Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling
Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling
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DOI：
10.1001/jamaneurol.2016.0389
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发表时间：
2016-06-01
期刊：
影响因子：
29
通讯作者：
Waxman, Stephen G.
中科院分区：
文献类型：
--
作者：
Geha, Paul;Yang, Yang;Waxman, Stephen G.
重要性需要更有效的药物治疗慢性疼痛，包括遗传性红斑痛(IEM)中的疼痛，其中钠通道Nav1.7的功能获得突变使背根神经节(DRG)神经元高度兴奋。目的确定是否可以通过基因组分析和功能图谱指导的药物治疗减轻IEM中的疼痛。通过结构建模和功能分析预测对卡马西平有反应的2名IEM患者的设计、背景和参与者的疼痛，在2014年9月至2015年4月21日进行的一项双盲安慰剂对照研究中进行了评估。功能磁共振成像评估了在安慰剂或卡马西平治疗期间与疼痛相关的大脑活动模式。使用多电极阵列技术评估卡马西平对携带S241T突变通道的DRG神经元放电的影响。主要结果和测量疼痛的行为评估；功能磁共振成像；以及携带S241T突变通道的DRG神经元的放电评估。结果本研究包括2例IEM和S241T Nav1.7突变的家系患者。我们发现，正如分子建模、热力学分析和功能分析所预测的那样，卡马西平减轻了由于S241T Nav1.7突变导致的IEM患者的疼痛。患者1报告，在15天的维持期内，每天的平均疼痛时间(TIP)从服用安慰剂的424分钟减少到服用卡马西平(400毫克/天)的231.9分钟，在15天的维持期内，总的TIP从服用安慰剂的6360分钟减少到服用卡马西平的3015分钟。患者2报告，在15天的维持期内，平均每天的小费减少，从服用安慰剂的61分钟减少到服用卡马西平的9.1分钟(然后每天400毫克到200毫克)，总小费从服用安慰剂的915分钟减少到服用卡马西平的136分钟。患者1报告平均发作持续时间从服用安慰剂时的615分钟减少到服用卡马西平时的274.1分钟，而患者2报告平均发作持续时间从服用安慰剂时的91.5分钟减少到服用卡马西平时的45分钟。患者1有夜间从疼痛中醒来的病史，报告了101次在维持期服用安慰剂时因疼痛而醒来，32次在服用卡马西平时醒来。疼痛的减轻与大脑活动从评估和疼痛区域转移到主要和次要的躯体感觉、运动和顶叶注意区域是平行的。卡马西平可减少表达S241T Nav1.7突变通道的DRG神经元对生理相关热刺激的反应。结论和相关性我们的结果表明，以基因组分析、分子模拟和功能图谱为指导的药物治疗可以减轻携带S241T突变的患者的神经病理性疼痛。
IMPORTANCE There is a need for more effective pharmacotherapy for chronic pain, including pain in inherited erythromelalgia (IEM) in which gain-of-function mutations of sodium channel NaV1.7 make dorsal root ganglion (DRG) neurons hyperexcitable.OBJECTIVE To determine whether pain in IEM can be attenuated via pharmacotherapy guided by genomic analysis and functional profiling.DESIGN, SETTING, AND PARTICIPANTS Pain in 2 patients with IEM due to the NaV1.7 S241T mutation, predicted by structural modeling and functional analysis to be responsive to carbamazepine, was assessed in a double-blind, placebo-controlled study conducted from September 2014 to April 21, 2015. Functional magnetic resonance imaging assessed patterns of brain activity associated with pain during treatment with placebo or carbamazepine. Multielectrode array technology was used to assess the effect of carbamazepine on firing of DRG neurons carrying S241T mutant channels.MAIN OUTCOMES AND MEASURES Behavioral assessment of pain; functional magnetic resonance imaging; and assessment of firing in DRG neurons carrying S241T mutant channels. RESULTS This study included 2 patients from the same family with IEM and the S241T NaV1.7 mutation. We showed that, as predicted by molecular modeling, thermodynamic analysis, and functional profiling, carbamazepine attenuated pain in patients with IEM due to the S241T NaV1.7 mutation. Patient 1 reported a reduction in mean time in pain (TIP) per day during the 15-day maintenance period, from 424 minutes while taking placebo to 231.9 minutes while taking carbamazepine (400mg/day), and a reduction in total TIP over the 15-day maintenance period, from 6360 minutes while taking placebo to 3015 minutes while taking carbamazepine. Patient 2 reported a reduction in mean TIP per day during the maintenance period, from 61 minutes while taking placebo to 9.1 minutes while taking carbamazepine (400mg then 200mg/day), and a reduction in total TIP, from 915 minutes while taking placebo over the 15-day maintenance period to 136 minutes while taking carbamazepine. Patient 1 reported a reduction of mean episode duration, from 615 minutes while taking placebo to 274.1 minutes while taking carbamazepine, while patient 2 reported a reduction of the mean episode duration from 91.5 minutes while taking placebo to 45.3 minutes while taking carbamazepine. Patient 1, who had a history of night awakenings from pain, reported 101 awakenings owing to pain while taking placebo during the maintenance period and 32 awakenings while taking carbamazepine. Attenuation of pain was paralleled by a shift in brain activity from valuation and pain areas to primary and secondary somatosensory, motor, and parietal attention areas. Firing of DRG neurons expressing the S241T NaV1.7 mutant channel in response to physiologically relevant thermal stimuli was reduced by carbamazepine.CONCLUSIONS AND RELEVANCE Our results demonstrate that pharmacotherapy guided by genomic analysis, molecular modeling, and functional profiling can attenuate neuropathic pain in patients carrying the S241T mutation.