Catechol-O-methyltransferase gene polymorphism and chronic human pain: a systematic review and meta-analysis.

Mini review 1

Catechol-O-methyltransferase gene polymorphism and chronic human pain: a systematic review and meta-analysis Anne Tammima¨ki and Pekka T. Ma¨nnisto¨ In human studies, low COMT (catechol-Omethyltransferase) activity has been associated with increased sensitivity to acute clinical preoperative or postoperative pain. We explored the association between the COMT genotype and three chronic pain conditions: migrainous headache, fibromyalgia, or chronic widespread pain and chronic musculoskeletal pain. Furthermore, we evaluated whether COMT genotype affects the efficacy of opioids in chronic pain. After a systematic literature review, we carried out meta-analyses on the three chronic pain conditions. The efficacy of opioids was evaluated using a systematic review only. The meta-analyses showed that fibromyalgia or chronic widespread pain is the only type of chronic pain that could be associated with the COMT single nucleotide polymorphism rs4680 (Val158Met). Met158, which results in the low-activity variant of COMT, is the risk allele. In chronic clinical pain, the effect of the COMT polymorphism depends on the pain condition. Low COMT activity is not associated with migrainous headache or chronic musculoskeletal pain conditions, but it may increase the risk for fibromyalgia or chronic widespread pain. Low COMT activity increases opioid receptors and

enhances opioid analgesia and adverse effects in some cancer pains. Findings from animal studies that have utilized COMT inhibitors elucidate the mechanism behind these findings. In rodent pain models, COMT inhibitors are pronociceptive, except for neuropathic pain models, where nitecapone was found to be antiallodynic. The complex interplay between enhanced adrenergic and dopaminergic activity in different parts of the nociceptive system probably explains the complicated actions of low COMT c activity. Pharmacogenetics and Genomics 00:000–000  2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Introduction

COMT [9] and uptake by the noradrenaline transporter [4,10–14] appear to control the dopaminergic transmission. Therefore, changes in the brain COMT activity are reflected mainly in functions that are dependent on the prefrontal cortex [1–4,14,15].

General

Several general factors can explain why catechol-Omethyltransferase (COMT) activity is associated with pain. First, COMT is one of the regulators of extracellular catecholamine concentrations, especially in prefrontal brain areas and peripheral tissues, and catecholamines in turn affect the pain tract at several levels. Second, there is some evidence that polymorphisms of the COMT gene, some of which substantially affect COMT activity, may affect pain perception and a patient’s ability to cope with pain. Third, compounds that inhibit COMT activity modify pain responses primarily by preventing the metabolism of catecholamines; however, COMT inhibitors could have their own properties, such as the alleviation of oxidative stress, which could interfere in at least some forms of pain. In the brain areas with a high dopamine transporter density, such as the striatum, uptake1 into dopamine nerve terminals by dopamine transporter is the primary mode of terminating the dopamine signal, and COMT plays a minor role [1–4]. In contrast, in brain areas with a low dopamine transporter density [5], for example in the prefrontal cortex, uptake2 into postsynaptic neurons or non-neuronal cells [6–8], followed by metabolism by c 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins 1744-6872 

Pharmacogenetics and Genomics 2012, 00:000–000 Keywords: catechol-O-methyltransferase, COMT activity, COMT gene, efficacy of opioids, fibromyalgia, function of COMT isoforms, headache, musculoskeletal pain, polymorphism Division of Pharmacology and Toxicology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland Correspondence to Anne Tammima¨ki, Institute for Behavioral Genetics, University of Colorado at Boulder, UCB 447, Boulder, CO 80309, USA Tel: + 1 303 735 6571; fax: + 1 303 492 8063; e-mail: [email protected] Received 23 November 2011 Accepted 4 May 2012

The COMT gene [COMT (human gene), Comt] codes for soluble (S-COMT) and membrane-bound (MB-COMT) COMT protein isoforms [16,17]. The COMT gene harbors dozens of single nucleotide polymorphisms (SNPs) and at least six of the most frequently occurring SNPs have been investigated for their association with human pain perception. One SNP (rs2075507) is located in the estrogen-sensitive portion of the MB-COMT promoter region, and the second (rs6269) is located in the promoter region of S-COMT [18]. The next three SNPs (rs4633, rs4818, and rs4680) are in the coding region of both S-COMT and MB-COMT. The sixth SNP (rs165599) is located at the end of the 30 -UTR of the gene [19]. Variations in SNPs rs4633 and rs4818 are synonymous whereas the variation in SNP rs4680 is nonsynonymous and codes for a substitution of valine (Val) to methionine (Met) at codon 158 for MB-COMT and at codon 108 for S-COMT. This scenario produces an enzyme with a lower thermostability, which results in decreased enzyme activity under physiological conditions. DOI: 10.1097/FPC.0b013e3283560c46

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2 Pharmacogenetics and Genomics 2012, Vol 00 No 00

This Val158Met polymorphism, which governs the level of COMT activity [20,21], has been linked to several mental diseases, such as schizophrenia, in which the cortical dopaminergic function is important [22–25]. This systematic review and meta-analysis explores the association between the COMT genotype and certain chronic pain conditions: migrainous headache, fibromyalgia or chronic widespread pain, and chronic musculoskeletal pain. We also investigated, by means of a systematic and narrative review, whether the COMT genotype affects the opioid response in chronic pain patients. The results from the meta-analyses show that fibromyalgia or chronic widespread pain is the only type of chronic pain that may be associated with COMT SNP rs4680. Catechol-O-methyltransferase activity and pain in animal studies

The effects of altered COMT activity on pain have been characterized using genetically modified mice [26,27]. The mouse lines include Comt knockout mice in which the Comt gene has been rendered inactive [28] and transgenic mice that locally overexpress the Val158 variant of the human COMT gene in the prefrontal cortex (COMT Val-tg [27]). In addition, the impact of COMT activity on pain sensation has been studied using normal mice and rats that were administered COMT inhibitors [29–32]. New selective COMT inhibitors undoubtedly interfere with pain perception [29,30,32]. The COMT Val-tg mice that overexpress the human highactivity COMT variant in the prefrontal cortex show diminished sensitivity to painful stimuli in tail flick and hot plate tests [27]. In agreement with this finding, homozygous Comt knockout mice that completely lack COMT activity showed increased pain sensitivity [27]. However, in our study, which also utilized the same tests, the pain sensitivity of homozygous knockout mice with no COMT activity and heterozygous knockout mice with 50% of the wild-type COMT activity did not differ from that of their wild-type littermates [26]. In acute pain models, COMT inhibitors such as OR-486 (3,5-dinitrocatechol; 30 mg/kg, intraperitoneally) and tolcapone (Ro 41-0960; 30 mg/kg, intraperitoneally) have been pronociceptive [29,30,32], and they have sensitized the rats to mechanical and thermal nociceptive stimuli [29,30]. The same effect was observed in mice after the administration of different types of COMT inhibitors [32]. Nitecapone, a COMT inhibitor, partially prevented the development of allodynia in two different neuropathic pain models in the rats: the diabetic neuropathy [31,33] and the spinal nerve ligation model.

Methods The questions we wanted to answer were as follows: Do COMT polymorphisms (rs4680 and others) affect the risk

of chronic pain conditions? Do they affect the response to analgesic treatments in chronic pain? Systematic searches were performed utilizing Pubmed and the ISI Web of Science, which were limited to human studies and covered articles published in English, French, German, Spanish, Italian, Portuguese, Swedish, Norwegian, Danish, Estonian, or Finnish, and were published or in press before 31 December 2011. We did not have access to any unpublished studies. We excluded abstracts, conference proceedings, case studies, reviews, and textbook chapters. We also hand-searched the reference lists for all retrieved studies and relevant review articles. The initial search terms were ‘catechol-O-methyltransferase’ and ‘chronic pain’. The papers that were retrieved from this search discussed several different chronic pain conditions including chronic musculoskeletal complaints or pain, chronic widespread pain, fibromyalgia, headache, postoperative pain in lumbar degenerative disc disease, postoperative shoulder pain, and temporomandibular joint disorder. On the basis of these findings, we performed the following searches: ‘Catechol-O-methyltransferase’ and ‘Musculoskeletal pain’; ‘Catechol-Omethyltransferase’ and ‘Chronic widespread pain’; ‘Catechol-O-methyltransferase’ and ‘Fibromyalgia’; ‘Catechol-O-methyltransferase’ and ‘Headache’; ‘Catechol-O-methyltransferase’ and ‘Postoperative pain’; ‘Catechol-O-methyltransferase’ and ‘Temporomandibular joint disease’. In addition, we decided to search for certain other chronic pain conditions that seemed to be missing: ‘Catechol-O-methyltransferase’ and ‘Cancer pain’, ‘Catechol-O-methyltransferase’ and ‘Neuropathic pain’, ‘Catechol-O-methyltransferase’ and ‘Back pain’ as well as ‘Catechol-O-methyltransferase’ and ‘Arthritis’. Furthermore, we were aware that the association between the COMT genotype and the effect of opioids had been studied and, therefore, we performed one more literature search with the terms ‘Catechol-O-methyltransferase’ and ‘Opioids’. Both authors evaluated the material independent of each other. Articles were selected in the following two stages: titles and abstracts, followed by full-text articles. Duplicate studies were excluded. The following information was abstracted from each study: first author, year of publication, phenotype, COMT polymorphism in question, number of participants, number of cases and controls, sex distribution, ethnicity of participants, enrollment strategy, minor allele frequency, DNA source, genotyping method, Hardy–Weinberg equilibrium (HWE), matching of cases and controls on the basis of ethnicity, mental conditions, and the main finding of the study. Studies were included in this review if they fulfilled the following criteria: (a) relevant phenotype studied [chronic headache, chronic musculoskeletal pain (fibromyalgia, chronic widespread pain, temporomandibular joint disorder, chronic low back pain, persistent postoperative pain), neuropathic pain, opioid response, or adverse effects of opioid treatment in chronic pain] and (b) adequate

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COMT polymorphism and chronic pain Tammima¨ki and Ma¨nnisto¨ 3

scientific quality (HWE analyzed, allele frequencies given, reasonable statistics, appropriate control group included, no population stratification reported). In some cases, the authors of the original articles were contacted for clarifications and supplementary information. Failure to report HWE was not an absolute exclusion criterion, but a thorough evaluation of the potential reasons for deviation was required for inclusion if the control group was not in HWE. If the authors did not carry out HWE analysis, we calculated it on the basis of the data given using an online calculator (http://www.oege.org/software/hwe-mr-calc.shtml [34]). When possible, w2 analyses, odds ratios (OR), and 95% confidence intervals (CIs) were also calculated for associations between the COMT polymorphism and the chronic pain phenotype if they were not given by the authors. In addition, the power was calculated using G*Power 3.1.2 software (Heinrich Heine University, Du ¨sseldorf, Germany [35]). Because the effects of most gene polymorphisms are minor [36], the power analyses were based on an assumption of a small effect size (0.1). Figure 0.1 refers to Cohen’s effect size measures, which he grouped into effect size conventions (‘small’ 0.1–0.3; ‘medium’ 0.3–0.5; and ‘large’ 0.5–0.8 [37]). Table 1 lists the studies that were included in or excluded from the review after the initial literature search. We continued the analysis by carrying out meta-analyses of the associations between the COMT Val158Met genotype and migrainous headache, fibromyalgia, or chronic widespread pain and musculoskeletal pain. Unfortunately, material on morphine response in chronic pain and morphine withdrawal symptoms was found to be too heterogeneous for a meta-analysis. Phenotypes were grouped as follows: meta-analysis I: migrainous headache, including both migraine with aura and migraine without aura. Meta-analysis II: Fibromyalgia and chronic widespread pain, defined according to the criteria of American College of Rheumatology. (Chronic widespread pain is the cardinal symptom of fibromyalgia.) Meta-analysis III: Chronic musculoskeletal pain conditions, including low back pain, osteoarthritis-related pain, upper limb and neck discomfort, and myofacial pain. We were also prepared to carry out meta-analyses of other COMT SNPs and haplotypes. However, the number of papers within each chronic pain condition group was not sufficient to study the associations between matching COMT haplotypes or SNPs other than rs4680. At least three papers were required for the meta-analyses. All of the articles that were eligible for the systematic review were included in the meta-analyses, provided that sufficient data were presented. The analyses were performed using Comprehensive Meta-Analysis Version 2 software (Biostat, Englewood, New Jersey, USA). A codominant genetic model was chosen because Val158 and Met158 alleles determine human COMT activity codominantly [75–77]. We used a random effects model

that accounts for the heterogeneity found between the studies. Between-study heterogeneity was assessed using Cochran’s Q (significant at P < 0.05) and I2 tests (25% = low heterogeneity, 50% = moderate heterogeneity, 75% = high heterogeneity [78]). One concern when carrying out a meta-analysis is the potential for publication bias, in which small and statistically nonsignificant studies may remain unpublished. This scenario, in turn, would result in overestimation of the effect sizes in a meta-analysis of published studies. We used two statistical methods, Duval and Tweedie’s trim and fill test and funnel plots, followed by Egger’s regression method (publication bias considered significant at P < 0.05) and Begg and Mazumdar’s rank correlation test (publication bias considered significant at P < 0.05) to address this problem. Duval and Tweedie’s trim and fill test calculates how the effect size would shift if the apparent bias was removed [79,80]. Funnel plots are plots of a measure of study size on the y-axis as a function of effect size on the x-axis. Larger studies are found at the top of the graph usually closer to the mean effect size, whereas smaller studies are found closer to the bottom of the graph scattered across a wider range of values. In the absence of publication bias, the studies included in the funnel plot are distributed symmetrically around the mean effect size. Symmetricity is verified by Egger’s regression test and Begg and Mazumdar’s rank correlation test.

Results General considerations

During the last phase of the data extraction, 10 articles were excluded from further analysis because of a failure to fulfill our inclusion criteria (Table 1). The most common reason was that the paper did not actually report an association between the COMT rs4680 and chronic pain condition. One article reported results that were already published in an earlier study and another was rejected because of a lack of HWE in the control group. Five articles could not be included in the meta-analyses because there were too few articles (one or two) on that specific pain condition (nonmigrainous headache, neuropathic pain, multisomatoform disorder, and persistent postsurgical pain) to carry out a meta-analysis. We could not carry out a meta-analysis on the opioid response studies because of the general heterogeneity of the published material. Instead, the opioid studies were reviewed in a traditional narrative manner. Altogether, 15 gene association studies on COMT and chronic pain were included in the meta-analyses. These studies included three papers on migrainous headache, eight papers on fibromyalgia or chronic widespread pain, and four papers on musculoskeletal pain conditions. The majority of the papers that were eligible for metaanalysis had studied Caucasian populations, including

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List of studies included in the systematic review and included in or excluded from the meta-analyses

References

Phenotype

Polymorphism

Meta-analysis I – migrainous headache + rs4680 Cevoli et al. [38] Migrainous headache and chronic headache with drug overuse

Population

Number of genotyped participants (overall/cases/ controls)

Selection of cases and controls

Variant allele frequency (overall/cases/controls, %)

Power to detect small size effects (calculated for rs4680)

rs4680

Caucasian Italian

259/158/101 (74 migraine cases, 84 drug overuse headache cases)

Cases enrolled from Emilia-Romagna, Italy. Controls healthy spouses of patients, healthy laboratory personnel, and neurological patients without migraine from the same geographical region.

48/45/47

0.36

2451/982/1469 (305 migraine cases, 677 nonmigraine cases)

Sample was randomized from HUNT (Helseundersøkelsen I Nord-Trøndelag, Nord-Trøndelag Health Survey) study participants.

57/56/57

1.00

Hagen et al. [39]

Migrainous and nonmigrainous headache

rs4680

Norwegian

Park et al. [40]

Migraine without aura

rs4680

Korean

191/97/94

Cases recruited from headache clinic of Catholic University of Korea. Recruitment strategy for controls not described.

27/25/30

0.28

Ferna´ndez-de-lasPen˜as et al. [41]

Chronic tensiontype headache in children

rs4680

Spanish

140/70/70

Cases recruited from the Neurology Department of Hospital Quiron, Madrid, Spain. Age-matched and sex-matched controls were recruited through a local announcement.

40/38/41

0.22

Postoperative shoulder pain

HPS, APS, and LPS haplotypes

American

58

Patients with discrete shoulder pain primarily managed with arthroscopic surgery were recruited at the University of Florida’s Orthopaedics Sports Medicine Institute.

Overall: HPS: 8%, APS: 53%, LPS: 39%

0.12

Outcome of surgery in patients with lumbar degenerative disc disease

rs2075507 (rs2097603), rs6269, rs4633, rs4818, rs4680, and HPS, APS and LPS haplotypes

Caucasian Americans

rs2075507: 66, rs6269: 66, rs4633: 67, rs4818: 59, rs4680: 68

Cases that were to undergo a surgical treatment for lumbar degenerative disc disease at New England Baptist Hospital, Boston, Massachusetts, USA, were prospectively enrolled.

Overall: rs2075507; 38%, rs6269; 47%, rs4633; 42%, rs4818; 45%, rs4680; 43%, HPS: 8%, APS: 39%, LPS: 50%

0.13

Persistent postsurgical pain George et al. [42]

Dai et al. [43]

Finding, OR vs. major allele

No association between rs4680 and migrainous headache Migrainous headache: OR 0.89, 95% CI 0.58–1.36, P = 0.6. Chronic headache with drug overuse: OR 1.13, 95% CI 0.75–1.70, P = 0.6 Included in the meta-analysis No significant association for migraine or nonmigrainous headache OR for allele frequencies in control vs. pain groups: migrainous headache: OR 0.92, 95% CI 0.77–1.10, P = 0.4 Nonmigrainous headache: OR 0.91, 95% CI 0.80–1.04, P = 0.2 Included in the meta-analysis rs4680 is apparently not associated with the risk of migraine without aura. However, it may be involved with the phenotype of migraine OR for allele frequencies in control vs. pain groups 1.26, 95% CI 0.80–1.97, P = 0.3 Included in the meta-analysis No association between chronic tensiontype headache and rs4680 OR for allele frequencies in control vs. pain groups 0.86, 95% CI 0.53–1.39, P = 0.6. Not included in the metaanalysis; not migrainous headache

COMT haplotype affects pain ratings together with pain catastrophizing ratings. Patients with APS or HPS haplotype and high pain catastrophizing score were more likely to demonstrate high postoperative pain rating (P = 0.03) COMT genotype vs. psychological factors affecting pain studied. Association between COMT genotype and postsurgical pain per se not studied Not included in the meta-analysis rs4633 significantly associated with greater improvement in disability index after surgery (P = 0.03). Average pain sensitivity haplotype of rs6269, rs4818, rs4633, and rs4680 may also be associated with better treatment outcome (P = 0.05) Association between lumbar degenerative disc disease and COMT genotype not studied, only genotype comparisons within cases regarding improvement in condition reported. Therefore, not included in the meta-analysis

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4 Pharmacogenetics and Genomics 2012, Vol 00 No 00

Table 1

Lee et al. [44]

Persistent postsurgical pain

Hickey et al. [45]

Persistent pain after breast cancer surgery

Ferna´ndez-deLas-Pen˜as et al. [46]

Persistent pain after breast cancer surgery

Meta-analysis II – fibromyalgia or chronic widespread pain + rs4680 Barbosa et al. [47]

rs4818, rs6269, rs4680,

rs4818: 95/7/88; rs6269: 94/6/88, rs4680: 97/7/ 90

Participants, who gave their written consent, were patients scheduled to undergo surgical extraction of at least 2 M3 teeth under general anesthesia.

rs4680

Irish

41/18/23

Women who had undergone breast reconstruction following mastectomy for breast cancer at the Cork Teaching Hospitals, Cork, Ireland, were invited to participate. Patients who had undergone the surgery but did not experience persistent postsurgical pain were recruited as controls.

45/28/59

0.10

rs4680

Spanish

128

Participants were recruited from the Unit of Breast Oncology of the Hospital Virgen de las Nieves, Granada, Spain.

Overall 48%

0.20

Brazilian Caucasian

222/112/110

Cases were inpatients from the University Hospital of Ribeirao Preto, Brazil. Controls were unrelated healthy volunteers.

rs4680: 63/41/85 rs4818: 68/47/89 Controls not in HWE

0.32

722/418/304

Patients and their relatives were enrolled from the Rheumatology Outpatient Clinic at the Soroka University Hospital, Beersheba, Israel. Participants were recruited from physician’s offices, advertisements, senior citizen groups, and mailings to members of the Arthritis Foundation in the Phoenix metropolitan area.

45/39/50

0.77

Overall 48%

0.10

Overall 48%

0.10

Fibromyalgia

rs4680, rs4818

Cohen et al. [48]

Fibromyalgia

rs4680

Israeli

Finan et al. [49]

Fibromyalgia

rs4680

American

46

Finan et al. [50]

Fibromyalgia

rs4680

American

46

Participants were recruited from physician’s offices, advertisements, senior citizen groups, and mailings to members of the Arthritis Foundation in the Phoenix metropolitan area.

Overall: rs4818: 56% rs6269: 43% rs4680: 47%

0.16

COMT genotype for rs6269 and rs4818 but not rs4860 is involved in persistent postsurgical pain OR for allele frequencies in control vs. pain groups: rs4818: OR 0.57, 95% CI 0.19–1.71, P = 0.4 rs6269: OR 1.38, 95% CI 0.43–4.45, P = 0.8 rs4680: OR 0.59, 95% CI 0.19–1.84, P = 0.4 Not included in the meta-analysis because there are too few (two) eligible studies in this pain group rs4680 genotype linked with the development of persistent postsurgical pain OR for allele frequencies in control vs. pain groups 0.27, 95% CI 0.11–0.69, P = 0.007 Not included in the meta-analysis because there are too few (two) eligible studies in this pain group Met158Met carriers exhibit higher pain scores Association between chronic postoperative pain and COMT genotype not studied Not included in the meta-analysis

Met allele of rs4680 (OR 7.92, 95% CI 5.04–12.46, P < 0.0001) and C allele of rs4818 (OR 8.41, 95% CI 5.10–13.88, P < 0.0001) are predictive of fibromyalgia Excluded from the meta-analysis due to lack of HWE Met allele of rs4680 is the risk allele for fibromyalgia (OR 1.56, 95% CI 1.16–2.11, P = 0.003) Included in the meta-analysis rs4680 was not associated with fibromyalgia pain intensity but it moderates the effect of pain on positive affect Comparisons performed in fibromyalgia patients, not between patients and healthy controls. Association between COMT genotype and fibromyalgia per se not studied Not included in the meta-analysis rs4680 moderates the relation of daily maladaptive coping and pain such that Met158Met carriers experienced more pain than other genotypes when pain catastrophizing was increased (P < 0.0001). However, rs4680 is not directly linked with pain intensity Apparently the same study population as in the previous study Comparisons performed in fibromyalgia patients, not between patients and healthy controls. Association between COMT genotype and fibromyalgia per se not studied Not included in the meta-analysis

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COMT polymorphism and chronic pain Tammima¨ki and Ma¨nnisto¨ 5

Irish

References

Phenotype

Polymorphism

Hocking et al. [51]

Chronic widespread pain

Caucasian British

Matsuda et al. [52]

Fibromyalgia

rs737866, rs1544325, rs174674, rs5993882, rs5993883, rs4633, rs4680, rs165774, rs174699, rs9332377, rs165599, three haploblocks: block 1 rs737866rs1544325rs174674rs5993882; block 2 rs4633rs4680rs165774; block 3 rs174699rs9332377rs165599 rs4680

Nicholl et al. [53]

Chronic widespread pain

rs4680; HPS, APS, and LPS haplotypes

Potvin et al. [54]

Chronic widespread pain

rs4680

Vargas-Alarco´n et al. [55]

Fibromyalgia

Rs2075507 (rs2097603), rs6269, rs4633, rs4818, rs4680, rs165599, HPS, APS and LPS haplotypes

Population

Number of genotyped participants (overall/cases/ controls)

Selection of cases and controls

Variant allele frequency (overall/cases/controls, %)

Power to detect small size effects (calculated for rs4680)

Finding, OR vs. major allele

rs737866: 1428/830/598; rs1544325: 1427/830/ 597; rs 174674: 1498/ 871/627; rs5993882: 1498/871/627; rs59931427: 784/829/ 598; rs4633: 1498/ 871/627; rs4680: 1736/1009/727; rs165774: 1395/809/ 586; rs174699: 1498/ 871/627; rs9332377: 1498/871/627; rs165599: 954/556/ 398

Cases and controls are part of The National Child Development Study, the 1958 British Birth Cohort. It consists of all people born in England, Scotland, and Wales during first week in March 1958.

Overall: rs737866: 29%, rs1544325: 43%, rs174674: 28%, rs5993882: 24%, rs5993883: 46%, rs4633: 50%, rs4680: 50%, rs165774: 30%, rs174699: 5%, rs9332377: 16%, rs165599: 29%

1.00

No association of pain status or chronic widespread pain with COMT SNPs or haplotypes. rs737866 OR 0.97, 95% CI 0.75–1.26, P = 0.8; rs1544325 OR 1.11, 95% CI 0.88–1.41, P = 0.4; rs174674 OR 0.85, 95% CI 0.66–1.10, P = 0.2; rs5993882 OR 0.98, 95% CI 0.75–1.28, P = 0.9; rs5993883 OR 0.97, 95% CI 0.77–1.23, P = 0.8; rs4633 OR 0.85, 95% CI 0.68–1.08, P = 0.2; rs4680 OR 1.13, 95% CI 0.92–1.40, P = 0.3; rs165774 OR 1.08, 95% CI 0.84–1.39, P = 0.6; rs174699 OR 1.02, 95% CI 0.60–1.73, P = 0.9; rs9332377 OR 1.03, 95% CI 0.75–1.41, P = 0.9; rs165599 OR 1.21, 95% CI 0.90–1.64, P = 0.2 Included in the meta-analysis

Brazilian Caucasian

102/51/51

Cases were enrolled from Clinical Centre Electro Bonini at University of Ribeirao Preto, Brazil. Controls were healthy volunteers.

50/60/40

0.17

European (Italian, Belgian, Polish, Swedish, British, Spanish, Hungarian, and Estonian)

1422/343/1079

Participants were selected from Epidemiology of Functional Disorders (EPIFUND) and European Male Aging Study (EMAS) cohorts.

rs4680: 52/52/52; HPS: 9/11/9 APS: 50/51/49 LPS: 41/37/42

0.96

47/47/46

0.14

rs6269: Spanish 54/46/ 61, Mexican 29/29/29 rs4633: Spanish 47/41/ 53, Mexican 35/39/29 rs4818: Spanish, 54/46/ 63 Mexican 32/29/36 rs4680: Spanish 45/37/ 48, Mexican 32/32/33 rs2075507: Spanish 42/38/ 46, Mexican 33/33/32 rs16559: Spanish 36/35/ 37, Mexican 49/51/47 HPS: Spanish 24/30/19, Mexican 29/29/29 APS: Spanish 19/22/16, Mexican 27/27/27 LPS: Spanish 26/26/26, Mexican 22/20/24

0.35

The Met/Met genotype of rs4680 was more common in the fibromyalgia group than in the controls (OR 2.21, 95% CI 1.27–3.88, P = 0.005) Included in the meta-analysis No association between rs4680 or pain haplotypes and the risk of chronic widespread pain (rs4680 OR 1.01, 95% CI 0.8501–1.199, P = 0.9, haplotypes, OR 1.22, 95% CI 0.82–1.83, P = 0.3) Included in the meta-analysis No association between rs4680 and chronic widespread pain (OR 1.06, 95% CI 0.55–2.03, P = 0.9) Included in the meta-analysis rs4680 is associated with fibromyalgia in the Spaniards but not in the Mexicans rs6269: Spaniards OR 0.54, 95% CI 0.35–0.85, P = 0.009; Mexicans OR 1.01, 95% CI 0.52–1.97, P = 1 rs4818: Spaniards OR 0.49, 95% CI 0.31–0.77, P = 0.002; Mexicans OR 0.71, 95% CI 0.37–1.36, P = 0.3 rs4680: Spaniards OR 1.82, 95% CI 1.16–2.85, P = 0.009; Mexicans OR 1.08, 95% CI 0.57–2.07, P = 0.9 Haplotype: Spaniards OR 1.74, 95% CI 1.03–2.93, P = 0.04. Mexicans OR 1.01, 95% CI 0.52–1.97, P = 1 Included in the meta-analysis

Canadian

Hispanic Spaniards and Mexicans

73/37/36

248/135/113

Patients were recruited through newspaper ads, fibromyalgia associations, and referrals from physicians. Recruitment strategy for controls not given. Patients were sourced from different private rheumatology clinics in Spain and Mexico. Controls were paramedics or family of paramedics, or blood donors.

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6 Pharmacogenetics and Genomics 2012, Vol 00 No 00

Table 1 (continued)

Fibromyalgia

rs4680

Turkish

171/80/91

Gu¨rsoy et al. [57]

Fibromyalgia

rs4680

Turkish

122/61/61

Multisomatoform disorder

Rs2075507 (rs2097603), rs6269, rs4633, rs4818, rs4680, rs165599 HPS, APS, and LPS haplotypes

German

298/149/149

Patients and controls were recruited through the outdoor clinic of the Department of Anesthesiology of the Medical School Hannover (MHH), Hannover, Germany. Healthy Controls were employees and students searched through MHH intranet.

Opioid response in postoperative pain in Crohn’s disease patients Opioid response in cancer pain

HPS, APS, and LPS haplotypes

German

308/145/163

rs4680, rs4633, rs2020917, rs5993882, rs4646312, rs165722

Caucasian European (Scandin avian, Finnish, British, German, Lithuanian, Italian, Swiss)

Multisomatoform disorder Jakobi et al. [58]

Chronic pain and opioid response Huehne et al. [59]

Klepstad et al. [60]

Development sample: rs4646312: 1416; rs4680: 1461; validation sample: rs4646312: 697; rs4680: 714

Patients were recruited from the outpatient clinics of Physical Medicine and Rehabilitation Department of Ondokuzmayis University School of Medicine, Samsun, Turkey. Controls were healthy volunteers from the same geographic area. Patients were recruited from the physical therapy and rehabilitation clinic of Gaziantep University Medical Hospital, Kolejtepe Gaziantep, Turkey. Controls were healthy volunteers, mostly hospital staff.

48/48/48

0.26

rs4680 is not linked with fibromyalgia (OR 1.04, 95% CI 0.68–1.58, P = 1) Included in the meta-analysis

41/47/36

0.20

rs4680 shows a nonsignificant trend towards association with fibromyalgia (OR 1.56, 95% CI 0.93–2.60, P = 0.09) Included in the meta-analysis

rs2075507: 44/45/43 rs6269: 41/41/41 rs4633: 46/49/43 rs4818: 33/36/30 rs4680: 46/50/43 rs165599: 30/31/30 HPS 9/8/9, APS 46/45/ 47, LPS 30/32/28

0.41

rs4680 or pain sensitivity haplotypes are not associated with multisomatoform disorder rs2075507: OR 1.10, 95% CI 0.80–1.52, P = 0.6; rs6269: OR 0.99, 95% CI 0.71–1.37, P = 1; rs4633: OR 1.28, 95% CI 0.86–3.15, P = 0.2; rs4818: OR 2.94, 95% CI 1.08–8.00, P = 0.2; rs4680: OR 1.29, 95% CI 0.94–1.78, P = 0.1; rs165599: OR 1.05, 95% CI 0.74–1.49, P = 0.9; HPS; OR 1.01, 95% CI 0.56–1.84, P = 0.9; APS; OR 1.00 (reference for haplotypes); LPS: OR 1.18, 95% 0.81–1.72, P = 0.5 Unique, not included in the meta-analysis.

All patients were treated in the inpatients clinic of the Department of Surgery at the University Hospital of Erlangen, Erlangen, Germany. Participants were patients from 17 centers in Europe with malignant disease and opioid medication for severe pain.

HPS: 8/8/8, APS: 52/49/ 55, LPS: 37/39/35

0.42

The COMT haplotype is not associated with high need for opioids Not included in the meta-analysis

rs4646312, overall 60% rs4680, overall 47%

1.00

In the development sample SNPs rs4646312 (P = 0.005) and rs4680 (P = 0.03) were associated with opioid dose However, in the validation sample neither of these SNPs (rs4646312: P = 0.8; rs4680: P = 0.5) was associated with opioid dose Not included in the meta-analysis rs4680 was not associated with opioid dose (P = 0.6), pain score (P = 0.4), or opioid side effects (P = 0.5) Not included in the meta-analysis The Met/Met genotype of rs4680 was associated with lower need for opioids (P = 0.03) Not included in the meta-analysis The COMT genotype influences the efficacy of morphine treatment in cancer patients (rs4818: P = 0.04; rs4680: P = 0.02, haplotype 1: P = 0.006) Not included in the meta-analysis

Lo¨tsch et al. [61]

Opioid response in chronic pain

rs4680

Caucasian German

348

Patients were enrolled from three different outpatient pain centers at German University Hospitals.

Random sample of healthy controls 52%, pain patients 47%

0.46

Rakva˚g et al. [62]

Opioid response in cancer pain

rs4680

Caucasian Norwegian

207

Participants were inpatients at St Olav University Hospital, Trondheim, Norway.

Overall 56%

0.30

Rakva˚g et al. [63]

Opioid response in cancer pain

rs2075507 (rs2097603), rs737866, rs7287550, rs5746849, rs740603, rs6269, rs2239393, rs4818, rs4680, rs174699, rs165728; haploblock containing all of these SNPs

Caucasian Norwegian

197

Participants were inpatients at St Olav University Hospital, Trondheim, Norway.

Overall: rs2075507: 47%, rs737866: 22%, rs7287550: 28%, rs5746849: 57%, rs740603: 44%, rs6269: 38%, rs2239393: 38%, rs4818: 37%, rs4680: 56%, rs174699: 96%, rs165728: 95%

0.29

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COMT polymorphism and chronic pain Tammima¨ki and Ma¨nnisto¨ 7

Tander et al. [56]

References

Phenotype

Polymorphism

Reyes-Gibby et al. [64]

Opioid response in cancer pain

rs4680

Ross et al. [65]

Opioid response in cancer pain

rs2075507 (rs2097603), rs737866, rs7287550, rs174680, rs7290221, rs5746849, rs740603, rs6269, rs4633, rs2239393, rs4680, rs174699, rs165728

Kolesnikov et al. [66]

Opioid response in postoperative pain

rs4680

Estonian, Russian

rs4680

Turkish

Meta-analysis III – Chronic musculoskeletal pain + rs4680 Erdal et al. [67]

Population Caucasian Norwegian

British

Number of genotyped participants (overall/cases/ controls)

Selection of cases and controls

207

Participants were inpatients at St Olav University Hospital, Trondheim, Norway.

228/64/164

Patients with cancer pain that required treatment with morphine were considered for entry in the study. Patients were recruited from Royal Marsden NHS Trust cancer center. Cases were patients with poor response to morphine; controls were patients with good response to morphine.

102

162/49/113

Abdominal surgery patients from East Tallinn Central Hospital.

Cases patients with myofacial paindysfunction syndrome, controls healthy

Variant allele frequency (overall/cases/controls, %)

Power to detect small size effects (calculated for rs4680)

Overall 56%

0.30

rs2075507: 43/37/46 rs737866: 29/29/27 rs7287550: 27/25/33 rs174680: 27/25/31 rs7290221: 50/54/40 rs5746849: 44/46/40 rs740603: 49/52/41 rs6269: 40/39/42 rs4633: 52/53/49 rs2239393: 40/39/42 rs4680: 52/53/49 rs174699: 5/5/4 rs165728: 5/6/3

0.33

Overall 48%

0.17

56/48/60

0.25

Finding, OR vs. major allele Patients with the Met/Met genotype of rs4680 with simultaneous OPRM1 Asn40Asn genotype require lower doses of morphine than the non-Met/ Met, non-AA controls (OR 0.278, 95% CI 0.102–0.756, P = 0.01) Not included in the meta-analysis Some COMT SNPs are associated with morphine response and morphine side effects rs2075507; response to morphine OR 0.67, 95% CI 0.44–1.02, P = 0.06; rs737866: response to morphine OR 0.90, 95% 0.57–1.43, P = 0.7; rs7287550: response to morphine OR 1.49, 95% CI 0.95–2.33, P = 0.08, central side effects, P = 0.04; rs174680: response to morphine OR 1.38, 95% CI 0.88–2.18, P = 0.2, central side effects, P = 0.05; rs7290221: response to morphine OR 0.57, 95% CI 0.37–0.86, P = 0.007, central side effects, P = 0.09; rs5746849: response to morphine OR 1.29, 95% CI 0.85–1.96, central side effects P = 0.007, rs740603: response to morphine OR 0.65, 95% CI 0.43–0.99, P = 0.04, central side effects P = 0.003; rs6269 response to morphine 1.14, 95% CI 0.75–1.73, P = 0.5; rs4633: response to morphine OR 0.86, 95% CI 0.57–1.31, P = 0.5; rs2239393: response to morphine OR 1.14, 95% CI 0.75–1.73, P = 0.5; rs4680: response to morphine OR 0.86, 95% CI 0.57–1.31, P = 0.5, central side effects, P = 1; rs174699 response to morphine OR 0.77, 95% CI 0.28–2.16, P = 0.6; rs165728 response to morphine OR 0.51, 95% CI 0.17–1.54, P = 0.2 Not included in the meta-analysis COMT rs4680 alone not associated with morphine response or side effects. However, COMT Val158Met and OPRM1 Asn40Asp carriers respond better to morphine and experience less morphine-induced nausea Not included in the meta-analysis

rs4680 shows a trend towards being associated with myofacial pain-

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8 Pharmacogenetics and Genomics 2012, Vol 00 No 00

Table 1 (continued)

Diatchenko et al. [29]

Myofacial paindysfunction syndrome Risk for temporomandibular joint disease, sensitivity to pain

volunteers. No further details on recruitment strategy given. rs2075507 (rs2097603) rs6269, rs4633, rs4818, rs4680, rs165599 HPS, APS, and LPS haplotypes

American

202

Female volunteers participating in a 3-year prospective cohort study identifying risk factors for temporomandibular joint disorder. Recruited through newspaper ads.

Overall: rs2075507: 40%, rs6269: 61%, rs4633: 50%, rs4818: 61%, rs4680: 50%, rs165599: 64% HPS: 11%, APS: 49%, LPS: 37%

0.30

Sample was randomized from HUNT (Helseundersøkelsen I Nord-Trøndelag, Nord-Trøndelag Health Survey) study participants. Advertisements, e-mails, flyers, and wordof-mouth were used to recruit people with temporomandibular joint disease and healthy controls.

57/56/58

1.00

Not available

0.98

Chronic musculoskeletal complaints

rs4680

Norwegian

3017/1529/1488

Smith et al. [69]

Temporomandibular joint disease

rs174697

Americans

1608/166/1442

Slade et al. [70]

Temporomandibular joint disease

HPS, APS, and LPS haplotypes

American, mostly Caucasian

238

Female volunteers participating in a 3-year prospective cohort study identifying risk factors for temporomandibular joint disorder.

Overall: HPS: 11%, APS: 49%, LPS: 37%

0.34

Tchivileva et al. [71]

Temporomandibular pain, propranolol therapy

HPS, APS, and LPS haplotypes

Caucasian American

42

Participants were recruited from patients that sought treatment at the Orofacial Pain Clinic of University of North Carolina, Chapel Hill.

Overall: HPS 1%, APS 55%, LPS 46%,

0.10

Van Meurs et al. [72]

Osteoarthritisrelated pain

rs4680

Caucasian Dutch

Vossen et al. [73]

Chronic low back pain

rs4680

Dutch

Neuropathic pain

rs4680

Spanish

Neuropathic pain Armero et al. [74]

3033/288/2745.

Participants were from the Rotterdam Study.

Overall 55%

1.00

115;/78/37

Participants were enrolled through an advertisement that was distributed door to door.

41/44/35

0.19

283/144/139

Patients were recruited from the Pain Unit at the University Hospital of Salamanca, Salamanca, Spain. The controls were healthy people matched by age and sex that were controlled by family physicians.

48/47/49

0.39

rs4680 is not associated with neuropathic pain OR for allele frequencies in control vs. pain groups 1.03, 95% CI 0.74–1.44, P = 0.9 Unique, not included in the meta-analyses

Nonshaded rows, studies included; gray rows, studies not included in meta-analysis; light gray rows, studies on opioid efficacy and side effects; dark gray rows, all others. APS, average pain sensitivity haplotype; CI, confidence interval; COMT, catechol-O-methyl transferase gene; HPS, high pain sensitivity haplotype; HWE, Hardy–Weinberg equilibrium; LPS, low pain sensitivity haplotype; OR, odds ratio; SNP, single nucleotide polymorphism.

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COMT polymorphism and chronic pain Tammima¨ki and Ma¨nnisto¨ 9

Hagen et al. [68]

dysfunction syndrome (OR 0.62, 95% CI 0.39–1.00, P = 0.05) Included in the meta-analysis Haplotypes with high pain sensitivity and low COMT activity substantially increase the risk of developing temporomandibular joint disease (incidence density ratio 2.3, 95% CI 1.1–4.8). rs6269 (P = 0.002) and rs4818 (P = 0.0007) as well as the pain sensitivity haplotype (P = 0.0004) are correlated with pain sensitivity, whereas rs2075507 (P = 0.3), rs4633 (P = 0.3), rs4680 (P = 0.2), and rs165599 (P = 0.5) are not Not included in the meta-analysis, only haplotype data available for temporomandibular joint disease rs4680 polymorphism was not associated with chronic musculoskeletal complaints (OR: 0.94, 95% CI: 0.85–1.04, P = 0.2) Included in the meta-analysis SNPs in COMT affect the risk for temporomandibular joint disease. rs174697: OR 1.62, 95% CI 1.12–2.34, P = 0.01 Not included in the meta-analysis – SNP not rs4680 The high pain sensitivity haplotypes substantially increase the risk of developing temporomandibular joint disease. This report used the same data as Diatchenko et al. [29] Not included in the meta-analysis COMT genotype may be a predictor for the outcome of propranolol therapy Association between the COMT haplotype and temporomandibular joint pain not studied Not included in the meta-analysis rs4680 may be associated with osteoarthritis-related hip pain in Dutch women. rs4680 was significantly associated with hip pain in total study population (OR 1.3, 95% CI 1.0–1.8, P = 0.02). All hip osteoarthritis patients OR 2.9, 95% CI 1.2–6.1, P = 0.02; female hip osteoarthritis patients OR 4.9, 95% CI 1.6–14.8, P = 0.005) Included in the meta-analysis rs4680 is not associated with chronic low back pain (OR 1.45, 95% CI 0.81–2.59, P = 0.2) Included in the meta-analysis

10 Pharmacogenetics and Genomics 2012, Vol 00 No 00

Hispanic Caucasians (Belgian, Brazilian, British, Canadian, Dutch, Estonian, Finnish, German, Hungarian, Irish, Italian, Lithuanian, Mexican, Norwegian, Polish, Spanish, Swedish, and Swiss). One report studied Koreans and another report studied Israelis; three reports studied Turks. The majority of papers had studied both sexes. However, four studies were performed on only women. One study did not report the sex distribution. On average, 58% of the participants were women in those studies that included both sexes. The percentage of women was somewhat higher in the cases (62%) than in the controls (55%).

widespread pain (Fig. 2a). The OR for the Met allele being a risk allele for fibromyalgia or widespread pain was 1.28, 95% CI 1.06–1.55, P = 0.01, n = 3811. One study [47] was excluded because of the lack of HWE in the control group. Heterogeneity tests found significant heterogeneity in these data (Q = 19.15, d.f. = 8, P = 0.01, I2 = 58%). We examined the role of ethnicity in heterogeneity by dividing the studies into three groups: Non-Hispanic Caucasians, Hispanic Caucasians, and Middle East populations. The Middle East group consisting of Israelis and Turks showed a significant association between rs4680 and fibromyalgia or chronic widespread pain (Fig. 2b, OR 1.38, 95% CI 1.07–1.79, P = 0.01, n = 1015), and heterogeneity was low (Q = 2.58, d.f. = 2, P = 0.3; I2 = 23%). The Hispanic Caucasian group also showed a significant association between rs4680 and fibromyalgia or chronic widespread pain (Fig. 2c, OR 1.69, 95% CI 1.17–2.46, P = 0.006, n = 350), and low heterogeneity (Q = 2.89, d.f. = 2, P = 0.2; I2 = 29%), although the sample was small. In the NonHispanic Caucasian group, in contrast, rs4680 was not associated with fibromyalgia or chronic widespread pain (Fig. 2d, OR 1.06, 95% CI 0.93–1.20, P = 0.4, n = 2410). Heterogeneity was very low within this group (Q = 0.66, d.f. = 2, P = 0.7; I2 = 0%).

Most of the studies had a relatively small sample size and, thus, weak statistical power. Our estimate of the statistical power may be considerably lower than that of the authors of some studies because we used the assumption of a small effect size and calculated the power for w2 contingency tables that were the basis of the metaanalyses. This assumption was based on studies showing that the relative risks of genetic factors for multigenetic diseases are small [36,81]. Migrainous headache and rs4680

The meta-analysis of three studies showed that migrainous headache is not associated with rs4680 (OR 0.95, 95% CI 0.81–1.11, P = 0.5, n = 2901; Fig. 1). Heterogeneity tests did not find heterogeneity in these data (Q = 1.723, d.f. = 2, P = 0.4, I2 = 0%). Publication bias tests suggested that it is unlikely that the result would be biased because of missing studies. Duval and Tweedie’s trim and fill test suggested no adjustments for the number of studies and the funnel plot was symmetrical (Egger’s test, P = 0.3; Begg and Mazumdar’s rank correlation test, P = 0.06).

Publication bias tests suggested that it is unlikely that the result would be biased because of missing studies. Duval and Tweedie’s trim and fill test suggested no adjustments for the number of studies and the funnel plot was symmetrical (Egger’s test, P = 0.06; Begg and Mazumdar’s rank correlation test, P = 0.1). Musculoskeletal pain conditions and rs4680

The meta-analysis of four studies showed that musculoskeletal pain conditions are not associated with rs4680 (OR 1.01, 95% CI 0.76–1.34, P = 1.0, n = 6327; Fig. 3). Heterogeneity tests found significant heterogeneity in these data (Q = 8.76, d.f. = 3, P = 0.03, I2 = 67%).

Fibromyalgia or chronic widespread pain and rs4680

The meta-analysis of eight studies showed that rs4680 is likely to be associated with fibromyalgia or chronic Fig. 1

Statistics for each study

References

Odds Lower Upper ratio limit limit

Odds ratio and 95% CI

Z-value P-value

Cevoli et al. [38] Hagen et al. [39]

0.89 0.92

0.58 0.77

1.36 1.10

−0.54 −0.92

0.59 0.36

Park et al. [40]

1.26 0.95

0.80 0.81

1.98 1.11

1.01 −0.64

0.31 0.52 0.1 0.2

0.5 1

Favors Val

2

5

10

Favors Met

Meta-analysis and forest plot of the correlation between rs4680 and migrainous headache. Analysis was performed using a random effects model. OR, 95% CI, Z-value of the meta-analysis, and P-value are shown. CI, confidence interval; COMT, catechol-O-methyltransferase gene; Met, minor allele of COMT SNP rs4680; OR, odds ratio; SNP, single nucleotide polymorphism; Val, major allele.

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COMT polymorphism and chronic pain Tammima¨ki and Ma¨nnisto¨ 11

Fig. 2

(a) References

Statistics for each study

Comparison Odds ratio

Odds ratio and 95% CI

Lower Upper limit limit Z-value P-value

Matsuda et al. [52] Vargas-Alarcón et al. [55] Vargas-Alarcón et al. [55] Cohen et al. [48] Gürsoy et al. [57] Tander et al. [56]

Hispanic Caucasian Hispanic Caucasian (Mexicans) Hispanic Caucasian (Spaniards) Middle East Middle East Middle East

2.21 1.82 1.08 1.56 1.56 1.04

1.26 1.16 0.57 1.16 0.93 0.68

3.86 2.85 2.06 2.10 2.61 1.59

2.78 2.61 0.23 2.91 1.70 0.18

0.01 0.01 0.82 0.00 0.09 0.86

Hocking et al. [51] Nicholl et al. [53] Potvin et al. [54]

Non-Hispanic Caucasian Non-Hispanic Caucasian Non-Hispanic Caucasian

1.13 1.00 1.06 1.28

0.92 0.87 0.58 1.07

1.39 1.14 1.92 1.54

1.14 0.00 0.19 2.68

0.25 1.00 0.85 0.01 0.1

0.2

0.5

1

Favors Val

2

5

10

5

10

5

10

5

10

Favors Met

(b) References

Comparison

Statistics for each study Odds ratio

Lower Upper limit limit

Odds ratio and 95% CI

Z-value P-value

Cohen et al. [48]

Middle East

1.56

1.16

2.10

2.91

0.00

Gursoy et al. [57]

Middle East

1.56

0.93

2.61

1.70

0.09

Tander et al. [56]

Middle East

1.04

0.68

1.59

0.18

0.86

1.38

1.07

1.79

2.46

0.01 0.1

0.2

0.5

1

2 Favors Met

Favors Val

(c) References

Comparison

Statistics for each study Odds ratio

Odds ratio and 95% CI

Lower Upper limit limit Z-value P-value

Matsuda et al. [52]

Hispanic Caucasian

2.21

1.26

3.86

2.78

0.01

Vargas-Alarcón et al. [55]

Hispanic Caucasian (Mexicans)

1.82

1.16

2.85

2.61

0.01

Vargas-Alarcón et al. [55]

Hispanic Caucasian (Spaniards) 1.08

0.57

2.06

0.23

0.82

1.69

1.17

2.46

2.77

0.01 0.1

0.2

0.5

1

Favors Val

2 Favors Met

(d) References

Comparison

Statistics for each study Odds ratio

Odds ratio and 95% CI

Lower Upper limit limit Z-value P-value

Hocking et al. [51]

Non-Hispanic Caucasian

1.13

0.92

1.39

1.14

0.25

Nicholl et al. [53]

Non-Hispanic Caucasian

1.01

0.85

1.20

0.11

0.91

Potvin et al. [54]

Non-Hispanic Caucasian

1.06

0.55

2.04

0.17

0.86

1.06

0.93

1.20

0.83

0.41 0.1

0.2

0.5

Favors Val

1

2 Favors Met

Meta-analysis and forest plot of the correlation between the rs4680 and fibromyalgia or chronic widespread pain. (a) Complete sample, (b) Middle East group, (c) Hispanic Caucasian group, and (d) Non-Hispanic Caucasian group. Chronic widespread pain and fibromyalgia were grouped because chronic widespread pain is the cardinal symptom of fibromyalgia. Analysis was performed using a random effects model. Ethnic or regional subgroups were analyzed to determine the source of heterogeneity in the complete sample. OR, 95% CI, Z-value of the meta-analysis, and the corresponding P-value are shown. CI, confidence interval; COMT, catechol-O-methyltransferase gene; Met, minor allele of COMT SNP rs4680; OR, odds ratio; SNP, single nucleotide polymorphism; Val, major allele.

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12 Pharmacogenetics and Genomics 2012, Vol 00 No 00

Fig. 3

References

Statistics for each study

Odds ratio and 95% CI

Odds Lower Upper ratio limit limit Z-value P-value 0.05 Erdal et al. [67] 0.62 0.39 0.99 −1.99 Hagen et al. [39] 0.23 0.94 0.85 1.04 −1.20 0.11 Van Meurs et al. [72] 1.30 0.94 1.80 1.58 1.45 0.81 2.59 1.25 0.21 Vossen et al. [73] 0.95 1.01 0.76 1.34 0.07 0.1 0.2

0.5 1

Favors Val

2

5

10

Favors Met

Meta-analysis and forest plot of the correlation between the rs4680 and chronic musculoskeletal pain. Chronic musculoskeletal pain includes different pains from muscles, bones, or joints, for example osteoarthritis-related pain and lower back pain. Analysis was performed using a random effects model. OR, 95% CI, Z-value of the meta-analysis, and the corresponding P-value are shown. CI, confidence interval; COMT, catechol-Omethyltransferase gene; Met, minor allele of COMT SNP rs4680; OR, odds ratio; SNP, single nucleotide polymorphism; Val, major allele.

Ethnicity may be one reason for the heterogeneity observed. However, the most likely source of heterogeneity is the various pain conditions included in this group and even within the individual studies. Publication bias tests suggested that it is unlikely that the result would be biased because of missing studies. Duval and Tweedie’s trim and fill test suggested no adjustments for the number of studies and the funnel plot was symmetrical (Egger’s test, P = 0.4; Begg and Mazumdar’s rank correlation test, P = 0.5).

Discussion Meta-analyses

The main finding of the present meta-analyses is that the Met allele of rs4680 SNP of the COMT gene seems to be associated with an elevated risk of fibromyalgia or chronic widespread pain. This effect is observed in several Caucasian populations and also in Israelis and Turks. Ethnicity seems to affect this association in such a way that Non-Hispanic Caucasians do not show an association between rs4680 and fibromyalgia or chronic widespread pain. The excluded study of Barbosa et al. [47] also suggests that fibromyalgia and pain sensitivity are associated with rs4680 in a Brazilian Caucasian population that is essentially a mix of Hispanic Caucasians, Brazil’s indigenous peoples, and Africans. In addition, two reports that were not included in the meta-analysis suggested that there is a moderating role for rs4680 in behaviors that were related to fibromyalgia pain. These studies showed that rs4680 moderates the relation of daily maladaptive coping as well as the effect of pain on the positive affect in fibromyalgia patients [49,50]. Our finding of a significant association between rs4680 and fibromyalgia or chronic widespread pain is at odds with the meta-analysis of Lee et al. [82]. Our metaanalysis included all those studies that were in their analysis and, in addition, four additional studies on the

basis of our different inclusion criteria (diagnoses included both fibromyalgia and chronic widespread pain; languages included Portuguese and literature searches spanned to the end of the year 2011). These additional studies apparently contributed toward the differential end result. Although migrainous headache is obviously not associated with rs4680, it might still affect the risk of other chronic headaches or the phenotype of the migraine. Hagen et al. [39] suggested that Met is the risk allele for nonmigrainous headache in Norwegian women. Park et al. [40] showed that female Korean migraine patients suffer from more severe headache, nausea, and vomiting if they are Met carriers. Because COMT contributes toward estrogen metabolism, and estrogen is involved in the pathophysiology of migraine, it is likely that COMT polymorphisms affect the risk of migraine in a way that has not yet been thoroughly explored. The meta-analysis on chronic musculoskeletal complaints did not show an association between rs4680 and musculoskeletal pain. However, COMT SNP rs4633 may modulate postsurgical improvement of the disability index score [43]. In addition, COMT pain sensitivity haplotypes affect pain ratings together with pain catastrophizing ratings, again suggesting a modulatory role for COMT in chronic pain [42]. The studies that are included in the meta-analysis of the chronic musculoskeletal complaints showed controversial results. The inconsistencies might result from the fact that the studies focused on different pain conditions; although the conditions are similar in a wider sense, their mechanisms may still differ from each other. One of the studies that we counted in the meta-analysis actually dealt with patients with very different musculoskeletal problems, ranging from elbow or shoulder pains to muscle-derived chest or abdominal pain [68]. The apparent problems in the meta-analysis of the chronic musculoskeletal

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

COMT polymorphism and chronic pain Tammima¨ki and Ma¨nnisto¨ 13

complaints reflect the overall problem of there being only a few studies of each pain type. The inclusion of different pain conditions of similar type in one analysis may yield very heterogeneous results. Additional and possibly better-defined replications of the existing studies would considerably benefit future meta-analyses and add to their power. Studies included only in the systematic review Opioid response in chronic pain

Several different studies have explored the effects of COMT genotypes and opioid responses or the adverse effects of opioids in patients who have either cancer or other types of chronic pain. Because of considerable differences in the experimental setup (exact polymorphisms or haplotypes studied, phenotypes studied, form of data presented) and repeated analyses of the same cohort, we could not carry out a meta-analysis on the association between opioid effects and COMT polymorphisms. Instead, here, we present a short, traditional review of the association of opioid responses and COMT polymorphisms. The pioneering positron emission tomography study by Zubieta et al. [83] in healthy human volunteers showed that a low COMT activity allele (Met158) increases the availability of the m-opioid receptors, analyzed as a binding potential of [11C]carfentanil in the anterior thalamus and thalamic pulvinar. This upregulation has been later verified by studies using human post-mortem tissue [84]. In an experimental pain study, rs4680 did not affect the acute analgesic response to a low dose of remifentanil [85]. Instead, the carriers of Met158Metallele were more sensitive to the pain than the Val158Met or Val158Val carriers 1 h after a single opioid administration, and thus showed an enhanced opioid-induced hyperalgesia. Supporting the results of Zubieta et al. [83], Rakva˚g et al. [62] suggested that Caucasian cancer patients with the Val158Val genotype of rs4680 required more morphine than the Met158 carriers to achieve the same level of analgesia. Val158Val carriers also showed higher concentrations of both morphine and morphine glucuronides than Val158Met or Met158Met carriers. The effect of the Met158Met genotype is further enhanced in patients with an Asp40Asp genotype of the m-opioid receptor gene OPRM1 rs1799971 SNP (Asn40Asp) [64]. The carriers of a common haplotype, including the Met158 allele of rs4680, required less morphine than the noncarriers [63]. Similarly, Kolesnikov et al. [66] showed that patients who were heterozygous both for Asn40Asp and for Val158Met consumed less opioids and experienced less nausea and sedation during recovery from acute postsurgical pain than patients with the Asn40Asn genotype. However, no Asp40Asp + Met158Met carriers were identified. The COMT genotype has

also been linked to drowsiness and confusion, caused by morphine treatment [65]. However, it was not rs4680 but rs740603 and haplotypes containing several SNPs in intron 1 that were associated with adverse effects. Subsequent studies could not confirm the role of the COMT polymorphism in opioid responses. Klepstad et al. [60] studied cancer patients, and suggested that both rs4646312 and rs4680 are associated with opioid dose requirements. In contrast to the findings of Rakva˚g et al. [62], Met158Met and Val158Met carriers showed higher median opioid doses per day than the Val158Val carriers. However, this finding was not replicated in the validation sample. Lo¨tsch et al. [61] failed to find an association between rs4680 and the opioid dose or adverse events in chronic pain. In conclusion, despite the promising results from the initial gene association studies, the evidence of an association between the COMT polymorphism and the opioid dose in chronic cancer pain is not convincing. Miscellaneous studies

The systematic review included a number of studies that could not be incorporated into any of the meta-analyses because of the different pain types on which they focused. Therefore, we summarize them here rather than in the results section. Armero et al. [74] studied neuropathic pain in a Spanish population, and they found no association between the susceptibility to neuropathic pain of different origins and rs4680. Persistent postoperative pain is likely related to neuropathic pain. Lee et al. [44] suggested that rs4818 and rs6269, but not rs4680, may be linked to long-lasting postsurgical pain after the removal of a third molar in a Caucasian Irish population. However, Hickey et al. [45] suggested that there may be a link between rs4680 and persistent pain after mastectomy in Irish patients, and Ferna´ndez-de-las˜as et al. [46] showed an association between rs4680 Pen and elevated pain ratings in mastectomized Spanish breast cancer survivors. Similarly, the COMT polymorphism was not found to affect the gene  pain interaction with mood in postdiscectomy sciatic pain patients [86]. Together, these findings suggest that rs4680 is not linked to the probability of developing a pain condition that involves nerve damage. However, other COMT polymorphisms could still contribute toward the risk of neuropathic pain. Multisomatoform disorder is characterized as a minimum of three medically unexplained, currently troublesome ailments that are accompanied by more than a 2-year history of somatization [87]. These patients show a higher prevalence of psychiatric comorbidity, worse functioning, and impaired symptom improvement compared with individuals without the disorder [88]. A recent study attempted to elucidate the possible genetic risk factors of this relatively unknown disease by exploring the association

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14 Pharmacogenetics and Genomics 2012, Vol 00 No 00

between six SNPs in the COMT gene, including rs4680 [58]. None of the SNPs investigated was found to be associated with multisomatoform disorder. However, it is likely that there is no single gene that would be clearly linked to this complex disorder. This negative finding does not exclude the possibility that the COMT polymorphism could affect a better-defined aspect of pain sensitivity in the multisomatoform disorder. Temporomandibular joint disease, which is defined by pain in the head and neck muscles that is related to chewing movements, pain in the temporomandibular joint, and limitations in jaw movements [89], is one type of musculoskeletal pain condition. We found only one paper that had studied the association between the COMT polymorphism and temporomandibular joint disease in a Caucasian American population [29]. Because it was designed to explore the association between high (HPS), average (APS), or low (LPS) pain sensitivity polymorphism and the risk of temporomandibular joint disease, we could not, unfortunately, group it together with studies using only single SNPs. These haplotypes are formed from SNPs rs6269, rs4633, rs4818, and rs4680. The pain sensitivity haplotypes were named on the basis of how sensitive the carriers of each haplotype were to acute experimental pain [29]. Diatchenko et al. [29] found that the presence of even one LPS haplotype significantly reduces the risk of temporomandibular joint disease. Although rs4680 was found to moderate the psychological factors that affect fibromyalgia pain [49,50], pain sensitivity haplotypes of COMT did not seem to regulate the psychological factors that were linked to pain sensitivity in temporomandibular joint disease [70]. Instead, it could possibly modulate the effect of propranolol therapy in the treatment of temporomandibular joint disease in Caucasian women [71]. General mechanistic discussion

There are several hypotheses on how the inhibition and/or the decrease of COMT activity would affect nociception. The impact of COMT is primarily believed to be related to its role as an enzyme metabolizing catecholamines, notably dopamine. Besides rs4680, a few other SNPs may also affect the enzymatic activity of COMT. At least SNPs rs4633, rs737865, rs165599, rs2097603 (presently known as rs2075507), and rs6267 have been shown to have an effect on COMT activity in vitro [20,90–93]. Consequently, these SNPs have been studied for their role in nociception. The potential mechanisms of altered methylation activity may be a change in the expression (rs4633, rs737865, and rs165599 [90,91]) or transcription (rs737865, rs2020917 [92]) of the COMT gene. In addition to genetic engineering of the COMT gene, COMT inhibitors can also reduce COMT activity significantly. To our knowledge, the effects of COMT inhibitors on pain have not been characterized in humans. They may have actions beyond COMT inhibition, and therefore, some particular properties of COMT inhibitors, relevant for pain, will be discussed later. As

catecholamines are essential components of both the ascending and the descending pain tracts, changes in catecholamine levels may modify nociception up and down. COMT is expressed in the following structures: (a) the prefrontal cortex and several other brain regions, (b) the spinal cord, for example in the superficial laminae of the dorsal horn of the spinal cord, and (c) peripheral structures, such as the ganglia of the primary sensory neurons [94,95], all of which are involved in the processing of nociception or pain perception. In the periphery, low COMT activity that leads to enhanced catecholaminergic tone is evidently nociceptive [30,96]. In the spinal cord and the brain, the situation is reverse: low COMT (high dopaminergic tone) appears to be antinociceptive [97] and associated with lower COMT activity in brain regions processing cognitive aspects of pain in response to a painful thermal stimulation of skin [98]. In addition, at least the effect of COMT activity on opioid-related analgesia depends on the pain model, and in humans, it also depends on the cause of pain; cancer pain may be different from transient postoperative pain and chronic pain forms. Increased pain sensitivity may not necessarily be observed under normal conditions in the absence of nociceptive stimuli, but instead, the pain symptoms that are related to pathological conditions are enhanced. This scenario could lead to a higher probability of reporting such symptoms and overdiagnosis of chronic pain conditions in patients. A monoamine oxidase-dependent catecholamine metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), produces mechanical hyperalgesia [99]. DOPEGAL is metabolized by aldehyde reductase to 3,4-dihydroxyphenylglycol and is further O-methylated by COMT. If COMT activity is compromised, then DOPEGAL may accumulate, acting as a pain inducer. Unfortunately, some of the original results have been retracted [100], and the role of this intriguing nociceptive metabolite remains unclear. Initially, it was suggested that the enhancing effects of low COMT activity on morphine analgesia are mediated through dopamine-triggered compensatory changes in the endogenous opioid system in the brain [83]. This hypothesis has later received some support from studies in humans. Notably, a low COMT activity would increase the amount of opioid receptors, as suggested by previous studies, and hence may enhance supraspinal responses to exogenous opioids [83,84]. Thus, even if low COMT activity decreases opioid peptide mRNA in the shell region of the nucleus accumbens, as observed in the study of Nikoshkov et al. [101], the change was not confirmed by Berthele et al. [84], and it was not sufficient to produce measurable behavioral changes in the stress-induced analgesia assay [26]. Recently, Kowarik et al. [102] have shown that there was a positive correlation between morphine receptor binding and morphine receptor expression levels, and a negative correlation between met-enkephalin peptide

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COMT polymorphism and chronic pain Tammima¨ki and Ma¨nnisto¨ 15

and pro-pre-enkephalin mRNA expression levels across the post-mortem globus pallidum samples that have different rs4680 genotypes. The periaqueductal gray (PAG) plays an important role in nociceptive modulation, and alterations in neural transmission within the PAG modify the antinociceptive effects of morphine [103]. There is a network of dopaminergic neurons within the ventral periaqueductal gray (vPAG). This network is a part of the dorsocaudal A10 group [104]. Dopamine neurons may communicate with neural areas that are involved in the affective aspects of pain [105,106]. Dopaminergic neuron depletion in the vPAG with 6-hydroxydopamine (6-OHDA) decreases opioid-induced antinociception in rats [107], and a more recent study suggests that dopamine may have a direct antinociceptive effect in addition to the modulation of the antinociceptive effects of morphine [108]. Both D1 and D2 dopamine receptors are expressed by PAG neurons; the former receptors are associated with morphine analgesia [107] and the latter receptors are associated with dopamine analgesia [108]. It has been suggested that there are synaptic connections between dopaminergic and GABAergic neurons in the vPAG, which implicates the participation of dopaminergic neurons in analgesia. Considering the involvement of vPAG dopaminergic neurons in the response to opioid drugs, a recent sleep deprivation study is of interest [109]. Increased pain perception and attenuated antinociceptive effects of morphine were found to be associated with low tyrosine hydroxylase staining in the PAG. This situation was effectively reversed by L-dopa treatment. Elevated levels of catecholamines are generally associated with the descending inhibition of pain in the spinal dorsal horn [110], and the antidepressants used to treat persistent pain conditions are believed to act by increasing the synaptic level of catecholamines at the spinal level [111,112]. Finally, stress-induced and opioidinduced analgesia was attenuated only in the tail flick test, which purely measures a spinal withdrawal reflex that is maintained even after spinal transection [113]. Several types of COMT inhibitors, even those that do not suppress COMT activity in the brain, produced pronociceptive effects. The pronociceptive effects of COMT inhibitors have been blocked by b2/3-antagonists and have been attributed to the activation of peripheral b2/3-adrenergic receptors [30]. This scenario was indirectly supported by other studies that showed that those receptors mediate adrenaline-induced hyperalgesia [96]. The administration of opioids activates the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis, causing an elevation in peripheral catecholamines [114]. Opioids, when administered at lower doses, have been shown to counteract analgesia or even to produce hyperalgesia that is mediated through peripheral/spinal b-adrenergic receptors [115]. Correspondingly,

in human volunteers, opioid hyperalgesia was increased in patients with low COMT activity (see below, [85]). With respect to the pronociceptive action of COMT inhibition, changes in opioid transmission do not explain all of the effects of COMT inhibitors, and therefore, other or supplementary mechanisms have been suggested [26,30]. Because it is obvious that low COMT activity is nociceptive, it is challenging to explain why nitecapone, a mainly peripherally acting COMT inhibitor, exerted an opposite effect: it alleviated neuropathic pain in two rat models: diabetic neuropathy [31] and the spinal nerve ligation [33]. The unexpected but clear antiallodynic and antihyperalgesic effect of nitecapone in diabetic neuropathy has been explained by the attenuation of the spontaneous activity of a wide dynamic range of neurons in the spinal dorsal horn [31]. An electrophysiological study showed that a fairly high dose of OR-486 (30 mg/kg, intravenously) reduced spinal responses to nociceptive stimulation and spinal long-term potentiation [97]. The antihyperalgesic effect of nitecapone was not dependent on a2-adrenoceptors or opioid receptors [31]; however, anatomical facts and the distribution of adrenergic receptors should be seriously considered. For example, the densities of adrenergic b2/3-receptors are low in the dorsal root ganglion but high in the peripheral tissues as well as in many parts of the brain [30,116]. A local spinal noradrenergic stimulation produced antinociception [117–119]. In addition, dopamine D2 receptor stimulation is antinociceptive [120–122]. As mentioned above, the beneficial spinal action of COMT inhibitors is strongly supported by the direct measurements of C-fiber responses from the dorsal horn after a single dose of OR-486 [97]. The spinal action of COMT inhibitors would become possible in this specific ligation model, where the blood–spinal cord barrier could be mechanically damaged at the site of the injury [123]. It is noteworthy that a direct intrathecal administration of nitecapone caused some antinociception in the rat [32]. In animal models of neuropathic pain, free radical scavengers have reduced the phosphorylation of NMDA receptors, central sensitization, allodynia, and hyperalgesia [124–126]. Nitecapone indeed scavenges reactive oxygen and nitric oxide species and prevents lipid peroxidation at clinically relevant concentrations [127–131]. Several studies have suggested that oxidative stress is involved in neuropathic and other persistent pains [125, 132–134]. Thus, the antioxidative properties of nitecapone can contribute toward its antihyperalgesic effects. Conclusion

Low COMT activity has been associated with increased pain sensitivity in human pain studies, and COMT inhibitors sensitize to thermal and mechanical pain in animal studies. Low COMT activity haplotypes, rather than any single SNP alone, are associated with human pain. In

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16 Pharmacogenetics and Genomics 2012, Vol 00 No 00

chronic clinical pain, the effects of COMT polymorphisms depend on the pain conditions. COMT activity does not affect pain sensitivity in neuropathic and cancer pains, but the situation may be different in other chronic pain conditions. Results from the meta-analyses show that rs4680 is significantly associated only with fibromyalgia or chronic widespread pain but not with migrainous headache or chronic musculoskeletal pain conditions. Low COMT activity may, however, enhance opioid analgesia and exacerbate adverse effects, at least in some cancer pains. Low COMT levels in the spinal cord and brain may even favor antinociception under some specific conditions. In support of this hypothesis, nitecapone acts as an analgesic in animal models of neuropathy.

Academy of Finland (No. 1131915/2008 and No. 117881/ 2006) and Sigrid Juselius Foundation to P.T.M. Conflicts of interest

There are no conflicts of interest.

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Strengths and weaknesses of the meta-analysis

The main limitation of this systematic review and metaanalysis is the small number of existing studies and thus the small sample size in each meta-analysis. This inevitably decreases the power of the analysis and may affect heterogeneity. It could also affect publication bias, although this was not a problem in our analyses. We observed some heterogeneity in the fibromyalgia/chronic widespread pain and musculoskeletal pain material. In the fibromyalgia/chronic widespread pain group, the heterogeneity is likely because of different ethnic groups. In the musculoskeletal pain group, the heterogeneity is most probably derived as a result of the wide variety of pains collected under one title – the pains vary from osteoarthritis-related pain to low back pain to musclederived chest pain. The reasons for and the mechanisms of these pains can be diverse and, in the case of the study of Hagen and coworkers, the possibility of fibromyalgia could not be excluded. Heterogeneity has been taken into account with the use of a random effects model of meta-analysis and by attempting to clarify the reasons for it. We also regret that we could not analyze other SNPs than rs4680 because especially including haplotypes would have been informative. The strength of this review is that we have analyzed the effect of COMT rs4680 on several different pain types and also attempted to explain the findings on the basis of the existing human and animal literature. In the future, we hope to find goodquality replication studies on the association between the COMT Val158Met polymorphism and different types of pain, possibly also including haplotypes containing the rs4680 SNP. These would considerably benefit subsequent efforts to summarize COMT gene association data.

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Acknowledgements The authors thank Dr Sabina Cevoli, Dr Luda Diatchenko, Dr Ana Lucia Fachin, Dr Rogelio Gonza´lez Sarmiento, Dr Oonagh Hickey, Dr Lynne Hocking, Dr Peter Lee, and Professor Manfred Stuhrmann-Spangenberg for providing additional information on their studies.

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