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

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。当前 传统疗法依赖于提供有限或短暂缓解、针对症状的药物，而不是 疼痛的根本原因，并与显著的副作用和成本有关。因此，它是 对于研究常规头痛治疗的非药物方法至关重要。欧米茄-6(n-6) 而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。 研究饮食变化对疼痛调制反应的对照临床试验，同时探索相关 人类的作用机制是缺乏的。 在最近一项针对慢性日常头痛(CDH)患者的可行性研究中，我们发现靶向多不饱和脂肪酸 修改-增加膳食n-3 EPA+DHA，减少n-6亚油酸(LA)摄入量-改变 循环中的内源性香草素，同时减少头痛频率，提高生活质量。这些发现 支持我们提出的模型，在该模型中，饮食诱导的内源性香草素的变化调节了TRPV1的活性 体内，导致对偏头痛和慢性疼痛的重要影响。然而，无论是减少 在饮食中，增加n-3多不饱和脂肪酸摄入量的代谢和临床益处需要LA是 未知。 这项研究的目的是评估饮食中多不饱和脂肪酸的修改是否旨在增加组织 N-3EPA和DHA，无论是否同时降低n-6LA，都可以导致循环的预期变化 内源性香草素与头痛相关临床结果的改善。拟议的3臂，20周， 随机、对照、单盲试验，每组51名受试者，包括4周的正常基线 护理，然后随机接受三种16周饮食干预中的一种加常规护理：1)高n-3 EPA+DHA，低n-6LA干预(饮食A)；2)高n-3EPA+DHA，高n-6LA干预(饮食B)；或3) 美国人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可预测的 循环多不饱和脂肪酸内源性香草酸衍生物的变化；2)比较偏头痛特异性的临床疗效 两种为期16周的止痛性饮食干预和对照饮食的结果；3)测试，在 以探索性的方式，我们提出的因果链模型将n-3和n-6多不饱和脂肪酸的变化联系在一起，其 香草素衍生物和令人头疼的临床终点。 这项建议利用创新的设计和假设来解决目前NCCAM的研究 通过检查一种有希望的饮食的临床疗效和潜在机制，资助优先事项 在改善慢性致残性疼痛方面具有明显的高影响潜力的手法 无序。

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.