Efficacy and safety of exogenous ketone bodies for preventive treatment of migraine: A study protocol for a single-centred, randomised, placebo-controlled, double-blind crossover trial

Abstract

BackgroundCurrently available prophylactic migraine treatment options are limited and are associated with many, often intolerable, side-effects. Various lines of research suggest that abnormalities in energy metabolism are likely to be part of migraine pathophysiology. Previously, a ketogenic diet (KD) has been reported to lead to a drastic reduction in migraine frequency. An alternative method to a strict KD is inducing a mild nutritional ketosis (0.4–2 mmol/l) with exogenous ketogenic substances. The aim of this randomised, placebo-controlled, double-blind, crossover, single-centre trial is to demonstrate safety and superiority of beta-hydroxybutyrate (βHB) in mineral salt form over placebo in migraine prevention.Methods/designForty-five episodic migraineurs (5–14 migraine days/months), with or without aura, aged between 18 and 65 years, will be recruited at headache clinics in Switzerland, Germany and Austria and via Internet announcements. After a 4-week baseline period, patients will be randomly allocated to one of the two trial arms and receive either the βHB mineral salt or placebo for 12 weeks. This will be followed by a 4-week wash-out period, a subsequent second baseline period and, finally, another 12-week intervention with the alternative treatment. Co-medication with triptans (10 days per months) or analgesics (14 days per months) is permitted. The primary outcome is the mean change from baseline in the number of migraine days (meeting International Classification of Headache Disorders version 3 criteria) during the last 4 weeks of intervention compared to placebo. Secondary endpoints include mean changes in headache days of any severity, acute migraine medication use, migraine intensity and migraine and headache-related disability. Exploratory outcomes are (in addition to routine laboratory analysis) genetic profiling and expression analysis, oxidative and nitrosative stress, as well as serum cytokine analysis, and blood βHB and glucose analysis (pharmacokinetics).DiscussionA crossover design was chosen as it greatly improves statistical power and participation rates, without increasing costs. To our knowledge this is the first RCT using βHB salts worldwide. If proven effective and safe, βHB might not only offer a new prophylactic treatment option for migraine patients, but might additionally pave the way for clinical trials assessing its use in related diseases.Trial registrationClinicalTrials.gov, NCT03132233. Registered on 27 April 2017.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-3120-7) contains supplementary material, which is available to authorized users.

The metabolic face of migraine — from pathophysiology to treatment

“…The ketogenic diet was superior to the non ketogenic diet for reducing monthly migraine days, and the 50% response rate was much higher (74.3% of patients on the ketogenic diet and 8.6% of patients on the non ketogenic diet) 201 . The potential for supplementation with the ketone body β hydroxybutyrate without a strict dietary change to prevent migraine is currently being examined in a randomized controlled trial 202 . Aerobic exercise is often recommended in migraine management, and a randomized study showed that regular aerobic exercise is associated with a decrease in migraine frequency comparable to that achieved with topiramate, a prophylactic drug with level A evidence for efficacy 203 .…”

Migraine and Diet

“…Currently, the ketogenic diet (high fat, low carbohydrate) [ 78 , 79 ] has shown promising results, potentially influencing several pathophysiological mechanisms (e.g., glucose transport, mitochondrial function, oxidative stress, cerebral excitability, cortical spreading depression, inflammation, and the gut microbiome). Supplementation with exogenous ketone bodies as a potential preventative strategy for migraine has also been proposed [ 80 ]. Increased fatty acids, amino acids, supplementation with medium-chain triglycerides [ 81 ], or other dietary changes, as well as the alteration of the microbiome, have been considered elements for modifying the disease.…”

Potential Protective Mechanisms of Ketone Bodies in Migraine Prevention

“…Additionally, third factors, such as increased fatty acids, amino acids, supplementation with medium-chain triglycerides [222] or other dietary changes as well as alteration of the microbiome could also be disease modifying. The potential preventative anti-migraine effect of supplementation with BHB without a strict dietary change is currently being examined in an RCT [223] and could help answer some of these questions.…”