Clinical trial NCT02012790: Nutrition for Migraine Prevention
Official title: Clinical & Metabolic Effects of Altering n-3 & n-6 Fatty Acids in Migraine (RCT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Migraine Disorders
Keywords: Migraine disorders
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: National Center for Complementary and Integrative Health (NCCIH)
First posted: 2013-12-16
Enrollment: 182
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Migraine is a widespread, debilitating, chronic pain disorder and a major public health challenge. Most conventional, pharmaceutical treatments fail to give satisfactory long-term relief and their repeated use can have important side effects. This project involves implementation of substantial dietary changes in adults with migraine. Our goal is to test the hypothesis that a causal relationship exists between migraine symptoms and the amount and proportions of foods consumed containing defined amounts of polyunsaturated fatty acids.

Significant findings supporting the hypothesis will lead to a major shift in both prevention and management of migraine and other chronic pain disorders. Emphasis is on low-cost, health improvement strategies utilizing specific dietary modifications for pain management, based on solid clinical research evidence.

Detailed description: 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. Certain fatty acids and their bioactive metabolites 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 fatty acid modifications 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 transient receptor potential cation channel subfamily V member 1 (TRPV1) activity in vivo, leading to important implications for migraine and chronic pain in general.

The goal of this research is to assess whether dietary PUFA modifications can result in predicted changes in circulating endovanilloids and improvement in headache-related clinical outcomes. The proposed 3-arm, 26-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 22-week dietary interventions plus usual care. Each of the three arms involves specific modifications of dietary fatty acid intakes through a whole foods diet. Participants in the dietary interventions receive food sufficient for 2 meals and 2 snacks daily along with extensive dietary counseling.

Specific aims are:

1. To assess the efficacy of the dietary interventions in inducing the predicted changes in circulating fatty acid 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 fatty acids, their endovanilloid derivatives, and headache clinical endpoints.

This proposal utilizes an innovative design and hypotheses to address current 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.

Eligibility criteria: Inclusion Criteria:

* 18 years of age or older
* Either gender
* Meets 2004 International Classification of Headache Disorders-II\* criteria for Episodic Migraine
* Frequent migraine headaches
* Headache history: \> 2 years leading up to study meeting migraine criteria
* Willing to complete daily diary for 26 weeks
* Able to attend 8 dietitian counseling sessions
* Under care of a physician for headaches
* Able to read and communicate in English

Exclusion Criteria:

* Marked depression, anxiety or psychosis.
* History of specific food allergies, such as, but not limited to, dairy or gluten products
* Pregnancy or anticipated pregnancy
* Active treatment for a major medical illness, such as malignancy, autoimmune, immune deficiency disorder, etc.
* History of significant head trauma or head/neck surgery within the past 3 years
* History of subarachnoid or intra-cerebral hemorrhage or subdural hematoma
* Allergy to fish or strong aversion to fish consumption.
* History of nervous system infection such as meningitis or encephalitis within the preceding 5 years
* History of vasculitis, intracranial mass, clotting disorder
* Cognitive dysfunction that would prevent informed consent

Primary outcomes:
measure: Primary metabolic outcome: 17-hydroxy docosahexaenoic acid (DHA)
timeFrame: Change in 17-hydroxy DHA at 16 weeks
measure: Primary clinical outcome: Headache-specific Quality of Life (HIT-6)
timeFrame: Change in HIT-6 at 16 weeks
Secondary outcomes:
measure: Headache hours per day (headache frequency) are measured by a daily Headache Diary
timeFrame: Trajectory of change: -4 to 0 weeks (pre-intervention), 0-16 weeks (intervention), and 16-22 weeks (post-intervention)
measure: Patient-Reported Outcomes Measurement Information System-29 Profile
timeFrame: Pre-post and trajectory of change measured at randomization and at 4,10, and 16 weeks after randomization
measure: 17-hydroxy DHA trajectory
timeFrame: Trajectory of change in 17-hydroxy DHA 0-16 weeks and 16-22 weeks
measure: HIT-6
timeFrame: Trajectory of change pre-intervention, 0-16 weeks, and 16-22 weeks
Other outcomes:
measure: Migraine Disability Assessment Score (MIDAS)
timeFrame: Change in MIDAS from randomization to 16 weeks after randomization
measure: Medication use for treatment of headache.
timeFrame: trajectory of change over 16 weeks
measure: Unusual symptoms
timeFrame: Daily for 4 weeks before randomization, and 22 weeks after randomization
Locations:
city: Chapel Hill
country: United States
facility: UNC Program on Integrative Medicine
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: John D Mann, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ramsden CE, Zamora D, Faurot KR, MacIntosh B, Horowitz M, Keyes GS, Yuan ZX, Miller V, Lynch C, Honvoh G, Park J, Levy R, Domenichiello AF, Johnston A, Majchrzak-Hong S, Hibbeln JR, Barrow DA, Loewke J, Davis JM, Mannes A, Palsson OS, Suchindran CM, Gaylord SA, Mann JD. Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine: randomized controlled trial. BMJ. 2021 Jun 30;374:n1448. doi: 10.1136/bmj.n1448.
citation: Miller VE, Faurot KR, Palssson OS, MacIntosh BA, Suchindran C, Honvoh G, Gaylord S, Ramsden CE, Mann JD. Comparing prospective headache diary and retrospective four-week headache questionnaire over 20 weeks: Secondary data analysis from a randomized controlled trial. Cephalalgia. 2020 Nov;40(13):1523-1531. doi: 10.1177/0333102420949180. Epub 2020 Aug 16.
citation: Mann JD, Faurot KR, MacIntosh B, Palsson OS, Suchindran CM, Gaylord SA, Lynch C, Johnston A, Maiden K, Barrow DA, Hibbeln JR, Ramsden CE. A sixteen-week three-armed, randomized, controlled trial investigating clinical and biochemical effects of targeted alterations in dietary linoleic acid and n-3 EPA+DHA in adults with episodic migraine: Study protocol. Prostaglandins Leukot Essent Fatty Acids. 2018 Jan;128:41-52. doi: 10.1016/j.plefa.2017.11.002. Epub 2017 Nov 16.