摘要
[目的与背景]
疼痛和术前焦虑状态是现代麻醉工作必须面临和禀待解决的问题。严重影响到患者对临床治疗的配合和围手术期的顺利渡过。随着人们生活水平不断的提高和对自身生活质量的重视,对医疗服务提出了更高的要求。现代高品质的医疗服务提倡人性化和个体化服务。所以,深入研究疼痛感知和术前焦虑状态的基因学背景十分必要。也是人性化服务和个体化治疗的必然趋势。
疼痛治疗是临床麻醉工作的一个重要方面。人类对疼痛敏感性存在明显的个体差异,导致这种个体差异的因素很多,如:以前疼痛经历、性格、性别、及遗传背景等。但是,至少这种差异部分是遗传学背景的造成的。
随着对基因研究的深入,对疼痛的研究更多地开始从基因角度考虑,而且越来越多可能与疼痛相关的基因被发现和验证。特别是从2003年人类基因组计划完成后,有关治疗药物与相应疾病的遗传标记和表型变异性研究被广泛开展。人类基因组计划揭开了几乎全部的人类基因序列,这也为疼痛的基因研究创造了可能性。大量参与疼痛形成的分子介质被提上研究日程:如炎症介质(5-羟色胺、组织胺、缓激肽和细胞因子等)、第二信使、受体和内源性神经递质等。人们可以据此在不同层面上研究影响疼痛感知、疼痛敏感性和疼痛状态的基因基础。也能据此开拓和发展新的基因治疗方法和药物等。在不久的将来,有望能为疼痛的个体化治疗提供策略。
术前焦虑状态是每个面临手术的患者或多或少都会经历的,也是临床医生所关注的棘手难题。疼痛和围手术期的焦虑两者关系密切。疼痛本身就会引起患者极度不适和精神焦虑。反之,围手术期的紧张和焦虑也会改变疼痛的感知。一些平时轻微的疼痛,在焦虑状态时,疼痛刺激可能会被放大或夸大。同时,除社会、心理因素外,两者都受遗传因素影响,甚至被遗传因素所决定。而两者又有很多共同的基因背景和遗传联系。所以对二者的联合研究具有重要意义。
本研究拟选择被大家广泛认可的与疼痛和精神神经因素相关的COMTval158met和OPRM1A118G基因多态性,首次探讨其对疼痛敏感性和术前焦虑的影响。以期为后续研究和临床工作提供一些有价值的信息和参考。
[材料与方法]
1.研究对象284例择期手术患者和28例健康志愿者,年龄20-50岁,体重指数(BMI)在正常范围(1±20%),美国麻醉医师协会ASA分级Ⅰ或Ⅱ级。排除标准:有慢性疼痛史、使用镇痛药物的患者,有酗酒、吸烟史、糖尿病、肝脏病、肾脏病、心血管疾病史的患者,有精神神经疾病史的患者。所有患者经医院伦理委员会同意并签署知情同意书后进入试验。
2.疼痛敏感性测量和焦虑状态评分使用电刺激仪进行测痛,并让患者熟悉测定的整个过程,使其能准确区分痛阈和耐痛阈。重复测定3次痛阈和耐痛阈,各取其平均值。所有患者术前接受特质焦虑状态问卷调查评分,记录焦虑评分(SAI评分)和特质评分(TAI评分)。
3.基因多态性检测外周静脉留置针采集静脉血5ml,提取基因组DNA;采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)技术,对COMTval158met和OPRM1A118G多态性位点进行检测分析。通过直接对PCR扩增产物进行测序以验证基因型检测结果的可靠性。
4.统计学分析统计学分析采用SPSS12.0软件进行,计量资料以x±s(均数±标准差)表示,等位基因和基因型分布是否符合Hardy-Weinberg平衡采用χ2检验进行检测;对多组计量数据进行单因素方差分析(ANOVA),各组间比较采用LSD法。不同基因型组间痛阈、耐痛阈、SAI和TAI评分比较采用协方差分析以排除其它影响因素。采用spearman等级相关分析突变等位基因与痛阈、耐痛阈、SAI和TAI评分之间的相关性。以P<0.05作为差别有统计学意义的检验标准。
[结果]
1.一般情况
284例患者中,平均年龄为38.8±9.5岁(21-50),体重指数(BMI)为18.4±2.5kg/m2。28例健康志愿者平均年龄为22.4±2.1岁(18-25),体重指数(BMI)为15.6±2.7kg/m2。所有患者和健康志愿者一般情况比较无差异(P>0.05)。
2.国内人群中COMTval158met和OPRM1A118G多态性等位基因突变率
COMTvall58met和OPRM1A118G等位基因在国内人群中的突变率分别为34.2%和32.1%。等位基因和基因型分布符合Hardy-weinberg平衡。
3.COMTval158met基因多态性对患者疼痛敏感性和术前焦虑的影响
按COMTvall58met基因型进行分组,患者一般情况比较三组之间差异无统计学意义(P>0.05);三组之间耐痛阈和痛阈比较差异有统计学意义(P<0.05),met/met(1.6±0.9mA,4.5±1.1mA)组低于val/val组(2.2±0.7mA,5.4±.2mA),val/val组与val/met组无差异。术前焦虑状态评分(SAI和TAI)met/met组(51.5±10.8,49.2±10.0)高于val/val组(44.4±9.5,43.1±7.3),val/val组与val/met组无差异(P>0.05)。与健康志愿者比较,术前焦虑评分(SAI)升高,特质评分(TAI)无差异(P>0.05),痛阈和耐痛阂均降低(P<0.05)。
4. COMTval158met和OPRM1A118G基因多态性对患者疼痛敏感性和术前焦虑
的联合影响
联合基因分型成功277例,按OPRM1A118G和COMTvall58met基因型联合分组后,九组之间一般情况比较差异无统计学意义(P>0.05);相对于中性的A/G并val/met组,G/G并val/met组和G/G并met/met组痛阈降低;G/G并val/val组、G/G并val/met组和G/G并met/met组耐痛阈降低(P<0.05)。相对于中性的A/G并val/met组,术前焦虑状态评分SAI和TAI在A/G并met/met组和G/G并met/met组升高(P<0.05)。
[结论]
1. COMTval158met基因多态性是术前焦虑的易感因素。相对野生型纯合子和杂
合子,携带met158met等位基因的个体更容易术前焦虑。
2.在疼痛敏感性方面,COMTval158met和OPRM1A118G基因多态性有协同作用,COMT基因met158met多态性加重患者术前焦虑,间接影响患者疼痛敏感性,使疼痛敏感性增强;痛阈和耐痛阈相应降低。
3.相对于COMTval158met, OPRM1A118G基因多态性是影响机体疼痛敏感性的主要因素。118G多态性提高患者疼痛敏感性,使患者痛阈、耐痛阈降低。
4. OPRM1A118G基因多态性对患者术前焦虑无影响。
Background and Objective
Pain and preoperative anxiety are serious problem that we have to be faced with clinical anesthesia, and which will affect therapy smoothly of perioperative. Adequate release of pain and anxiety are necessary before and after operation to decrease the incidence of complication. As that to be considered, much things should be done with this.
Since the completion of the Human Genome project in2003, there has been an increasing trend in medicine to correlate disease to genetic markers and phenotypic variance. The Human Genome Project revealed nearly complete genomic sequence data which provide the basis for further research on genomic variations influencing nociception, susceptibility to pain conditions, as well as response to pharmacotherapy. Polymorphisms of receptors, transporters, metabolizing enzymes, and other targets of pharmacotherapy and the nociceptive system are currently under investigation. Molecular mediators of pain processing such as inflammatory mediators (serotonin, histamine, bradykinin and cytokines), second messengers, receptors and endogenous neurotransmitters are under investigation, and will hopefully reveal new strategies for individualized pain management in the future.
An individualized profile for patients at risk for severe pain or anxiety disorders, and a pharmacotherapy considering the patients'genetic background might considerably improve pain and anxiety disorders management.
Research in the field of pain and anxiety management has revealed various genomic variations influencing sensitivity to pain, susceptibility to anxiety disorders. Future developments have to focus on the translation of these findings into clinical practice. Multiple genes are involved and single genes only have small contributions to the overall genetic impact. Up to now, however, most studies have addressed only one or a few single gene variations. The complexity of these genetic disorders still has to be elucidated.
Our research aims the commonly candidate genetic polymorphism to determine the frequencies of COMTval158met and OPRM1A118G alleles in Chinese patients and to observe the associated impact of COMTval158met and OPRM1A118G on pain sensitivity and preoperative anxiety. The present study seem to provides an important foundation and theoretical evidence for the gene-directed treatment of pain and preoperative anxiety.
Materials and Methods
Subjects
Two hundred and eighty-four patients and twenty-eight healthy volunteers, aged20-50yr, within±20%of ideal body weight, and having an American Society of Anesthesiologists (ASA) physical status of I or II, undergoing selective operation were enrolled. Exclusion criteria included the following:known history of psychiatric disease, nervous disease, significant cardiovascular disease, hepatic or renal dysfunction, diabetes mellitus, alcohol or drug abuse, chronic analgesic use, pregnancy or nursing. All patients were of Chinese Han nationality and live in Henan province of China. The study design was approved by Institutional Ethics Committee of Zhengzhou University.
Measurement of pain sensitivity and score of anxiety state
Preoperatively, the pain threshold and pain tolerance threshold were measured three times using electrical stimulation and to recorded the average number. All patients to be enrolled in the trial accepted the investigation of anxiety state and recorded the score of SAI and TAI.
Genotyping assays
Venous blood samples (5ml) were collected from all patients in this study. DNA was extracted from leukocytes using a standard phenol/chloroform procedure. Genotyping of COMTval158met and OPRM1A118G alleles was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Statistical analysis
SPSS12.0software was used for statistical analyses. Chi-square test was used to verify Hardy-Weinberg equilibrium. Data for the pain threshold, pain tolerance threshold, SAI and TAI score were compared among the genotype group using one-way analysis of variance with covariance analysis correction for multiple comparisons was performed before and after adjusted for age and weight. P-values <0.05were considered with statistically significant.
Results General information
Among the two hundred and eighty-four subjects, the mean of age was38.8years, and the mean of body mass index was18.4. Among the twenty-eight healthy volunteers, correspondingly, the mean of age was22.4years, and the mean of body mass index was15.6. There was no significant difference between patients and volunteers in general information except the age.
Frequencies of OPRM1A118G and COMTval158met
The frequencies of COMTval158met and OPRM1A118G alleles in Chinese patients were0.342and0.321, respectively. The allele frequencies were in Hardy-Weinberg equilibrium.
Effects of COMTval158met genetic polymorphism on pain sensitivity and preoperative anxiety
There was no significant differences in general information among the three genotype groups. PT and PTT were statistical different between met/met (1.6±0.9mA,4.5±1.1mA) and val/val (2.2±0.7mA,5.4±1.2mA) groups (P<0.05), SAI and TAI score were statistical different also between met/met (51.5±10.8,49.2±10.0) and val/val (44.4±9.5,43.1±7.3) groups (P<0.05), and there were no significant difference between val/val and val/met groups in PT, PTT, SAI and TAI score. However, compared with healthy volunteers'groups correspondingly, there were significantly lower in PT and PTT, and significantly higher in SAI score(P<0.05). There was no significant difference in TAI score(P>0.05).
Association effects of COMTvall58met and OPRM1A118G genetic polymorphism on pain sensitivity and preoperative anxiety
There were twe hundreds and seventy-seven patients had carried out succeed in the joint genotyping. After association studied the COMTval158met and OPRM1A118G genetic polymorphism, they were divided into nine groups. Group A/A and val/val(n=68), group A/A and val/met(n=50), group A/A and met/met(n=17), group A/G and val/val(n=43), group A/G and val/met(n=46), group A/G and met/met(n=17), group G/G and val/val(n=18), group G/G and val/met(n=10), and group G/G and met/met(n=8). There was no significant differences in general information among the nine genotype groups. According to the neutral group A/G and val/met, there was significantly lower in PT at group G/G and val/met, and group G/G and met/met; there was significantly lower in PTT at group G/G and val/val, group G/G and val/met, and group G/G and met/met(P<0.05); there were significantly higher in SAI and TAI score at group A/G and met/met, and group G/G and met/met (P<0.05).
Conclusions
1. The COMTvall58met genetic polymorphism is a predisposing factor of preoperative anxiety. Compare with val158val and val158met, the patients with met158met genotype have the more probability in preoperative anxiety state.
2. The COMTval158met genetic polymorphism would exacerbate the preoperative anxiety, and at the same time enhance pain sensitivity, through the remote effects on pain sensitivity.
3. The OPRM1A118G genetic polymorphism is the main factor which affect pain sensitivity, the gene mutation of118G will enhance pain sensitivity and decrease the PT and PTT.
4. There is no significantly relationship between the OPRM1A118G genetic polymorphism and preoperative anxiety.
引文
1. Victoria G. Pain care. Nurse Care North American,1994,29:534-544.
2.庄心良,曾因明,陈伯銮.现代麻醉学.北京,人民卫生出版社,第三版:2505-2506.
3. LehoferM, LiebmannPM, MoserM, et al. Nervousness and Pain sensitivity:LA Positive correlation.Psyehiatry Res,1998,79(1):51-53.
4. Orbach I, Mikulincer M, King R, et al. Thresholds and tolerance of physical pain in suicidal and nonsuicidal adolescents. Consult Clin Psychol,1997,65(4): 646-652.
5.张雅坤,周玲君,郭振华,等.认知行为疗法在疼痛治疗中的运用现况及展望.中国疼痛医学杂志,2003,9(3):163-166.
6. Edwards R, Augustson EM, Fillingim R. Sex-specific effects of pain-related anxiety on adjustment to chronic pain. Clin J Pain,2000,16(1):46-53.
7. Keogh E, Mansoor L. Investigating the effects of anxiety sensitivity and coping on the perception of cold pressor pain in healthy women. Eur J Pain, 2001,51:11-22.
8. Schumacher R, Velden M. Anxiety, pain experience, and pain report:a signal-detection study. Percept Mot Skills,1984,58(2):339-349.
9. Stamer UM, Stiiber F. Genetic factors in pain and its treatment. Cur Opin Anaesthesiol,2007,20:478-484.
10. Lotsch J, Skarke C, Liefhold J, et al. Genetic predictors of the clinical response to opioid analgesics:clinical utility and future perspectives. Clin Pharmacokinet 2004,43:983-1013.
11. Abood ME. Molecular biology of cannabinoid receptors. Handb Exp Pharmacol 2005,168:81-115.
12. Lundstrom K, Salminen M, Jalanko A, et al. Cloning and characterization of human placental catechol-O-methyltransferase cDNA. DNA Cell Biol.1991; 10:181-189.
13. Salminen M, Lundstrom K, Tilgmann C, Savolainen R, Kalkkinen N, Ulmanen I. Molecular cloning and characterization of rat liver catechol-Omethyltransferase. Gene.1990; 93:241-247.
14. Belfer I, Wu T, Kingman A, et al. Candidate gene studies of human pain mechanisms. Anesthesiology.2004; 100:1562-1572.
15. Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase(COMT):effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet.2004; 75:807-821.
16. Lotta T, Vidgren J, Tilgmann C, et al. Kinetics of human soluble and membrane-bound catechol-O-methyltransferase:arevised mechanism and
description of the thermolabile variant of the enzyme. Biochemistry.1995; 34:4202-4210.
17. Zubieta JK, Heitzeg MM, Smith YR, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science, 2003;299(5610):1240-1243.
18. George SZ, Wallace MR, Wright TW, et al. Evidence for a biopsychosocial influence on shoulder pain:Pain catastrophizing and catechol-O-methyltransferase (COMT) diplotype predict clinical pain ratings. Pain.2008; 136:53-61.
19. Hong J, Shu-Leong H, Tao X, Lap-Ping Y. Distribution of catechol-Omethyltransferase expression in human central nervous system. Neuroreport.1998; 9:2861-2864.
20. Karhunen T, Ulmanen I, Panula P. Catechol-O-methyltransferase in rat sensory ganglia and spinal cord. Neuroscience.1996; 73:267-276.
21. Nielsen PR, N(?)rgaard L, Rasmussen LS, et al. Prediction of post-operative pain by an electrical pain stimulus. Acta Anaesthesiol Scand 2007,51:582-586.
22. Barnett JH, Jones PB, Robbins TW, et al. Effects of the catechol-Omethyltransferase Val(158)Met polymorphism on executive function:a meta-analysis of theWisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry.2007; 12:502-509.
23. Bertolino A, Caforio G, Blasi G, et al. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry.2004; 161:1798-1805.
24. Munafo MR, Bowes L, Clark TG, et al. Lack of association of the COMT (Val158/108 Met) gene and schizophrenia:a meta-analysis of case-control studies. Mol Psychiatry.2005; 10:765-770.
25. Tunbridge EM, Harrison PJ,Weinberger DR. Catechol-o-methyltransferase, cognition, and psychosis:Val158Met and beyond. Biol Psychiatry.2006; 60:141-151.
26.宋传贵,胡震,袁文涛,等.COMT基因val158met多态性在BRCA1/2基因无突变的遗传倾向乳腺癌中的分布.中华外科杂志,2006;44(19):1310-1313.
27. Papaleo F, Crawley JN, Song J, et al. Genetic dissection of the role of catechol-o-methyltransferase in cognition and stress reactivity in mice. J Neurosic. 2008;28(35):8709-8723.
28. Staahl C, Drewes AM. Experimental human pain models:a review of standardised methods for preclinical testing of analgesics. Basic Clin Pharmacol Toxicol 2004,95:97-111.
29. Gracely RH. Pain measurement. Acta anaesthesiol Scand,1999,43:897-908.
30.黄飞龙,王宁华,谭维溢,等.健康妇女斜方肌与三角肌压痛阈重测信度研究.国外医学·物理医学与康复学分册,2004,3:99-100.
31. Mustafa AA, Lorentz E, Deanna E, et al. Sex Differences in Pain and Hypothalamic-Pituitary-Adrenocortical Responses to Opioid Blockade. Psychosomatic Medicine 2004,66:198-206.
32. Loggia ML, Jensen K, Gollub RL, et al. The catechol-o-methyltransferase (COMT) val158met polymorphismaffects brain responses to repeated painful stimuli. PLoS One.2011; 6:e27764.
33. Mobascher A, Brinkmeyer J, Thiele H, et al. The val158met polymorphism of human catechol-O-methyltransferase (COMT) affects anterior cingulate cortex activation in response to painful laser stimulation. Mol Pain.2010; 6:32.
34. Jensen KB, Lonsdorf TB, Schalling M, et al. Increased Sensitivity to Thermal Pain Following a Single Opiate Dose Is Influenced by the COMT val158met Polymorphism. PLoS One.2009; 4:e6016.
35. Rakvag TT, Ross JR, Sato H, et al. Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Mol Pain.2008; 4:64.
36. Armero P, Muriel C, Santos J, et al. COMT (Val158Met) polymorphism is not associated to neuropathic pain in a Spanish population. Eur J Pain. 2005;9:229-232.
37. Kim H, Lee H, Rowan J, et al. Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute postsurgical pain in humans. Mol Pain.2006; 2:24.
38.张卫,常琰子,阚全程,等.术前焦虑状态对妇科手术患者痛阂和耐痛阈的影响.中华麻醉学杂志,2009,29(3):210-211.
39. Diatchenko L, Nackley AG, Slade GD, et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain. 2006;125(3):216-224.
40. Schumacher MA, Basbaum AI, Way WL. Opioid analgesics and antagonists. In: Katzung BG, editor. Basic and clinical pharmacology.10th ed. New York: McGraw-Hill; 2006. pp:492.
41. Sehgal N, Smith HS, Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician.2011; 14:249-258.
42. Chou WY, Wang CH, Liu PH, et al. Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology.2006; 105:334-337.
43. Zhang W, Chang YZ, Kan QC, et al. Association of human m-opioid receptor gene polymorphism A118G with fentanyl analgesia consumption in Chinese gynaecological patients. Anaesthesia.2010; 65:130-135.
44. Bruehl S, Chung OY, Burns JW. The mu opioid receptor A118G gene polymorphism moderates effects of trait anger-out on acute pain sensitivity. Pain. 2008; 139(2):406-415.
45. Raymonda R, Romberg, Erik Olofsen, et al. Polymorphism of μ-Opioid Receptor Gene (OPRM1:c.l 18A>G) Does Not Protect Against Opioid induced Respiratory Depression despite Reduced Analgesic Response. Anesthesiology 2005, 102:522-530.
46. Tan EC, Tan CH, Karupathivan U, et al. Mu opioid receptor gene polymorphisms and heroin dependence in Asian populations. Neuroreport 2003,14:569-572.
47.王中玉,张卫,阚全程,等.μ阿片受体A118G基因多态性对妇科手术患者疼痛敏感性的影响.中华麻醉学杂志,2010;30(2):159-161.
48. Berthele A, Platzer Stefan, Jochim B, et al. COMT Val108/158Met genotype affects the mu-opioid receptor system in the human brain:Evidence from ligand-binding, G-protein activation and preproenkephalin mRNA expression. Neurolmage. 2005;28(1):185-193.
49. Finan PH, Zautra AJ, Davis MC, et al. COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia. Pain.2011; 152:300-307.
50. Slade GD, Diatchenko L, Bhalang K, et al. Influence of psychological factors on risk of temporomandibular disorders. J Dent Res.2007; 86:1120-1125.
51. Lu Y, Belfer I, Gershon E, et al. Neuropathic pain levels following surgical nerve injury are controlled genotypes and haplotypes of COMT-the gene encoding catecholamine-O-methyltransferase. Eur J Pain.2007;11(S1):S59-S207.
52. Tammimaki A, Mannisto PT. Catechol-O-methyltransferase gene polymorphism and chronic human pain:a systematic review and meta-analysis. Pharmacogenetics and Genomics.2012; 22(9):673-691.
53. Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase(COMT):effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet.2004; 75:807-821.
54. Bray NJ, Buckland PR, Williams NM, et al. A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet.2003;73:152-161.
55. Dempster EL, Mill J, Craig IW, et al. The quantification of COMT mRNA in post mortem cerebellum tissue:diagnosis, genotype, methylation and expression. BMC Med Genet.2006; 7:10.
56. Ji Y, Olson J, Zhang J, et al. Breast cancer risk reduction and membrane-bound catechol-O-methyltransferase genetic polymorphisms. Cancer Res.2008; 68:5997-6005.
57. Lee SG, Joo Y, Kim B, et al. Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. Hum Genet.2005; 116:319-328.
1. Body SC. Genomics:Implications for anesthesia, perioperative care and outcomes. Adv Anesth.2009; 27:73-94.
2. Mirnezamim R, Nicholson J, Darzi A. Preparing for precision medicine. N Engl J Med.2012; 366:489-491.
3. Candiotti KA. Anesthesia and pharmacogenomics:not ready for prime time. Anesth Analg.2009; 109:1377-1378.
4. Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature,2006;444:894-898.
5. Ahmad S, Dahllund L, Eriksson AB, et al. A stop codon mutation in SCN9A causes lack of pain sensation. Hum Mol Genet.2007; 16(17):2114-2121.
6. Dichgans M, Freilinger T, Eckstein G, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet, 2005;366:371-377.
7. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+channel gene CACNL1A4. Cell,1996; 87:543-52.
8. Schumacher MA, Basbaum AI, Way WL. Opioid analgesics and antagonists. In: Katzung BG, editor. Basic and clinical pharmacology.10th ed. New York: McGraw-Hill; 2006. pp:492.
9. Sehgal N, Smith HS, Manchikanti L. Peripherally acting opioids and clinical implications for pain control. Pain Physician.2011; 14:249-258.
10. Chou WY, Wang CH, Liu PH, et al. Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology.2006; 105:334-337.
11. Kleine-Brueggeney M, Musshoff F, Stuber F, et al. Pharmacogenetics in palliative care. Forensic Sci Int.2010; 203:63-70.
12. Kosarac B, Fox A, Collard C. Effect of genetic factors on opioid action. Curr Opin Anaesthesiol.2009; 22:476-482.
13. Zwisler ST, Enggaard TP, Mikkelsen S, et al. Lack of association of OPRM1 and ABCB1 single nucleotide polymorphisms to oxycodone response in postoperative pain. J Clin Pharmacol.2012; 52:234-242.
14.王中玉,张卫,阚全程,等.μ阿片受体A118 G基因多态性对妇科手术患者疼痛敏感性的影响.中华麻醉学杂志,2010;30(2):159-161.
15. Lotsch J, Geisslinger G. Current evidence for a genetic modulation of the response to analgesics. Pain.2006; 121:1-5.
16. Lotsch J, Stuck B, Hummel T. The human mu-opioid receptor gene polymorphism 118A>G decreases cortical activation in response to specific nociceptive stimulation. Behav Neurosci.2006; 120:1218-1224.
17. Lotsch J, Skarke C, Grosch S, et al. The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics.2002; 12:3-9.
18. Lotsch J, Skarke C, Wieting J, et al. Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther.2006;79:72-89.
19. Jorn L, Carsten S, Jurgen L, et al. Genetic predictors of the clinical response to opioid analgesics. Clin Pharmacokinet,2004,43(14):983-1013.
20. Romberg, Raymonda R, et al. Polymorphism of μ-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology.2005,102: 522-530.
21. Klepstad P, Rakvag TT, Kaasa S, et al. The 118 A> G polymorphism in the human m-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand.2004; 48:1232-1239.
22. Chou WY, Yang LC, Lu HF, et al. Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiol Scand.2006; 50:787-792.
23. Belfer I, Wu T, Kingman A, et al. Candidate gene studies of human pain mechanisms. Anesthesiology.2004; 100:1562-1572.
24. Max MB. Assessing pain candidate gene studies. Pain.2004; 109:1-3.
25. Camorcia M, Capogna G, Stirparo S, et al. Effect of 1-opioid receptor A118G polymorphism on the ED50 of epidural sufentanil for labor analgesia. Int J Obstet Anesth.2012; 21:40-44.
26. Zhang W, Chang YZ, Kan QC, et al. Association of human m-opioid receptor gene polymorphism A118G with fentanyl analgesia consumption in Chinese gynaecological patients. Anaesthesia.2010; 65:130-135.
27. Bruehl S, Chung OY, Burns JW. The mu opioid receptor A118G gene polymorphism moderates effects of trait anger-out on acute pain sensitivity. Pain. 2008; 139(2):406-415.
28. Landau R. One size does not fit all:genetic variability of mu-opioid receptor and postoperative morphine consumption. Anesthesiology.2006; 105:235-237.
29. Walter C, Lotsch J. Meta-analysis of the relevance of the OPRM1118A>G genetic variant for pain treatment. Pain.2009; 146:270-275.
30. Spina E, Scordo MG. Clinically significant drug interactions with antidepressants in the elderly. Drugs Aging.2002; 19:299-320.
31. Daly AK, Brockmoller J, Broly F, et al. Nomenclature for human CYP2D6 alleles. Pharmacogenetics.1996; 6:193-201.
32. Marez D, Legrand M, Sabbagh N, et al. Polymorphism of the cytochrome P450 CYP2D6 gene in a European population:characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics.1997; 7:193-202.
33. Leppert W. CYP2D6 in the metabolism of opioids for mild to moderate pain. Pharmacology.2011; 87:274-285.
34. Mikus G, Weiss J. Influence of CYP2D6 genetics on opioid kinetics, metabolism and response. Curr Pharmacogenomics.2005; 3:43-52.
35. Candiotti KA, Yang Z, Rodriguez Y, et al. The impact of CYP2D6 genetic polymorphism on postoperative morphine pain relief. Pain Med.2009; 10: 799-805.
36. Samer CF, Daali Y, Wagner M, et al. Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety. Br J Pharmacol.2010; 160:919-930.
37. Sachse C, Brockmoller J, Bauer S, et al. Cytochrome P450 2D6 variants in a Caucasian population:allele frequencies and phenotypic consequences. Am J Hum Genet.1997; 60:284-295.
38. Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cytochrome P450 enzymes:an opportunity for individualized drug treatment. Trends Pharmacol Sci.1999; 20:342-349.
39. Raimundo S, Toscano C, Klein K, et al. A novel intronic mutation,2988G>A, with high predictivity for impaired function of cytochrome P4502D6 in white subjects. Clin Pharmacol Ther.2004; 76:128-138.
40. Stamer UM, Lehnen K, Hothker F, et al. Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain.2003; 105:231-238.
41. Wang G, Zhang H, He F, Fang X. Effect of the CYP2D6_10 C188T polymorphism on postoperative tramadol analgesia in a Chinese population. Eur J Clin Pharmacol.2006; 62:927-931.
42. Andreassen TN, Eftedal I, Klepstad P, et al. Do CYP2D6 genotypes reflect oxycodone requirements for cancer patients treated for cancer pain? A crosssectional multicentre study. Eur J Clin Pharmacol.2012; 68:55-64.
43. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J.2007; 7:257-265.
44. Klees TM, Sheffels PB, Thummel KE, et al. Pharmacogenetic determinants of human Liver microsomal alfentanil metabolism and the role of Cytochrome P4503A5. Anesthesiologist.2005,102; 550-556.
45. Kharasch ED, Thummel KE. Human alfentanil metabolism by cytochrome P450 3A3/4. An explanation for the interindividual variability in alfentanil clearance? Anesth Analg.1993,76:1033-1039.
46. Hong J, Shu-Leong H, Tao X, Lap-Ping Y. Distribution of catechol-Omethyltransferase expression in human central nervous system. Neuroreport.1998; 9:2861-2864.
47. Karhunen T, Ulmanen I, Panula P. Catechol-O-methyltransferase in rat sensory ganglia and spinal cord. Neuroscience.1996; 73:267-276.
48. Lundstrom K, Salminen M, Jalanko A, et al. Cloning and characterization of human placental catechol-O-methyltransferase cDNA. DNA Cell Biol.1991; 10:181-189.
49. Salminen M, Lundstrom K, Tilgmann C, Savolainen R, Kalkkinen N, Ulmanen I. Molecular cloning and characterization of rat liver catechol-Omethyltransferase. Gene.1990; 93:241-247.
50. Xie T, Ho SL, Ramsden D. Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol.1999; 56:31-38.
51. Shifman S, Bronstein M, Sternfeld M, et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet.2002; 71:1296-1302.
52. Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase(COMT):effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet.2004; 75:807-821.
53. Lotta T, Vidgren J, Tilgmann C, et al. Kinetics of human soluble and membrane-bound catechol-O-methyltransferase:arevised mechanism and description of the thermolabile variant of the enzyme. Biochemistry.1995; 34:4202-4210.
54. Zubieta JK, Heitzeg MM, Smith YR, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science, 2003;299(5610):1240-1243.
55. Barnett JH, Jones PB, Robbins TW, et al. Effects of the catechol-Omethyltransferase Val(158)Met polymorphism on executive function:a meta-analysis of theWisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry.2007; 12:502-509.
56. Bertolino A, Caforio G, Blasi G, et al. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry.2004; 161:1798-1805.
57. Munafo MR, Bowes L, Clark TG, et al. Lack of association of the COMT (Vai158/108 Met) gene and schizophrenia:a meta-analysis of case-control studies. Mol Psychiatry.2005; 10:765-770.
58. Tunbridge EM, Harrison PJ,Weinberger DR. Catechol-o-methyltransferase, cognition, and psychosis:Val158Met and beyond. Biol Psychiatry.2006; 60:141-151.
59. George SZ, Wallace MR, Wright TW, et al. Evidence for a biopsychosocial influence on shoulder pain:Pain catastrophizing and catechol-O-methyltransferase (COMT) diplotype predict clinical pain ratings. Pain.2008; 136:53-61.
60. Papaleo F, Crawley JN, Song J, et al. Genetic dissection of the role of catechol-o-methyltransferase in cognition and stress reactivity in mice. J Neurosic. 2008;28(35):8709-8723.
61. Kambur O, Mannisto PT, Viljakka K, et al. Stress-induced analgesia and morphine responses are changed in catechol-O-methyltransferase-deficient male mice. Basic Clin Pharmacol Toxicol.2008; 103:367-373.
62. Gogos JA, Morgan M, Luine V, et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA.1998; 95:9991-9996.
63. Diatchenko L, Slade GD, Nackley AG, et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet.2005; 14:135-143.
64. Nackley AG, Tan KS, Fecho K,et al. Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta(2)-and beta(3)-adrenergic receptors. Pain.2007; 128:199-208.
65. Pertovaara A, Wei H, Kalmari J, et al. Pain behavior and response properties of spinal dorsal horn neurons following experimental diabetic neuropathy in the rat: modulation by nitecapone, a COMT inhibitor with antioxidant properties. Exp Neurol.2001; 167:425-434.
66. Kambur O, Talka R, Ansah OB, et al. Inhibitors of catechol-O-methyltransferase sensitize mice to pain. Br J Pharmacol.2010; 161:1553-1565.
67. Kambur O, Mannisto PT, Pusa AM, et al. Nitecapone reduces development and symptoms of neuropathic pain after spinal nerve ligation in rats. Eur J Pain.2011; 15:732-740.
68. Graf WD, Unis AS, Yates CM, et al. Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism. NEUROLOGY. 2001;57:410-416.
69. Berthele A, Platzer Stefan, Jochim B, et al. COMT Val108/158Met genotype affects the mu-opioid receptor system in the human brain:Evidence from ligand-binding, G-protein activation and preproenkephalin mRNA expression. NeuroImage. 2005;28(1):185-193.
70. Loggia ML, Jensen K, Gollub RL, et al. The catechol-o-methyltransferase (COMT) vall58met polymorphismaffects brain responses to repeated painful stimuli. PLoS One.2011; 6:e27764.
71. Mobascher A, Brinkmeyer J, Thiele H, et al. The val158met polymorphism of human catechol-O-methyltransferase (COMT) affects anterior cingulate cortex activation in response to painful laser stimulation. Mol Pain.2010; 6:32.
72. Jensen KB, Lonsdorf TB, Schalling M, et al. Increased Sensitivity to Thermal Pain Following a Single Opiate Dose Is Influenced by the COMT val158met Polymorphism. PLoS One.2009; 4:e6016.
73. Wilson VG, Grohmann M, Trendelenburg U. The uptake and O-methylation of 3H-(+/-)-isoprenaline in rat cerebral cortex slices. Naunyn Schmiedebergs Arch Pharmacol.1988; 337:397-405.
74. Matsumoto M, Weickert CS, Akil M, et al. Catechol-O-methyltransferase mRNA expression in human and rat brain:evidence for a role in cortical neuronal function. Neuroscience.2003;116:127-137.
75. Finan PH, Zautra AJ, Davis MC, Lemery-Chalfant K, Covault J, Tennen H. Genetic influences on the dynamics of pain and affect in fibromyalgia. Health Psychol.2010; 29:134-142.
76. Finan PH, Zautra AJ, Davis MC, et al. COMT moderates the relation of daily maladaptive coping and pain in fibromyalgia. Pain.2011; 152:300-307
77. Slade GD, Diatchenko L, Bhalang K, et al. Influence of psychological factors on risk of temporomandibular disorders. J Dent Res.2007; 86:1120-1125.
78. Lu Y, Belfer I, Gershon E, et al. Neuropathic pain levels following surgical nerve injury are controlled genotypes and haplotypes of COMT-the gene encoding catecholamine-O-methyltransferase. Eur J Pain.2007;11(S1):S59-S207.
79. HickeyOT, Nugent NF, Burke SM, et al. Persistent pain after mastectomy with reconstruction. J Clin Anesth.2011; 23:482-488.
80. Fernandez-de-Las-Penas C, Fernandez-Lao C, Cantarero-Villanueva I, et al. Catechol-O-methyltransferase genotype (Val158met) modulates cancerrelated fatigue and pain sensitivity in breast cancer survivors. Breast Cancer Res Treat. 2012; 133:405-412.
81. Lee PJ, Delaney P, Keogh J, et al. Catecholamine-Omethyltransferase polymorphisms are associated with postoperative pain intensity. Clin J Pain.2011; 27:93-101.
82. Diatchenko L, Nackley AG, Slade GD, et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain. 2006; 125(3):216-224.
83. Chen J, Lipska BK, Halim N, et al. Functional analysis of genetic variation in catechol-O-methyltransferase(COMT):effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet.2004; 75:807-821.
84. Bray NJ, Buckland PR, Williams NM, et al. A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet.2003;73:152-161.
85. Dempster EL, Mill J, Craig IW, et al. The quantification of COMT mRNA in post mortem cerebellum tissue:diagnosis, genotype, methylation and expression. BMC Med Genet.2006; 7:10.
86. Ji Y, Olson J, Zhang J, et al. Breast cancer risk reduction and membrane-bound catechol-O-methyltransferase genetic polymorphisms. Cancer Res.2008; 68:5997-6005.
87. Lee SG, Joo Y, Kim B, et al. Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. Hum Genet.2005; 116:319-328.
88. Dai F, Belfer I, Schwartz CE, et al. Association of catechol-O-methyltransferase genetic variants with outcome in patients undergoing surgical treatment for lumbar degenerative disc disease. Spine J.2010; 10:949-957.
89. Orrey DC, Bortsov AV, Hoskins JM, et al. Catechol-O-methyltransferase genotype predicts pain severity in hospitalized burn patients. J Burn Care Res. 2012.33(4):518-523.
90. Nackley AG, Shabalina SA, Tchivileva IE, et al. Human catechol-Omethyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science.2006; 314:1930-1933.
91. Tchivileva IE, Lim PF, Smith SB, et al. Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: a randomized, doubleblind, placebo-controlled, crossover pilot study. Pharmacogenet Genomics.2010; 20:239-248.
92. Rakvag TT, Ross JR, Sato H, et al. Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Mol Pain.2008; 4:64.
93. Klepstad P, Fladvad T, Skorpen F, et al. Influence from genetic variability on opioid use for cancer pain:a European genetic association study of 2294 cancer pain patients. Pain.2011;152:1139-1145.
94. Rakvag TT, Klepstad P, Baar C, et al. The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients. Pain.2005; 116:73-78.
95. Lotsch J, von Hentig N, Freynhagen R, et al. Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers. Pharmacogenet Genomics.2009; 19:429-436.
96. Reyes-Gibby CC, Shete S, Rakvag T, et al. Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain:OPRM1 and COMT gene. Pain. 2007; 130:25-30.
97. Tammimaki A, Mannisto PT. Catechol-O-methyltransferase gene polymorphism and chronic human pain:a systematic review and meta-analysis. Pharmacogenetics and Genomics.2012; 22(9):673-691.
98. Hagen K, Pettersen E, Stovner LJ, et al. The association between headache and Val158Met polymorphism in the catechol-Omethyltransferase gene:the HUNT Study. J Headache Pain.2006; 7:70-74.
99. Park JW, Lee KS, Kim JS, et al. Genetic Contribution of catechol-O-methyltransferase polymorphism in patients with migraine without aura. J Clin Neurol.2007; 3:24-30.
100. Christopher GG. Influence of COMT inhibition on levodopa pharmacology and therapy. NEUROLOGY.1998;50(Suppl5):S26-S30.
101. Armero P, Muriel C, Santos J, et al. COMT (Val158Met) polymorphism is not associated to neuropathic pain in a Spanish population. Eur J Pain. 2005;9:229-232.
102. Kim H, Lee H, Rowan J, et al. Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute postsurgical pain in humans. Mol Pain.2006; 2:24.
103. Kim H, Neubert JK, Miguel AS, et al. Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain.2004; 109:488-496.
104. Edward RR. Genetic predictors of acute and chronic pain. Curr Rheumatol Rep. 2006;8(6):411-417.
105. Wandel C, Kim R, Wood M, et al. Interaction of morphine, fentanyl, sufentanil, alfentanil and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology.2002; 96:913-920.
106. Shi Q, Cleeland CS, Klepstad P, et al. Biological pathways and genetic variables involved in pain. Qual Life Res.2010; 19:1407-1417.
107. Campa D, Gioia A, Tomei A, et al. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008;83:559-566.
108. Roninson IB, Abelson HT, Housman DE, et al. Amplification of specific DNA sequences correlates with multidrug resistance in Chinese hamster cells. Nature. 1984; 309:626-628.
109. Hoffmeyer S, Urk O, von Richter O, et al. Functional polymorphisms of the human multi-resistance gene:multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA.2000,97:3473-3478.
110. Cirella VN, Pantuck CB, Lee YJ, et al. Efects of cyclosporin on anesthetic action. Anesth Analg.1987; 66:703-706.
111. Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology.2000; 92: 1392-1399.
112. Zwisler ST, Enggaard TP, Noehr-Jensen L, et al. The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes. Fundam Clin Pharmacol. 2010; 24:517-524.
113. Crettol S, Deqlon JJ, Besson J, et al. ABCB1 and cytochrome P450 genotyes and phenotyes:influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther.2006,80:668-681.
114. Coulbault L, Beaussier M, Verstuyft C, et al. Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther.2006,79:316-324.
115. Tegeder I, Costigan M, Griffin RS, et al. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006; 12:1269-1277.
116. Coffman BL, Rios GR, King CD, et al. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos.1997,25:1-4.
117. Coffman BL, King CD, Rios GR, et al. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y (268) and UGT2B7H(268). Drug Metab Dispos.1998,26:73-77.
118. Hirota T, Ieiri I, Takane H, et al. Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine therapy. Drug Metab Dispos.2003,31:677-680.
119. Mogil JS, Ritchie J, Smith SB, et al. Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans. J Med Genet. 2005;42:583-587.
120. Delaney A, Keighren M, Fleetwood-Walker SM, et al. Involvement of the melanocortin-1 receptor in acute pain and pain of inflammatory but not neuropathic origin. PLoS One.2010; 5:e12498.
121. Mogil JS, Wilson SG, Chesler EJ, et al. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci USA.2003; 100:4867-4872.
122. Gear RW, Miaskowski C, GordonNC, et al. Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med.1996; 2:1248-1250.
123. Gear RW, Miaskowski C, Gordon NC, et al. The kappa opioid nalbuphine produces gender-and dose-dependent analgesia and antianalgesia in patients with postoperative pain. Pain.1999; 83:339-345.
124. Liem EB, Lin CM, Suleman MI, et al. Anesthetic requirement is increased in redheads. Anesthesiology.2004; 101:279-283.
125. Liem EB, Joiner TV, Tsueda K, et al. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology.2005; 102:509-514.
126. Lichtman AH, Shelton CC, Advani T, et al. Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia. Pain. 2004; 109:319-327.
127. Bessler H, Shavit Y, Mayburd E, et al. Postoperative pain, morphine, consumption and genetic polymorphism of IL-lb and IL-1 receptor antagonist. Neurosci Lett.2006; 404 (1-2):154-158.
128. Candiotti K, Yang Z, Morris R, et al. Polymorphism in the interleukin-1 receptor antagonist gene is associated with serum interleukin-1 receptor antagonist concentrations and postoperative opioid consumption. Anesthesiology. 2011;114:1162-1168.
129. Solovieva S, Leino-Arjas P, Saarela J, et al. Possible association of interleukin 1 gene locus polymorphisms with low back pain. Pain.2004; 109:8-19.
130. AtturM, Belitskaya-Levy I, Oh C, et al. Increased interleukin-1 gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. Arthritis Rheum.2011; 63:1908-1917.
131. Cohen SB, Proudman S, Kivitz AJ, et al. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res Ther.2011; 13:R125.