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

描述（由申请人提供）：阵发性偏头痛是一种使人衰弱的慢性疼痛状况，折磨着12%的美国成年人。目前的传统治疗依赖于提供有限或短暂缓解的药物，针对的是症状而不是疼痛的根本原因，并且与显著的副作用和费用相关。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）调节多种与疼痛相关的生化途径。研究饮食变化对疼痛调节的对照临床试验，同时探索人类的相关作用机制尚缺乏。在最近一项针对慢性每日头痛（CDH）患者的可行性研究中，我们发现靶向PUFA修饰-增加饮食中n-3 EPA+DHA，减少n-6亚油酸（LA）摄入量-改变循环内源性vanililids，同时减少头痛频率并改善生活质量。这些发现支持我们提出的模型，即饮食诱导的内源性vanililids改变体内TRPV1活性，导致偏头痛和一般慢性疼痛的重要意义。然而，是否需要减少膳食LA来引起观察到的n-3 PUFA摄入量增加的代谢和临床益处尚不清楚。本研究的目的是评估膳食PUFA修饰是否可以增加组织n-3 EPA和DHA，同时或不同时降低n-6 LA，从而导致循环内vaniloid的预测变化和头痛相关临床结果的改善。拟议的三组、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，随后随机分为三种16周的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) a高n-3 EPA+DHA、高n-6 LA干预（饮食B）；或3)对照干预与平均美国摄入量（低n-3，高n-6，饮食C）。具体目的是：1)评估饮食干预对诱导循环PUFA内vanilloid衍生物预测变化的效果；2)比较两种16周镇痛饮食干预与对照饮食对偏头痛特异性结局的临床效果；3)以探索性的方式检验我们提出的n-3和n-6 PUFAs及其内源性香草素衍生物变化与头痛临床终点之间的因果链模型。本提案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，通过检查一种有前途的饮食控制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潜力。

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.