SCN9A基因多态性与肺癌疼痛发生及阿片镇痛剂量的相关性
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摘要
目的:探讨SCN9A基因多态性与肺癌病人疼痛发生之间的相关性,同时分析其与阿片类药物镇痛剂量间的关系。方法:采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法检测246例肺癌病人和106例对照者的SCN9A-rs6746030位点基因分型。对影响肺癌疼痛发生的混杂因素进行单因素分析及多因素logistic回归分析。采用Mann-Whitney检验比较不同基因型间阿片类药物用量的差异。结果:(1)疼痛组、无痛组和对照组的rs6746030等位基因(G/A)频率分别为0.83/0.17、0.94/0.06和0.95/0.05,无痛组和对照组基因分型无统计学差异;(2)疼痛组与无痛组相比,基因型GA/AA为肺癌疼痛发生的独立危险因素(P <0.001, OR=3.695, 95%CI=1.883-7.253);Ⅲ-Ⅳ期肺癌病人的疼痛发生风险显著增高(P=0.009, OR=2.339, 95%CI=1.235-4.431);(3)中、重度疼痛组病人不同基因型间24 h阿片类药物用量无统计学差异。结论:尚不认为SCN9A-rs6746030多态性影响肺癌疼痛病人阿片类药物的镇痛剂量,但基因型GA/AA可能是影响肺癌病人疼痛发生的独立危险因素之一。
Objective: To investigate the association between SCN9 A gene polymorphism and pain susceptibility in patients with lung cancer, and to analyze the effect of the gene polymorphism on the analgesic dose of opioids. Methods: The genotypes of SCN9A-rs6746030 in 246 lung cancer patients and 106 healthy people were detected by the polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The mixed factors of pain susceptibility in patients with lung cancer were analyzed by univariate analysis and logistic regression model. The difference of opioids dosage between different genotypes was compared by the Mann-Whitney test. Results:(1) The frequencies of rs6746030 allele(G/A) in pain group, painless group and control group were 0.83/0.17, 0.94/0.06 and 0.95/0.05 respectively. There was no difference in genotypes between painless group and control group;(2) In the comparison between pain group and painless group, the logistic regression analysis showed that genotype GA/AA was an independent risk factor of pain susceptibility in lung cancer patients(P < 0.001, OR = 3.695, 95%CI = 1.883-7.253). The risk of cancer pain was significantly higher in the stage of Ⅲ-Ⅳ(P = 0.009, OR = 2.339, 95%CI = 1.235-4.431);(3) There was no significant difference in the analgesic dose of opioids in different genotypes among patients with moderate and severe pain. Conclusions: The polymorphism of SCN9A-rs6746030 may not affect the analgesic dose of opioids in patients with lung cancer pain, but the genotype GA/AA may be one of the independent risk factors of pain susceptibility in lung cancer patients.
Objective: To investigate the association between SCN9 A gene polymorphism and pain susceptibility in patients with lung cancer, and to analyze the effect of the gene polymorphism on the analgesic dose of opioids. Methods: The genotypes of SCN9A-rs6746030 in 246 lung cancer patients and 106 healthy people were detected by the polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP). The mixed factors of pain susceptibility in patients with lung cancer were analyzed by univariate analysis and logistic regression model. The difference of opioids dosage between different genotypes was compared by the Mann-Whitney test. Results:(1) The frequencies of rs6746030 allele(G/A) in pain group, painless group and control group were 0.83/0.17, 0.94/0.06 and 0.95/0.05 respectively. There was no difference in genotypes between painless group and control group;(2) In the comparison between pain group and painless group, the logistic regression analysis showed that genotype GA/AA was an independent risk factor of pain susceptibility in lung cancer patients(P < 0.001, OR = 3.695, 95%CI = 1.883-7.253). The risk of cancer pain was significantly higher in the stage of Ⅲ-Ⅳ(P = 0.009, OR = 2.339, 95%CI = 1.235-4.431);(3) There was no significant difference in the analgesic dose of opioids in different genotypes among patients with moderate and severe pain. Conclusions: The polymorphism of SCN9A-rs6746030 may not affect the analgesic dose of opioids in patients with lung cancer pain, but the genotype GA/AA may be one of the independent risk factors of pain susceptibility in lung cancer patients.
引文
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[20]Estacion M,Harty TP,Choi JS,et al.A sodium channel gene SCN9A polymorphism that increases nociceptor excitability[J].Ann Neurol,2009,66(6):862-866.
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[22]Brown E.Genetics:An incomplete mosaic[J].Nature,2016,535(7611):S12-13.
[2]Nielsen CS,Stubhaug A,Price DD,et al.Individual differences in pain sensitivity:genetic and environmental contributions[J].Pain,2008,136(1-2):21-29.
[3]Dib-Hajj SD,Black JA,Waxman SG,et al.Voltage-gated sodium channels:therapeutic targets for pain[J].Pain Med,2009,10(7):1260-1269.
[4]Stadler T,O'Reilly AO,Lampert A.Erythromelalgia mutation Q875E Stabilizes the activated state of sodium channel Nav1.7[J].J Biol Chem,2015,290(10):6316-6325.
[5]Suter MR,Bhuiyan ZA,Laedermann CJ,et al.pL1612P,a novel voltage-gated sodium channel Nav1.7mutation inducing a cold sensitive paroxysmal extreme pain disorder[J].Anesthesiology,2015,122(2):414-423.
[6]Cox JJ,Reimann F,Nicholas AK,et al.An SCN9Achannelopathy causes congenital inability to experience pain[J].Nature,2006,444(7121):894-898.
[7]Kurzawski M,Rut M,Dziedziejko V,et al.Common missense variant of SCN9A gene is associated with pain intensity in patients with chronic pain from disc herniation[J].Pain Med,2017.
[8]Caraceni A,Hanks G,Kaasa S,et al.Use of opioid analgesics in the treatment of cancer pain:evidence-based recommendations from the EAPC[J].Lancet Oncology,2012,13(2):58-68.
[9]Kanellopoulos AH,Matsuyama A.Voltage-gated sodium channels and pain-related disorders[J].Clin Sci,2016,130(24):2257-2265.
[10]Treister R,Pud D,Ebstein RP,et al.Association between polymorphisms in serotonin and dopamine-related genes and endogenous pain modulation[J].J Pain,2011,12(8):875-883.
[11]Schou WS,Ashina S,Amin FM,et al.Calcitonin gene-related peptide and pain:a systematic review[J].JHeadache Pain,2017,18(1):34.
[12]Casals-Díaz L,Casas C,Navarro X.Changes of voltage-gated sodium channels in sensory nerve regeneration and neuropathic pain models[J].Restor Neurol Neurosci,2015,33(3):321-334.
[13]Reeder JE,Byler TK,Foster DC,et al.Polymorphism in the SCN9A voltage-gated sodium channel gene associated with interstitial cystitis/bladder pain syndrome[J].Urology,2013,81(1):210.e1-4.
[14]Drenth JP,Waxman SG.Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders[J].J Clin Invest,2007,117(12):3603-3609.
[15]Reimann F,Cox JJ,Belfer I,et al.Pain perception is altered by a nucleotide polymorphism in SCN9A[J].Proc Natl Acad Sci USA,2010,107(11):5148-5153.
[16]Minett MS,Pereira V,Sikandar S,et al.Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7[J].Nat Commun,2015,6:8967.
[17]Oh SY,Shin SW,Koh SJ,et al.Multicenter,cross-sectional observational study of the impact of neuropathic pain on quality of life in cancer patients[J].Support Care Cancer,2017,25:3759-3767.
[18]Greenbaum L,Tegeder I,Barhum Y,et al.Contribution of genetic variants to pain susceptibility in Parkinson disease[J].Eur J Pain,2012,16(9):1243-1250.
[19]李杨,段开明,汪赛赢.SCN9A基因多态性与妇科腹腔镜手术罗哌卡因局部浸润镇痛效果的相关性研究[J].临床麻醉学杂志,2015,31(4):317-319.
[20]Estacion M,Harty TP,Choi JS,et al.A sodium channel gene SCN9A polymorphism that increases nociceptor excitability[J].Ann Neurol,2009,66(6):862-866.
[21]Kumar SP.Reporting characteristics of cancer pain:a systematic review and quantitative analysis of research publications in palliative care journals[J].Indian J Palliat Care,2011,17:57-66.
[22]Brown E.Genetics:An incomplete mosaic[J].Nature,2016,535(7611):S12-13.