Clinical & metabolic effects of altering n-3 & n-6 fatty acids in migraine (RCT)

描述（由申请人提供）：发作性偏头痛是一种使人衰弱的慢性疼痛状况，困扰着12%的美国成年人。目前的常规治疗依赖于提供有限或短暂缓解的药物，靶向症状而不是疼痛的根本原因，并且与显著的副作用和成本相关。因此，有必要研究传统头痛治疗的非药物方法。欧米茄-6（n-6）和欧米茄-3（n-3）多不饱和脂肪酸（PUFA）调节多种疼痛相关的生化途径。缺乏对照临床试验，研究饮食变化对疼痛的调节作用，同时探索人类的相关作用机制。 在最近对慢性每日头痛（CDH）患者进行的可行性研究中，我们发现有针对性的PUFA修改-增加饮食n-3 EPA+DHA，减少n-6亚油酸（LA）摄入量-改变循环内香草素，同时减少头痛频率并改善生活质量。这些发现支持了我们提出的模型，其中饮食诱导的类香草素改变调节体内TRPV 1活性，从而对偏头痛和慢性疼痛产生重要影响。然而，是否需要减少膳食LA来引起观察到的提高n-3 PUFA摄入量的代谢和临床益处尚不清楚。本研究的目的是评估旨在增加组织n-3 EPA和DHA的饮食PUFA修改，同时减少或不减少n-6 LA，是否可以导致循环内香草素的预测变化和头痛相关临床结局的改善。建议的3组、20周、随机、对照、单盲试验，每组51名受试者，包括4周的常规护理基线，随后随机分配至三种16周饮食干预加常规护理之一：1）高n-3 EPA+DHA、低n-6 LA干预（饮食A）; 2）高n-3 EPA+DHA、高n-6 LA干预（饮食B）;或3）具有美国平均摄入量的对照干预（低n-3，高n-6，饮食C）。 具体目标是：1）评估饮食干预在诱导循环PUFA类香草内酯衍生物的预测变化中的功效; 2）比较两种16周止痛饮食干预彼此之间以及对照饮食在偏头痛特定结果中的临床效果; 3）以探索性方式测试我们提出的n-3和n-6 PUFA、其香草素衍生物和头痛临床终点的因果链连接变化模型。该提案利用创新的设计和假设，以解决当前NCCAM研究资金的优先事项，通过检查临床疗效和潜在的机制，有前途的饮食操作具有明显的潜力，在改善慢性，致残性疼痛障碍方面的高影响。

DESCRIPTION (provided by applicant): Episodic migraine is a debilitating chronic pain condition afflicting 12% of American adults. Current conventional treatments rely on medications that provide limited or transient relief, target symptoms rather than the underlying causes of pain, and are associated with significant side effects and costs. It is therefore essential to investigate non-pharmacologic approaches to conventional headache treatments. Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) regulate multiple pain-related biochemical pathways. Controlled clinical trials investigating pain modulation in response to dietary changes while exploring relevant mechanisms of action in humans are lacking. In a recent feasibility study in patients with chronic daily headache (CDH), we found that targeted PUFA modifications - increased dietary n-3 EPA+DHA with reduced n-6 linoleic acid (LA) intake - altered circulating endovanilloids, while reducing headache frequency and improving quality of life. These findings support our proposed model in which diet-induced alterations in endovanilloids modulate TRPV1 activity in vivo, leading to important implications for migraine and chronic pain in general. However, whether a reduction in dietary LA is required to elicit the observed metabolic and clinical benefits of raising n-3 PUFA intake is unknown. The goal of this research is to assess whether dietary PUFA modifications designed to increase tissue n-3 EPA and DHA, with or without concurrent reduction in n-6 LA, can result in predicted changes in circulating endovanilloids and improvement in headache-related clinical outcomes. The proposed 3-arm, 20-week, randomized, controlled, single-blind trial, with 51 subjects in each group, includes a 4-week baseline of usual care, followed by randomization to one of three 16-week dietary interventions plus usual care: 1) a High n-3 EPA+DHA, Low n-6 LA intervention (Diet A); 2) a High n-3 EPA+DHA, High n-6 LA intervention (Diet B); or 3) a control intervention with average U.S. intakes (Low n-3, High n-6, Diet C). Specific aims are: 1) To assess the efficacy of the dietary interventions in inducing the predicted changes in circulating PUFA endovanilloid derivatives; 2) To compare the clinical effects in migraine specific outcomes of two 16-week analgesic dietary interventions with each other and a control diet; 3) To test, in an exploratory manner, our model of the proposed causal chain linking changes in n-3 and n-6 PUFAs, their endovanilloid derivatives, and headache clinical endpoints. This proposal utilizes an innovative design and hypotheses to address current NCCAM research funding priorities, by examining clinical efficacy and underlying mechanisms of a promising dietary manipulation with the distinct potential for high impact in terms of ameliorating a chronic, disabling pain disorder.