation of recurrent and chronic pain phenotypes other than sickle cell disease with respect to variability in the COMT gene has been widely studied in fibromyalgia, temporomandibular disorders, cancer pain, and other syndromes. Similar to the results from acute pain and analgesia studies, the results have been somewhat variable (Table 2).24–53 However, unlike studies in acute pain, of 30 studies evaluating chronic pain syndromes, only 1 found that reduced COMT enzyme activity was associated with reduced pain or analgesic utilization that was statistically significant.

Table 2

Table 2

Pertinent to both reports, several studies have suggested that COMT genotype is not related to pain severity itself, but exerts its effects through modulation of psychological factors such as anxiety and depression with which catechol metabolism is strongly associated.26,27 Both anxiety and depression are strongly associated with pain and analgesic use. For example, a study of fibromyalgia patients and pain-free controls found that patients homozygous for COMT 158Met scored worst on tests for anxiety, depression catastrophizing, perceived health, and functional status, while those homozygous for Val158 scored more favorably.28 The largest study of acute pain in 1000 breast cancer patients12 did not find an association between COMT SNPs known to affect enzyme activity and postoperative pain, but did not assess symptoms of anxiety and/or depression.

Another source of variability is that the primary outcome variables are quite different between studies. Behavioral outcomes as complex as pain and analgesic requirement can be analyzed in many different ways. Because authors often highlight those associations that are statistically significant, it is not surprising that different studies present different outcomes. Not only does post hoc selection of “important findings” make comparison among studies difficult, but it is almost certain to introduce bias into the published results for behavioral studies. Although the primary outcome variable was clearly addressed in the current studies, the presence of multiple behavior outcomes in other studies raises the specter of improper statistical adjustment for multiple comparisons, potentially exaggerating the significance of positive findings.

Given the complex biology that underlies nociceptive transmission and pain manifestation, it is not surprising that the interpretation of findings in studies of COMT genotype and pain manifestation are not straightforward. Although there is ample scientific rational to consider the relationship, particularly in chronic pain syndromes such as those listed in Table 2, it may be that we are looking at the wrong end point. Although the effect of catecholamine concentration on pain transmission is variable, the relationship with psychological modulators such as anxiety, depression, and catastrophizing may be better supported. Consider how this may have affected the current reports; perhaps sickle cell patients who express the 158Met form of COMT experienced similar nociceptive input, but were more motivated to seek treatment thus explaining the higher incidence of reported crises.

Future studies on catecholaminergic modulation of pain might best include complete genotyping of the 4 SNPs that have been found to relate to enzyme activity. In addition, they should include in their analysis gender and psychological variables that are known to be influenced by COMT genotype. To properly assess these variables, a careful multivariable analysis will be required that is powered to allow consideration of these factors. Finally, there is a growing expectation that nonexploratory reports include replication datasets to confirm or refute the findings of the primary analyses.

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Dr. Pamela Flood is the wife of Dr. Steven Shafer, Editor-in-Chief of Anesthesia & Analgesia. This manuscript was handled by James G. Bovill, Guest Editor-in-Chief, and Dr. Shafer was not involved in any way with the editorial process or decision.

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Name: Pamela Flood, MD, MA.

Contribution: This author helped write the manuscript.

Attestation: Pamela Flood approved the final manuscript.

Name: David Clark, MD, PhD.

Contribution: This author helped write the manuscript.

Attestation: David Clark approved the final manuscript.

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1. Candiotti KA, Yang Z, Buric D, Arheart K, Zhang Y, Rodriguez Y, Gitlin MC, Carvalho E, Jaraba I, Wang L. Catechol-O-methyltransferase polymorphisms predict opioid consumption in postoperative pain. Anesth Analg. 2014;119:1194–200
2. Jhun E, He Y, Yao Y, Molokie RE, Wilkie DJ, Wang ZJ. Dopamine D3 receptor Ser9Gly and catechol-O-methyltransferase Val158Met polymorphisms and acute pain in sickle cell disease. Anesth Analg. 2014;119:1201–7
3. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14:135–43
4. Belfer I, Segall SK, Lariviere WR, Smith SB, Dai F, Slade GD, Rashid NU, Mogil JS, Campbell CM, Edwards RR, Liu Q, Bair E, Maixner W, Diatchenko L. Pain modality- and sex-specific effects of COMT genetic functional variants. Pain. 2013;154:1368–76
5. Nackley AG, Shabalina SA, Lambert JE, Conrad MS, Gibson DG, Spiridonov AN, Satterfield SK, Diatchenko L. Low enzymatic activity haplotypes of the human catechol-O-methyltransferase gene: enrichment for marker SNPs. PLoS One. 2009;4:e5237
6. Segall SK, Maixner W, Belfer I, Wiltshire T, Seltzer Z, Diatchenko L. Janus molecule I: dichotomous effects of COMT in neuropathic vs nociceptive pain modalities. CNS Neurol Disord Drug Targets. 2012;11:222–35
7. Rut M, Machoy-Mokrzyńska A, Ręcławowicz D, Słoniewski P, Kurzawski M, Droździk M, Safranow K, Morawska M, Białecka M. Influence of variation in the catechol-O-methyltransferase gene on the clinical outcome after lumbar spine surgery for one-level symptomatic disc disease: a report on 176 cases. Acta Neurochir (Wien). 2014;156:245–52
8. Sadhasivam S, Chidambaran V, Olbrecht VA, Esslinger HR, Zhang K, Zhang X, Martin LJ. Genetics of pain perception, COMT and postoperative pain management in children. Pharmacogenomics. 2014;15:277–84
9. De Gregori M, Garbin G, De Gregori S, Minella CE, Bugada D, Lisa A, Govoni S, Regazzi M, Allegri M, Ranzani GN. Genetic variability at COMT but not at OPRM1 and UGT2B7 loci modulates morphine analgesic response in acute postoperative pain. Eur J Clin Pharmacol. 2013;69:1651–8
10. Ahlers SJ, Elens LL, van Gulik L, van Schaik RH, van Dongen EP, Bruins P, Tibboel D, Knibbe CA. The Val158Met polymorphism of the COMT gene is associated with increased pain sensitivity in morphine-treated patients undergoing a painful procedure after cardiac surgery. Br J Clin Pharmacol. 2013;75:1506–15
11. Landau R, Liu SK, Blouin JL, Carvalho B. The effect of OPRM1 and COMT genotypes on the analgesic response to intravenous fentanyl labor analgesia. Anesth Analg. 2013;116:386–91
12. Kambur O, Kaunisto MA, Tikkanen E, Leal SM, Ripatti S, Kalso EA. Effect of catechol-o-methyltransferase-gene (COMT) variants on experimental and acute postoperative pain in 1,000 women undergoing surgery for breast cancer. Anesthesiology. 2013;119:1422–33
13. Mamie C, Rebsamen MC, Morris MA, Morabia A. First evidence of a polygenic susceptibility to pain in a pediatric cohort. Anesth Analg. 2013;116:170–7
14. Lee PJ, Delaney P, Keogh J, Sleeman D, Shorten GD. Catecholamine-o-methyltransferase polymorphisms are associated with postoperative pain intensity. Clin J Pain. 2011;27:93–101
15. McLean SA, Diatchenko L, Lee YM, Swor RA, Domeier RM, Jones JS, Jones CW, Reed C, Harris RE, Maixner W, Clauw DJ, Liberzon I. Catechol O-methyltransferase haplotype predicts immediate musculoskeletal neck pain and psychological symptoms after motor vehicle collision. J Pain. 2011;12:101–7
16. Orrey DC, Bortsov AV, Hoskins JM, Shupp JW, Jones SW, Cicuto BJ, Hwang J, Jordan MH, Holmes JH, Haith LR, Roane BM, Diatchenko L, Cairns BA, McLean SA. Catechol-O-methyltransferase genotype predicts pain severity in hospitalized burn patients J Burn Care Res. 2012;33:518–23
17. Kim H, Lee H, Rowan J, Brahim J, Dionne RA. Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans. Mol Pain. 2006;2:24
18. Potvin S, Larouche A, Normand E, de Souza JB, Gaumond I, Grignon S, Marchand S. DRD3 Ser9Gly polymorphism is related to thermal pain perception and modulation in chronic widespread pain patients and healthy controls. J Pain. 2009;10:969–75
19. Storm H, Støen R, Klepstad P, Skorpen F, Qvigstad E, Raeder J. Nociceptive stimuli responses at different levels of general anaesthesia and genetic variability. Acta Anaesthesiol Scand. 2013;57:89–99
20. Klepstad P, Fladvad T, Skorpen F, Bjordal K, Caraceni A, Dale O, Davies A, Kloke M, Lundström S, Maltoni M, Radbruch L, Sabatowski R, Sigurdardottir V, Strasser F, Fayers PM, Kaasa SEuropean Palliative Care Research Collaborative (EPCRC); European Association for Palliative Care Research Network. . Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain. 2011;152:1139–45
21. Martikainen IK, Hagelberg N, Mansikka H, Hietala J, Någren K, Scheinin H, Pertovaara A. Association of striatal dopamine D2/D3 receptor binding potential with pain but not tactile sensitivity or placebo analgesia. Neurosci Lett. 2005;376:149–53
22. Pertovaara A, Martikainen IK, Hagelberg N, Mansikka H, Någren K, Hietala J, Scheinin H. Striatal dopamine D2/D3 receptor availability correlates with individual response characteristics to pain. Eur J Neurosci. 2004;20:1587–92
23. Thein SL. Genetic modifiers of sickle cell disease. Hemoglobin. 2011;35:589–606
24. Desmeules J, Chabert J, Rebsamen M, Rapiti E, Piguet V, Besson M, Dayer P, Cedraschi C. Central pain sensitization, COMT Val158Met polymorphism, and emotional factors in fibromyalgia. J Pain. 2014;15:129–35
25. Martínez-Jauand M, Sitges C, Rodríguez V, Picornell A, Ramon M, Buskila D, Montoya P. Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene. Eur J Pain. 2013;17:16–27
26. Fernández-de-Las-Peñas C, Ambite-Quesada S, Gil-Crujera A, Cigarán-Méndez M, Peñacoba-Puente C. Catechol-O-methyltransferase Val158Met polymorphism influences anxiety, depression, and disability, but not pressure pain sensitivity, in women with fibromyalgia syndrome. J Pain. 2012;13:1068–74
27. Desmeules J, Piguet V, Besson M, Chabert J, Rapiti E, Rebsamen M, Rossier MF, Curtin F, Dayer P, Cedraschi C. Psychological distress in fibromyalgia patients: a role for catechol-O-methyl-transferase Val158met polymorphism. Health Psychol. 2012;31:242–9
28. Finan PH, Zautra AJ, Davis MC, Lemery-Chalfant K, Covault J, Tennen H. COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia. Pain. 2011;152:300–7
29. Nicholl BI, Holliday KL, Macfarlane GJ, Thomson W, Davies KA, O’Neill TW, Bartfai G, Boonen S, Casanueva F, Finn JD, Forti G, Giwercman A, Huhtaniemi IT, Kula K, Punab M, Silman AJ, Vanderschueren D, Wu FC, McBeth JEuropean Male Ageing Study Group. . No evidence for a role of the catechol-O-methyltransferase pain sensitivity haplotypes in chronic widespread pain. Ann Rheum Dis. 2010;69:2009–12
30. Hocking LJ, Smith BH, Jones GT, Reid DM, Strachan DP, Macfarlane GJ. Genetic variation in the beta2-adrenergic receptor but not catecholamine-O-methyltransferase predisposes to chronic pain: results from the 1958 British Birth Cohort Study. Pain. 2010;149:143–51
31. Cohen H, Neumann L, Glazer Y, Ebstein RP, Buskila D. The relationship between a common catechol-O-methyltransferase (COMT) polymorphism val(158) met and fibromyalgia. Clin Exp Rheumatol. 2009;27:S51–6
32. Hagen K, Pettersen E, Stovner LJ, Skorpen F, Zwart JA. No association between chronic musculoskeletal complaints and Val158Met polymorphism in the Catechol-O-methyltransferase gene. The HUNT study. BMC Musculoskelet Disord. 2006;7:40
33. Michelotti A, Liguori R, Toriello M, D’Antò V, Vitale D, Castaldo G, Sacchetti L. Catechol-O-methyltransferase (COMT) gene polymorphisms as risk factor in temporomandibular disorders patients from Southern Italy. Clin J Pain. 2014;30:129–33
34. Schwahn C, Grabe HJ, Meyer zu Schwabedissen H, Teumer A, Schmidt CO, Brinkman C, Kocher T, Nauck M, Völzke H, Biffar R, Bernhardt O. The effect of catechol-O-methyltransferase polymorphisms on pain is modified by depressive symptoms. Eur J Pain. 2012;16:878–89
35. Slade GD, Diatchenko L, Bhalang K, Sigurdsson A, Fillingim RB, Belfer I, Max MB, Goldman D, Maixner W. Influence of psychological factors on risk of temporomandibular disorders. J Dent Res. 2007;86:1120–5
36. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14:135–43
37. Fernández-de-las-Peñas C, Fernández-Lao C, Cantarero-Villanueva I, Ambite-Quesada S, Rivas-Martínez I, del Moral-Avila R, Arroyo-Morales M. Catechol-O-methyltransferase genotype (Val158met) modulates cancer-related fatigue and pain sensitivity in breast cancer survivors. Breast Cancer Res Treat. 2012;133:405–12
38. Klepstad P, Fladvad T, Skorpen F, Bjordal K, Caraceni A, Dale O, Davies A, Kloke M, Lundström S, Maltoni M, Radbruch L, Sabatowski R, Sigurdardottir V, Strasser F, Fayers PM, Kaasa SEuropean Palliative Care Research Collaborative (EPCRC); European Association for Palliative Care Research Network. . Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. Pain. 2011;152:1139–45
39. Rakvåg TT, Ross JR, Sato H, Skorpen F, Kaasa S, Klepstad P. Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Mol Pain. 2008;4:64
40. Reyes-Gibby CC, Shete S, Rakvåg T, Bhat SV, Skorpen F, Bruera E, Kaasa S, Klepstad P. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain. 2007;130:25–30
41. George SZ, Parr JJ, Wallace MR, Wu SS, Borsa PA, Dai Y, Fillingim RB. Biopsychosocial influence on exercise-induced injury: genetic and psychological combinations are predictive of shoulder pain phenotypes. J Pain. 2014;15:68–80
42. George SZ, Dover GC, Wallace MR, Sack BK, Herbstman DM, Aydog E, Fillingim RB. Biopsychosocial influence on exercise-induced delayed onset muscle soreness at the shoulder: pain catastrophizing and catechol-o-methyltransferase (COMT) diplotype predict pain ratings. Clin J Pain. 2008;24:793–801
43. George SZ, Wallace MR, Wright TW, Moser MW, Greenfield WH 3rd, Sack BK, Herbstman DM, Fillingim RB. Evidence for a biopsychosocial influence on shoulder pain: pain catastrophizing and catechol-O-methyltransferase (COMT) diplotype predict clinical pain ratings. Pain. 2008;136:53–61
44. Fernández-de-las-Peñas C, Ambite-Quesada S, Rivas-Martínez I, Ortega-Santiago R, de-la-Llave-Rincón AI, Fernández-Mayoralas DM, Pareja JA. Genetic contribution of catechol-O-methyltransferase polymorphism (Val158Met) in children with chronic tension-type headache. Pediatr Res. 2011;70:395–9
45. Hagen K, Pettersen E, Stovner LJ, Skorpen F, Zwart JA. The association between headache and Val158Met polymorphism in the catechol-O-methyltransferase gene: the HUNT Study. J Headache Pain. 2006;7:70–4
46. Cargnin S, Magnani F, Viana M, Tassorelli C, Mittino D, Cantello R, Sances G, Nappi G, Canonico PL, Genazzani AA, Raffaeli W, Terrazzino S. An opposite-direction modulation of the COMT Val158Met polymorphism on the clinical response to intrathecal morphine and triptans. J Pain. 2013;14:1097–106
47. Jacobsen LM, Schistad EI, Storesund A, Pedersen LM, Rygh LJ, Røe C, Gjerstad J. The COMT rs4680 Met allele contributes to long-lasting low back pain, sciatica and disability after lumbar disc herniation. Eur J Pain. 2012;16:1064–9
48. Hall KT, Lembo AJ, Kirsch I, Ziogas DC, Douaiher J, Jensen KB, Conboy LA, Kelley JM, Kokkotou E, Kaptchuk TJ. Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome. PLoS One. 2012;7:e48135
49. Karling P, Danielsson Å, Wikgren M, Söderström I, Del-Favero J, Adolfsson R, Norrback KF. The relationship between the val158met catechol-O-methyltransferase (COMT) polymorphism and irritable bowel syndrome. PLoS One. 2011;6:e18035
50. Bortsov AV, Diatchenko L, McLean SA. Complex multilocus effects of catechol-O-methyltransferase haplotypes predict pain and pain interference 6 weeks after motor vehicle collision. Neuromolecular Med. 2014;16:83–93
51. Li W, Chen Y, Yin B, Zhang L. Pain in Parkinson’s disease associated with COMT gene polymorphisms. Behav Neurol. 2014;2014:304203
52. Kolesnikov Y, Gabovits B, Levin A, Veske A, Qin L, Dai F, Belfer I. Chronic pain after lower abdominal surgery: do catechol-O-methyl transferase/opioid receptor μ-1 polymorphisms contribute? Mol Pain. 2013;8:9–19
53. Armero P, Muriel C, Santos J, Sànchez-Montero FJ, Rodríguez RE, González-Sarmiento R. COMT (Val158Met) polymorphism is not associated to neuropathic pain in a Spanish population. Eur J Pain. 2005;9:229–32
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