Background/Aims: Several factors influencing postoperative pain and the effect of opioid analgesics have been investigated on an individual level. The aim of this study was to clarify the impact of catecholamine-O-methyltransferase (COMT) gene Val158Met on opioid consumption in postoperative patients. Methods: A systematic review and meta-analysis of the literature up to September 30, 2017, were performed by using PubMed, Cochrane Library, ISI Web of Science, and Chinese National Knowledge Infrastructure (CNKI) database. The meta-analysis examined all studies involving the association between genetic polymorphisms of COMT Val158Met and opioid consumption during the acute postoperative period. Results: Of the 153 identified studies, 23 studies were retrieved for systematic review and 10 studies were retrieved for meta-analysis. However, it was impossible to conduct meta-analysis on the association between COMT Val158Met polymorphism and postoperative pain because of heterogeneity of the data. Overall, meta-analysis showed that COMT Val/Met carriers consumed less opioid for analgesia within the first 24 hours after surgery (SMD = 0.14, 95% CI = [0.03, 0.25], P = 0.01) but not within 48 hours (SMD = 0.14, 95% CI = [0.08, 0.36], P = 0.21). There was no significant difference in opioid consumption between Val/ Val and Met/Met patients. Conclusion: Patients with Val/Met but not Met/Met allele variant consumed less opioid, though larger and better-designed studies are required to obtain an exclusive conclusion about the correlation between postoperative pain and COMT Val158Met polymorphism.

Patients undergoing major surgery are often inflicted with acute pain during the postoperative period, and their pain perception and response to analgesics vary greatly with individuality and are affected by several factors including difference in the type of procedures, sex, age and genetic variation [1, 2]. Recently, polymorphisms of several genes have been recognized as a potential risk factor for the severity of acute postoperative pain [3-5]. However, what genes contribute to the variability of pain perception and analgesic effects remains unclear.

The catecholamine-O-methyltransferase (COMT) gene is located at the gene map locus of 22q11.2 and encodes the COMT protein [6]. Ample evidence has shown that single-nucleotide polymorphisms (SNP) in COMT are associated with pain perception [7, 8]. The most studied SNP in COMT gene is rs4680, which is known as a functional polymorphism. G to A transition results in a valine (Val) to methionine (Met) amino-acid substitution. It may cause three possible SNP genotypes: GG (Val/Val) genotype, which has high enzymatic activity, AA (Met/Met) genotype, which produces defective enzymes, and GA (Val/Met) genotype, which has moderate enzymatic activity [9, 10].

COMT metabolizes biogenic amines including dopamine, epinephrine, and norepinephrine, and therefore its activity would affect the opioid behaviors [11]. Opioids are common analgesics used for pain management, especially after surgery. The sensitivity to pain and the response to analgesics, even following the same surgery, are highly variable among patients [12]. Therefore, exploring conclusive evidence of the association between COMT genetic variants and the analgesic effects of opioids is clinically significant. However, there is no systematic review and meta-analysis about the association between the COMT Val158Met gene polymorphism and postoperative pain and opioid analgesics. In this article, we summarize retrieved studies to clarify the effect of COMT genetic variants on pain and the analgesic effect of opioids in patients with postoperative pain.

Search strategy

This review was performed according to the Preferred Reporting Item for systematic reviews and Meta-Analysis (PRISMA). Studies were identified through the databases of PubMed, Cochrane Library, ISI Web of Science, and Chinese National Knowledge Infrastructure (CNKI), which were published in English and Chinese. The final search strategy was as follows: ((“Pain, Postoperative” [Mesh] OR “Postoperative Pains” [Mesh] OR “Postoperative Pain” [Mesh]) OR (“Pain” AND “Surgery”)) AND (“O-Methyltransferase, Catechol” [Mesh] OR “Catechol-O-Methyltransferase” [Mesh] OR “Catechol O Methyltransferase” [Mesh] OR “Catechol Methyltransferase” [Mesh] OR “Methyltransferase, Catechol” [Mesh]) AND (“Polymorphisms, Genetic” [Mesh] OR “Genetic Polymorphism” [Mesh] OR “Polymorphism (Genetics)” [Mesh] OR “Genetic Polymorphisms”). All studies were limited to the availability of abstracts and human subjects.

Study selection and inclusion criteria

We included eligible studies that met the following criteria: (1) observational cohort studies, case-control studies, and randomized controlled trials; (2) studies reporting any type of surgery in adults; (3) studies reporting the postoperative following-up time between 24 and 48 hours; (4) pain assessed by primary outcome parameters; (5) opioid consumption in patients after surgery; and (6) studies measuring genetic polymorphisms directly. The following information was abstracted from each study: first author, year of publication, surgery setting, COMT polymorphisms, ethnicity of participants, Hard-Weinberg equilibrium, opioid category, and main finding of the study.

Data extraction and analysis

The titles and abstracts of the retrieved studied were independently screened by more than three investigators. Studies were excluded if they failed to meet the above-mentioned criteria. The full texts for the included articles were obtained and further assessed.

Statistical analysis

We considered performing a meta-analysis for polymorphisms that were reported by more than three studies. The association between COMT gene Val158Met polymorphisms and opioid consumption was calculated by the mean difference (MD) or STD mean difference (SMD) and corresponding 95% confidence interval (95% CIs). The heterogeneity between these studies was evaluated using the Cochrane Q-test (significant at P < 0.05) and I2 test (low heterogeneity = 25%, moderated heterogeneity = 50%, high heterogeneity = 75%) in the random effect model.

Characteristics of the studies

There were 23 studies relevant to the search words, and 10 studies were included in meta-analysis. The flow chart of selection of studies and reasons for exclusion is presented in Fig. 1. The study characteristics are summarized in Table 1. The COMT genotypes fell into three very distinct genotypes; GG (Val/Val), GA (Val/Met) and AA (Met/Met).

Table 1.

Characteristics of the studies included in meta-analysis. Note: NA: Not available; LPS: Low pain sensitivity; APS: Average pain sensitivity; HPS: High pain sensitivity

Characteristics of the studies included in meta-analysis. Note: NA: Not available; LPS: Low pain sensitivity; APS: Average pain sensitivity; HPS: High pain sensitivity
Characteristics of the studies included in meta-analysis. Note: NA: Not available; LPS: Low pain sensitivity; APS: Average pain sensitivity; HPS: High pain sensitivity
Fig. 1.

Flow chart of selection of studies and specific reasons for exclusion from the systemic review and meta-analysis.

Fig. 1.

Flow chart of selection of studies and specific reasons for exclusion from the systemic review and meta-analysis.

Close modal

Systematic review of COMT and postoperative pain

Single-nucleotide polymorphism rs4680 in the COMT enzyme gene has been extensively studied in association with pain perception, including acute and chronic pain [13-16]. The Met/Met carrier is associated with a 3-4 fold reduction in COMT enzyme activity compared with the Val/Val carrier. The AA (Met/Met) allele diminished the regional µ-opioid system responding to pain and increased the µ-opioid receptor binding potential [17], suggesting that the increased density of opioid receptor of the Met/Met carrier may improve the efficacy of morphine. Some postoperative studies showed that the Met/Met carrier was associated with the highest pain scores compared with patients with the wild type (Val/Val) [18-21]. Controversially, according to the study of Wesmiller and Henker, Val/Val patients had significantly high pain scores after surgery [22, 23]. Furthermore, several other studies also found that COMT variants had a small effect on pain perception [24-30]. We performed meta-analysis to explore the association between pain perception and COMT polymorphisms but failed to find significant differences between the three types of variants in pain scores. Heterogeneity in the meta-analysis was severe, and therefore the correlation between COMT and postoperative pain needs to be further investigated in the future.

Other than rs4680 in the COMT gene, several other SNPs were also reported to be associated with pain sensitivity, including rs6269, rs4633 and rs4818 [12, 26]. These four SNPs of COMT were used to construct three pain sensitivity haplotypes: low pain sensitivity (LPS; GCGG), average pain sensitivity (APS; ATCA), and high pain sensitivity (HPS; ACCG) [31]. In Tan’s study, they found that LPS haplotype had the highest pain score [25]. In contrast, the results form Orrey and Kolesnikov suggested that patients without LPS haplotype had maximum pain and would require a higher opioid amount [21, 32]. Meanwhile, APS haplotype might associate with the lowest pain perception but involve long-term postsurgical pain [33, 34]. Besides the haplotype of COMT, the interaction between OPRM1, sex, and COMT may also affect patients’ pain perception [12, 35].

Meta-analysis of Val/Val-Val/Met and opioid consumption

Ten studies [19, 21, 23, 25-27, 30, 33, 36, 37] reported opioid consumption within the first 24 hours in their meta-analyses, and 4 studies [21, 23, 26, 30] reported opioid consumption within 48 hours. These studies included 808 patients for Val/Val and 807 patients for Val/Met within 24-hour. Several kinds of opioids were tested in all studies. Within first 24 hours after surgery, Val/Met carriers exhibited significant low opioid consumption compared with Val/Val carriers (Fig. 2A, random model: SMD = 0.14, 95% CI= [0.03, 0.25], P = 0.01, Pheterogeneity = 0.39). However, we did not find the same trend 48 hours after surgery (Fig. 2B, random model: SMD = 0.14, 95% CI = [0.08, 0.36], P = 0.21, Pheterogeneity = 0.7). No heterogeneity was found across all the studies.

Fig. 2.

Opioid consumption in COMT Val/Val vs. Val/Met carriers within the first 24 and 48 hours after surgery.

Fig. 2.

Opioid consumption in COMT Val/Val vs. Val/Met carriers within the first 24 and 48 hours after surgery.

Close modal

Meta-analysis of Val/Val-Met/Met and opioid consumption

The GG (Val/Val) genotype of COMT included 808 patients, and AA (Met/Met) genotype included 294 patients for the first 24-hour after surgery. The studies included 166 patients for GG (Val/Val) and 53 patients for AA (Met/Met) genotype within 48 hours. Overall pooled analysis indicated no significant difference in opioid consumption between Val/Val and Met/ Met carriers within the first 24 hours (Fig. 3A, random model: SMD = 0.11, 95% CI = [-0.14, 0.36], P = 0.41, Pheterogeneity = 0.01) and 48 hours (Fig. 3B, random model: SMD = 0.07, 95% CI = [-0.25, 0.39], P = 0.67, Pheterogeneity = 0.95) after surgery. Since the heterogeneity was significant in patients 24 hours after surgery, we performed Galbraith’s test to estimate all 10 studies and singled out the study from Wesmille [22] as the main contributor to heterogeneity (Fig. 4A). After excluding this study, the heterogeneity disappeared but still no significant association was found (Fig. 4B, random model: SMD = 0.2, 95% CI = [-0.01, 0.41], P = 0.07, Pheterogeneity = 0.13

Fig. 3.

Opioid consumption in COMT Val/Val vs. Met/Met carriers within the 24 and 48 hours after surgery.

Fig. 3.

Opioid consumption in COMT Val/Val vs. Met/Met carriers within the 24 and 48 hours after surgery.

Close modal
Fig. 4.

Heterogeneity of the meta-analysis. A. Galbraith plot of the COMT gene GG-AA (Val/Val-Met/Met) polymorphism and opioid consumption within 24 hours. B. Forest plot showed the COMT gene GG-AA (Val/Val-Met/Met) polymorphism and opioid consumption within 24 hours after excluding the study causing heterogeneity.

Fig. 4.

Heterogeneity of the meta-analysis. A. Galbraith plot of the COMT gene GG-AA (Val/Val-Met/Met) polymorphism and opioid consumption within 24 hours. B. Forest plot showed the COMT gene GG-AA (Val/Val-Met/Met) polymorphism and opioid consumption within 24 hours after excluding the study causing heterogeneity.

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Publication bias

We applied several strategies to investigate publication bias, including Funnel plot, Egger’s test. No publication bias was evident in any comparison model: for Val/Val vs. Val/Met, Val/Val vs. Met/Met and opioid consumption within 24 hours and 48 hours. Egg’s Test P = 0.873, for Val/Val vs. Val/Met and opioid consumption within 24 hour. Egg’s Test P = 0.946, for Val/Val vs. Val/Met and opioid consumption within 48 hours. Egg’s Test P = 0.858, for Val/Val vs. Met/Met and opioid consumption in 24 hours. Egg’s Test P = 0.761, for Val/Val vs. Met/Met and opioid consumption within 48 hours (Fig. 5).

Fig. 5.

Funnel plot of statistically significant meta-analysis. No significant publication bias was found in the COMT SNP and opioid consumption.

Fig. 5.

Funnel plot of statistically significant meta-analysis. No significant publication bias was found in the COMT SNP and opioid consumption.

Close modal

Acute postoperative pain is an inevitable problem encountered in clinical practice and often results in multiple outcomes if an inadequate pain management is applied. The worst consequence is a chronic postoperative pain. Increasing evidence suggests that genetic factors significantly contribute to individual differences in pain perception, and are associated with risk for developing chronic pain conditions [13, 38]. The COMT gene is polymorphic, and the variants include rs4680, rs6269, rs4633, rs4818, rs165774, rs174696 [39-41]. In previous studies, it reported that these COMT SNPs associate with pain and analgesic effect. But the most widely studies variant in this gene SNP was adenosine (A) to guanosine (G) substitution at sequence 4680. Val158Met variant of COMT causes enzyme activity and affects pain perception in volunteers [17, 42]. Although considerable studies suggest that SNP rs4680 of COMT associated with pain and opioid consumption, the reported data are unable to get a convincible conclusion. Hence, we performed a systematic review and meta-analysis to evaluate the association between COMT gene Val158Met polymorphism and postoperative pain and opioid consumption.

AA (Met/Met) allele is known to be associated with reduced enzyme activity and difference in the clinical dose of opioids between individual patients suffering from cancer and undergoing major surgery [36, 43]. Most investigations focused on the difference in pain or opioid consumption between AA (Met/Met) and GG (Val/Val) allele. Although we found that AA (Met/Met) homozygotes were not significantly associated with opioid consumption, GA (Val/Met) heterozygote carriers required lower opioid doses compared with Val/Val carriers and there was no bias publication in all studies. Therefore, the GA (Val/Met) heterozygotes should be further investigated in the future.

There was no significant correlation between the COMT gene Val158Met polymorphism and opioid consumption within 48 hours after surgery. There may be two reasons for this. Firstly, the data included in the meta-analysis were so small that limited the statistical significance. In addition, pain management was applied to patients who suffered less pain in 48 hours.

In this study, we failed to find any significant association between postoperative pain and COMT gene Val158Met polymorphism. We further explored all the data and found most of the present 10 studies used in meta-analysis were population-mixed. COMT variants have different distributions in Caucasian and Asian populations [25]. Such as, the frequency of AA allele (Met/Met) in Caucasians ranges from 0.53 to 0.63, while its frequency in East Asians ranges from 0.11 to 0.35. Hence, the AA (Met/Met) allele is the major allele in Caucasian population but not in East Asians [44]. These inconsistencies in the COMT variants and population might be the major reason.

Pain perception and opioid analgesic response are complex traits, which are likely to be modulated by gene and gene-gene network. COMT gene has four important SNPs: rs4680, rs6269, rs4633 and rs4818, all of which produce three pain sensitivity haplotypes: HPS, APS, and LPS. The present study failed to obtain an exclusive conclusion, but the correlation between the haplotype and opioid consumption cannot be ignored [12, 25, 32-34, 45]. Furthermore, some recent studies have begun to explore the relationship between gene-gene (COMT and OPRM1) interactions to the pain susceptibility and opioid analgesic effect. Patients having AA (Met/Met) of COMT rs4680 and AG of OPRM1 rs1799971 consumed the largest amount of opioid compared to those having other combinations after orthopedic surgery [12]. While Henker revealed that heterozygous patients with GA (Val/Met) of COMT and AG of OPRM1 consumed significantly less morphine in the postanesthetic recovery room and 48 hours after surgery [21]. Besides the postoperative pain, many studies found that carriers of the COMT AA (Met/Met) and OPRM1 AA genotype required the lowest opioid dose compared to other combinations in cancer pain [33, 46]. But we could not get an exclusive conclusion, larger randomized studies involving postoperative patient screening for the COMT and OPRM1 mutation are needed. Hence, more genes and variants need to be discovered to explain the phenotypic variance in the analgesic effect of opioids.

In summary, the present meta-analysis indicates that the studied SNP rs4680 of COMT had insignificant association between 24- and 48-h postoperative pain. Patients with COMT rs4680 GA (Val/Met) heterozygotes consumed lower opioid does than those with GG homozygotes within 24 hours after surgery, which might provide valuable information for clinicians to better manage the use of opioids and pain individually.

This work is supported by the National Natural Science Foundation of China (No. 81501043 and 31460258), the Science and Technology Planning Project of Jiaxing (2017AY33056), and the Science and Technology Planning Project of Zhejiang Province (2015C37130, 2017C37114). We thank Ph.D. Susan W. Wesmiller (University of Pittsburgh School of Nursing, United States) to provide the unpublished data.

The authors report no conflicts

1.
Zheng H, Schnabel A, Yahiaoui-Doktor M, Meissner W, Van Aken H, Zahn P, Pogatzki-Zahn E: Age and preoperative pain are major confounders for sex differences in postoperative pain outcome: A prospective database analysis. PLoS One 2017; 12:e0178659.
2.
Aubrun F, Salvi N, Coriat P, Riou B: Sex- and age-related differences in morphine requirements for postoperative pain relief. Anesthesiology 2005; 103: 156-160.
3.
Nielsen LM, Olesen AE, Branford R, Christrup LL, Sato H, Drewes AM: Association Between Human Pain-Related Genotypes and Variability in Opioid Analgesia: An Updated Review. Pain Pract 2015; 15: 580-594.
4.
Fernandez Robles CR, Degnan M, Candiotti KA: Pain and genetics. Curr Opin Anesthesio 2012; 25: 444-449.
5.
Amano K, Nishizawa D, Mieda T, Tsujita M, Kitamura A, Hasegawa J, Inada E, Hayashida M, Ikeda K: Opposite Associations Between the rs3845446 Single-Nucleotide Polymorphism of the CACNA1E Gene and Postoperative Pain-Related Phenotypes in Gastrointestinal Surgery Versus Previously Reported Orthognathic Surgery. J Pain 2016; 17: 1126-1134.
6.
Grossman MH, Emanuel BS, Budarf ML: Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11.1––q11.2. Genomics 1992; 12: 822-825.
7.
Yao P, Ding YY, Wang ZB, Ma JM, Hong T, Pan SN: Effect of gene polymorphism of COMT and OPRM1 on the preoperative pain sensitivity in patients with cancer. Int J Clin Exp Med 2015; 8: 10036-10039.
8.
Schmahl C, Ludäscher P, Greffrath W, Kraus A, Valerius G, Schulze TG, Treutlein J, Rietschel M, Smolka MN, Bohus M: COMT val158met polymorphism and neural pain processing. PLoS One 2012; 7:e23658.
9.
Kambur O, Männistö PT: Catechol-O-methyltransferase and pain. Int Rev Neurobiol 2010; 95: 227-279.
10.
Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melén K, Julkunen I, Taskinen J: Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34: 4202-4210.
11.
Kowarik MC, Einhäuser J, Jochim B, Büttner A, Tölle TR, Riemenschneider M, Platzer S, Berthele A: Impact of the COMT Val(108/158)Met polymorphism on the mu-opioid receptor system in the human brain: mu-opioid receptor, met-enkephalin and beta-endorphin expression. Neurosci Lett 2012; 506: 214-219.
12.
Khalil H, Sereika SM, Dai F, Alexander S, Conley Y, Gruen G, Meng L, Siska P, Tarkin I, Henker R: OPRM1 and COMT Gene-Gene Interaction Is Associated With Postoperative Pain and Opioid Consumption After Orthopedic Trauma. Biol Res Nurs 2017; 19: 170-179.
13.
Hoofwijk DM, van Reij RR, Rutten BP, Kenis G, Buhre WF, Joosten EA: Genetic polymorphisms and their association with the prevalence and severity of chronic postsurgical pain: a systematic review. Brit J Anaesth 2016; 117: 708-719.
14.
Zhang L, Zhu J, Chen Y, Zhao J: Meta-analysis reveals a lack of association between a common catechol-O-methyltransferase (COMT) polymorphism val(158)met and fibromyalgia. Int J Clin Exp Patho 2014; 7: 8489-8497.
15.
Tammimäki A, Männistö PT: Catechol-O-methyltransferase gene polymorphism and chronic human pain: a systematic review and meta-analysis. Pharmacogenet Genom 2012; 22: 673-691.
16.
Jiao JH, Li Y, Liu L, Wang YH, Jiang XJ, Chen XG: Association of catechol-O-methyltransferase val158Met polymorphism with postoperative analgesic opioid use. Int J Clin Exp Med 2016; 9: 15494-15501.
17.
Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D: COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 2003; 299: 1240-1243.
18.
Somogyi AA, Sia AT, Tan EC, Coller JK, Hutchinson MR, Barratt DT: Ethnicity-dependent influence of innate immune genetic markers on morphine PCA requirements and adverse effects in postoperative pain. Pain 2016; 157: 2458-2466.
19.
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. Brit J Clin Pharmaco 2013; 75: 1506-1515.
20.
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 Tr 2012; 133: 405-412.
21.
Kolesnikov Y, Gabovits B, Levin A, Voiko E, Veske A: Combined Catechol-O-Methyltransferase and mu-Opioid Receptor Gene Polymorphisms Affect Morphine Postoperative Analgesia and Central Side Effects. Anesth Analg 2011; 112: 448-453.
22.
Wesmiller SW, Sereika SM, Bender CM, Bovbjerg D, Ahrendt G, Bonaventura M, Conley YP: Exploring the multifactorial nature of postoperative nausea and vomiting in women following surgery for breast cancer. Auton Neurosci 2017; 202: 102-107.
23.
Henker RA, Lewis A, Dai F, Lariviere WR, Meng L, Gruen GS, Sereika SM, Pape H, Tarkin IS, Gowda I, Conley YP: The associations between OPRM 1 and COMT genotypes and postoperative pain, opioid use, and opioid-induced sedation. Biol Res Nurs 2013; 15: 309-317.
24.
Thomazeau J, Rouquette A, Martinez V, Rabuel C, Prince N, Laplanche JL, Nizard R, Bergmann JF, Perrot S, Lloret-Linares C: Acute pain Factors predictive of post-operative pain and opioid requirement in multimodal analgesia following knee replacement. Eur J Pain 2016; 20: 822-832.
25.
Tan EC, Lim EC, Ocampo CE, Allen JC, Sng BL, Sia AT: Common variants of catechol-O-methyltransferase influence patient-controlled analgesia usage and postoperative pain in patients undergoing total hysterectomy. Pharmacogenomics J 2016; 16: 186-192.
26.
Zhang F, Tong J, Hu J, Zhang H, Ouyang W, Huang D, Tang Q, Liao Q: COMT gene haplotypes are closely associated with postoperative fentanyl dose in patients. Anesth Analg 2015; 120: 933-940.
27.
Baber M, Chaudhry S, Kelly L, Ross C, Carleton B, Berger H, Koren G: The pharmacogenetics of codeine pain relief in the postpartum period. Pharmacogenomics J 2015; 15: 430-435.
28.
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: 1194-1200.
29.
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: 1422-1433.
30.
Wen LL, Liao Q, Li L, Wang YC: No relationship of COMT Val 158 Met with pain sensitivity and fentanyl requirement after gastric cancer operation in humans. Pain Clin J 2015; 4: 246-251.
31.
Kim H, Dionne RA: Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 2006; 125: 216-224.
32.
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 gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 2006; 125: 216-224.
33.
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: 1651-1658.
34.
Dimova V, Lötsch J, Hühne K, Winterpacht A, Heesen M, Parthum A, Weber PG, Carbon R, Griessinger N, Sittl R, Lautenbacher S: Association of genetic and psychological factors with persistent pain after cosmetic thoracic surgery. J Pain Res 2015; 8: 829-844.
35.
Meloto CB, Bortsov AV, Bair E, Helgeson E, Ostrom C, Smith SB, Dubner R, Slade GD, Fillingim RB, Greenspan JD, Ohrbach R, Maixner W, McLean SA, Diatchenko L: Modification of COMT-dependent pain sensitivity by psychological stress and sex. Pain 2016; 157: 858-867.
36.
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.
37.
Tang QP, Ma X, Liao Q, Chen YH: The Correlation Between COMT Polymorphisms, Preoperative Anxiety and Postoperative Fentanyl Dose. Chin J Clin Psychol 2008; 3: 321-323.
38.
Correll, D: Chronic postoperative pain: recent findings in understanding and management. F1000Res 2017; 6: 1054.
39.
van Esch AA, de Vries E, Te Morsche RH, van Oijen MG, Jansen JB, Drenth JP: Catechol-O-methyltransferase (COMT) gene variants and pain in chronic pancreatitis. Neth J Med 2011; 7: 330-4.
40.
Vargas-Alarcón G, Fragoso JM, Cruz-Robles D, Vargas A, Vargas A, Lao-Villadóniga JI, García-Fructuoso F, Ramos-Kuri M, Hernández F, Springall R, Bojalil R, Vallejo M, Martínez-Lavín M: Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia. Arthritis Res Ther 2007; 5:R110.
41.
Park DJ, Kim SH, Nah SS, Lee JH, Kim SK, Lee YA, Hong SJ, Kim HS, Lee HS, Kim HA, Joung CI, Kim SH, Lee SS: Association between catechol-O-methyl transferase gene polymorphisms and fibromyalgia in a Korean population: A case-control study. Eur J Pain 2016; 7: 1131-9.
42.
Loggia ML, Jensen K, Gollub RL, Wasan AD, Edwards RR, Kong J: The catechol-O-methyltransferase (COMT) val158met polymorphism affects brain responses to repeated painful stimuli. PLoS One 2011; 11:e27764.
43.
Rakvåg TT, Klepstad P, Baar C, Kvam TM, Dale O, Kaasa S, Krokan HE, Skorpen F: The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain 2005; 116: 73-78.
44.
ALFRED: the Allele Frequency Databas. http://alfred.med.yale.edu/alfred/index.asp.
45.
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: 101-107.
46.
Reyes-Gibby CC, Shete S, Rakvåg T, Bhat SV, Skorpen F, Bruera E, Kaasa S, Klepstad: Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain 2007; 1-2: 25-30.
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