COMT Genotype and Efficacy of Propranolol for TMD Pain: A Randomized Trial.
COMT Genotype and Efficacy of Propranolol for TMD Pain: A Randomized Trial.
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DOI：
10.1177/0022034520962733
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发表时间：
2021-03
影响因子：
7.6
通讯作者：
Tchivileva IE
中科院分区：
文献类型：
--
作者：
Slade GD;Fillingim RB;Ohrbach R;Hadgraft H;Willis J;Arbes SJ Jr;Tchivileva IE
普萘洛尔是一种非选择性β-肾上腺素能受体拮抗剂，可有效减轻面部疼痛。有证据表明，它的镇痛效果可能被儿茶酚-O-甲基转移酶（COMT）基因的变体所修饰。我们在一项随机对照试验中对143名非西班牙裔白人疼痛性颞下颌关节紊乱病（TMD）患者进行了假设检验。对患者进行rs 4680（COMT的单核苷酸多态性）基因分型，并随机分配至普萘洛尔60 mg每日两次组或安慰剂组。在为期9周的随访期间，患者记录面部疼痛强度和持续时间的每日评级;产品计算为面部疼痛指数。将第9周时指数的基线后变化（主要终点）作为连续变量进行分析，并在降低≥30%和≥50%的阈值下进行二分。假设加性遗传模型，对重复测量的混合模型进行基因型×治疗组相互作用检验，并估计COMT基因型内疗效的平均值、比值比（OR）和95%置信限（95% CL）。在次要分析中，绘制了二分降低范围（≥20%至≥ 70%）的累积应答曲线，并计算了曲线下面积百分比（%AUC）的基因型差异，以表示疗效。根据基因型，平均指数降低没有显著差异（P = 0.277），而二分的≥30%降低显示G：G纯合子（OR = 10.9，95%CL = 2.4，50.7）比A：A纯合子（OR = 0.8，95%CL = 0.2，3.2）具有统计学显著的相互作用（P = 0.035）。累积响应曲线证实G：G纯合子（%AUC差异= 43.7，95%CL = 15.4，72.1）的功效大于A：A纯合子（%AUC差异= 6.5，95%CL =-30.2，43.2）的功效（P = 0.003）。观察到的A等位基因对普萘洛尔疗效的拮抗作用与先验假设的协同作用相反。这个意想不到的结果强调了需要更好地了解COMT在疼痛发病机制中的作用，如果该基因被用于TMD的精确药物治疗（ClinicalTrials.gov NCT 02437383）。
Propranolol is a nonselective β-adrenergic receptor antagonist that is efficacious in reducing facial pain. There is evidence that its analgesic efficacy might be modified by variants of the catechol-O-methyltransferase (COMT) gene. We tested the hypothesis in a subset of 143 non-Hispanic Whites from a randomized controlled trial of patients with painful temporomandibular disorder (TMD). Patients were genotyped for rs4680, a single nucleotide polymorphism of COMT, and randomly allocated to either propranolol 60 mg twice daily or placebo. During the 9-wk follow-up period, patients recorded daily ratings of facial pain intensity and duration; the product was computed as an index of facial pain. Postbaseline change in the index at week 9 (the primary endpoint) was analyzed as a continuous variable and dichotomized at thresholds of ≥30% and ≥50% reduction. Mixed models for repeated measures tested for the genotype × treatment group interaction and estimated means, odds ratios (ORs), and 95% confidence limits (95% CLs) of efficacy within COMT genotypes assuming an additive genetic model. In secondary analysis, the cumulative response curves were plotted for dichotomized reductions ranging from ≥20% to ≥70%, and genotype differences in area under the curve percentages (%AUC) were calculated to signify efficacy. Mean index reduction did not differ significantly (P = 0.277) according to genotype, whereas the dichotomized ≥30% reduction revealed greater efficacy among G:G homozygotes (OR = 10.9, 95%CL = 2.4, 50.7) than among A:A homozygotes (OR = 0.8, 95%CL = 0.2, 3.2) with statistically significant interaction (P = 0.035). Cumulative response curves confirmed greater (P = 0.003) efficacy for G:G homozygotes (%AUC difference = 43.7, 95%CL = 15.4, 72.1) than for A:A homozygotes (%AUC difference = 6.5, 95%CL = -30.2, 43.2). The observed antagonistic effect of the A allele on propranolol’s efficacy was opposite the synergistic effect hypothesized a priori. This unexpected result highlights the need for better knowledge of COMT’s role in pain pathogenesis if the gene is to be used for precision-medicine treatment of TMD (ClinicalTrials.gov NCT02437383).
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影响因子：
3.5
作者：
Diatchenko, L;Slade, GD;Maixner, W
通讯作者：
Maixner, W
影响因子：
14.8
作者：
Clarke, Geraldine M.;Anderson, Carl A.;Pettersson, Fredrik H.;Cardon, Lon R.;Morris, Andrew P.;Zondervan, Krina T.
通讯作者：
Zondervan, Krina T.
影响因子：
2.5
作者：
Schiffman E;Ohrbach R;Truelove E;Look J;Anderson G;Goulet JP;List T;Svensson P;Gonzalez Y;Lobbezoo F;Michelotti A;Brooks SL;Ceusters W;Drangsholt M;Ettlin D;Gaul C;Goldberg LJ;Haythornthwaite JA;Hollender L;Jensen R;John MT;De Laat A;de Leeuw R;Maixner W;van der Meulen M;Murray GM;Nixdorf DR;Palla S;Petersson A;Pionchon P;Smith B;Visscher CM;Zakrzewska J;Dworkin SF;International RDC/TMD Consortium Network, International association for Dental Research;Orofacial Pain Special Interest Group, International Association for the Study of Pain
通讯作者：
Orofacial Pain Special Interest Group, International Association for the Study of Pain
DOI：
10.3109/10601338609051233
发表时间：
1986-01-01
期刊：
Clinical Research Practices and Drug Regulatory Affairs
影响因子：
--
作者：
DUBEY S D
通讯作者：
DUBEY S D
影响因子：
11
作者：
Niculescu, A. B.;Le-Niculescu, H.;White, F. A.
通讯作者：
White, F. A.