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虚弱的慢性疼痛状况，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，针对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，研究传统头痛治疗的非药物方法是必要的。Omega-6(n-6)和omega-3(n-3)多不饱和脂肪酸(PUFAs)调节多种疼痛相关的生化途径。在探索人类相关作用机制的同时，还缺乏研究饮食变化对疼痛调制的对照临床试验。在最近对慢性日常头痛(CDH)患者的可行性研究中，我们发现有针对性的PUFA修饰-增加饮食n-3EPA+DHA，减少n-6亚油酸(LA)摄入量-改变循环中的内毒素，同时减少头痛频率和改善生活质量。这些发现支持我们提出的模型，在该模型中，饮食诱导的血管内皮样物质的变化调节体内TRPV1的活性，导致对偏头痛和慢性疼痛的重要影响。然而，增加n-3多不饱和脂肪酸摄入量是否需要减少饮食LA才能产生观察到的代谢和临床益处尚不清楚。这项研究的目的是评估饮食中旨在增加组织n-3EPA和DHA的多不饱和脂肪酸修改，在同时或不同时降低n-6LA的情况下，是否可以导致循环内皮样物质的预期变化和头痛相关临床结果的改善。这项拟议的为期3周、为期20周的随机对照单盲试验，每组51名受试者，包括4周的日常护理基线，然后随机进入三种为期16周的饮食干预和常规护理之一：1)高n-3EPA+DHA，低n-6LA干预(饮食A)；2)高n-3EPA+DHA，高n-6LA干预(饮食B)；或3)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)评估饮食干预措施在诱导循环中多不饱和脂肪酸内源性香草酸衍生物预期变化方面的有效性；2)比较两种16周止痛饮食干预措施彼此和对照饮食对偏头痛特定结局的临床效果；3)以探索性方式测试我们提出的将n-3和n-6多不饱和脂肪酸及其内源性香草酸衍生物的变化与头痛临床终点联系起来的因果链模型。这项建议利用创新的设计和假设来解决当前NCCAM研究资金的优先事项，通过研究一种有希望的饮食操作的临床疗效和潜在机制，在改善慢性致残性疼痛障碍方面具有明显的高影响。

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.