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Can omega-3s prevent migraines?

Study under review: A double-blind, randomized, and placebocontrolled clinical trial with omega-3 polyunsaturated fatty acids (OPFA ω-3) for the prevention of migraine in chronic migraine patients using amitriptyline.

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Introduction

Migraine is a common and often debilitating neurological condition in which patients experience severe headaches, frequently called “attacks,” that last from four to 72 hours and can cause significant disability. Migraines are estimated to affect 11-12% of the worldwide population, with rates being higher in Central and South America (16.4%) compared to other parts of the world (9.7-11.4%) and higher in women than men (13.8 vs. 6.9%). However, it is estimated that a large proportion of those with migraine go undiagnosed.

Migraine is a diagnosis of exclusion and can present in several forms and with many different symptoms, as shown in Figure 1. While throbbing or pulsing headaches located on one side of the head is the most common characteristic[1], sufferers (sometimes called migraineurs) can experience a number of other neurological symptoms, including face and extremity tingling, visual changes, nausea and vomiting, or light or sound sensitivity. There is a strong genetic component for incidence of migraine. First degree relatives of migraineurs are about two to four times more likely to develop migraine. Of those who experience migraines, there are two classifications[14] based on migraine frequency. Those who have migraine fewer than 15 days per month are said to have “episodic migraine.” More frequent migraines are considered “chronic migraine.”

Figure 1: Migraine symptoms that occur in most people

Reference: Lipton et al. Headache. 2001 Jul/Aug.

An enduring mystery is why migraines happen and why they frequently happen after “triggers.” Migraineurs are encouraged to track what behaviors or events happen prior to a migraine attack in order to identify and potentially avoid these triggers. However, it is unclear if events frequently classified as triggers (like lack of sleep, bright light, or hunger) bring on the attack or if they are simply the early effects of migraine onset, called premonitory symptoms[1].

While the triptan class of drugs, a type of selective serotonin receptor antagonist, is usually effective for treating acute migraine, migraine prevention is a key priority for people who experience chronic migraine. Currently, the FDA has[3] approved only five drugs for the prevention of episodic migraine, and only one for chronic migraine: the injectable botulinum neurotoxin, Botox. However, tricyclic antidepressants (TCAs), including the drug amitriptyline, can be used off-label for migraine prophylaxis.

Naturally, there is a lot of interest in how lifestyle modification, including diet and supplementation, may affect the frequency and intensity of migraine. Food additives like nitrites[15] and MSG have been implicated in triggering migraines, though evidence is not currently conclusive. Fasting, hunger, and alcohol are consistently associated with migraine onset. Additionally, various (and often contradictory[16]) versions of “anti-migraine” diets have been examined for migraine prevention, with many of them finding benefits. However, altered diets often caused significant weight loss that may confound results, as obesity is associated with greater prevalence of migraine and weight loss is associated with some migraine relief.

Like dietary changes, supplements may be used in the hope of reducing migraine frequency and at least 10%[6] of migraine sufferers in the US report using supplements as preventive therapy. Currently, migraineurs can be advised to try any number of supplements[7], often based on small studies or poor quality evidence, including magnesium, riboflavin (vitamin B2), CoQ10, lipoic acid, and the herbs butterbur and feverfew.

Omega-3 fatty acids, often considered with relation to cardiovascular disease, are frequently examined in relation to numerous inflammatory and autoimmune diseases due to their touted anti-inflammatory effects. While intake of polyunsaturated fatty acids (PUFAs) are generally recommended for reduction in cardiovascular disease risk, research has shown that the type of unsaturated fatty acid (omega-6 vs. omega-3) matters for systemic inflammation. Diets higher in omega-3 fatty acids, which are found in fish oil, are associated with lower risks of autoimmune disease and inflammation. This may be due to modulation of proinflammatory prostaglandin synthesis in a diet with a higher ratio of omega-3 to omega-6 fatty acids. Increasing this ratio is often theorized to reduce many unpleasant symptoms, including migraine. However, current research linking omega-3 intake and migraine prevention is not robust[7].

In the study under review, researchers examined the effect of omega-3 fatty acids on frequency of migraine in subjects with chronic migraine.

Migraine is a common and often debilitating condition that is characterized primarily by a severe headache and categorized as an episodic migraine (EM, less than 15 days per month) or chronic migraine (CM, more than 15 days per month) depending on the frequency of headaches. The only treatment currently approved by the FDA for chronic migraines is a Botox injection. However, several supplements have also been investigated for their efficacy. The study under review investigated whether supplemental omega-3 fatty acids had an effect on frequency of migraine.

Who and what were studied?

This study, a double-blind randomized controlled trial, enrolled 60 men and women suffering from chronic migraines with daily headaches. The participants were between the ages of 18 and 50 (average of 36 years), with BMIs of 18-25, and no confounding comorbidities. Most patients reported a history of migraine greater than 10 years. Participant selection was not random, as researchers enrolled the first 60 eligible patients who visited one headache clinic in Teresina, Piaui, Brazil, and agreed to join.

Participants were all prescribed low-dose amitriptyline, a tricyclic antidepressant (with efficacy versus other drugs shown in Figure 2), for headache prevention. Additionally, half of the participants were assigned to take an omega-3 fatty acid supplement (400 milligrams of EPA, 350 milligrams of DHA) while the second half received a placebo (starch). Both the omega-3 and placebo supplements were dispensed as powders in sachets, to be mixed with 150 mL water and taken twice daily with meals (total daily omega-3 dose was therefore 1.5 grams). In order to match the look and taste of the experimental and control supplements, both were flavored with the sweeteners sucralose and acesulfame and dyed with riboflavin. Both groups were instructed to follow the protocol for 60 days.

Figure 2: Amitriptyline vs. other drugs' effectiveness for migraine prevention

Adapted from: Jackson et al. PLoS One. 2015 Jul.

Prior to starting, all participants were interviewed to determine migraine diagnosis and severity at baseline. All participants were instructed to maintain a headache diary throughout the trial to document frequency and intensity of migraine. Frequency was measured by number of days headaches occurred, and pain was measured using a visual analog scale with participants ranking pain on a scale from 1-10.

Over the course of the study, nine participants dropped out due to side effects from the medication, supplements, or placebo. Fifty-one patients remained, 27 in the omega-3 arm and 24 in the placebo arm.

At the end of the 60 days, researchers compared the frequency of headache reported throughout the trial with that reported during the baseline interview, and measured the differences in headache frequency in both groups.

The study consisted of 51 men and women with chronic migraine. The experimental arm of the study was provided with 750 milligrams of omega 3 fatty acids (400 milligrams of EPA, 350 milligrams of DHA) to be taken twice daily before meals (1.5 grams of EPA + DHA per day). The control arm was given a placebo with similar look and flavoring. All participants were prescribed low-dose amitriptyline for migraine prevention and instructed to keep a headache diary to monitor the frequency and intensity of headaches.

What were the findings?

After 60 days, researchers found that both groups experienced a reduction in headache frequency and intensity. However, those assigned omega-3 fatty acids showed significantly greater improvements. In the arm assigned to take omega-3 fatty acids, 66.7% of participants reported fewer than six headaches per month over the course of the study, compared to only 33.3% of the control group, a statistically significant difference.

Overall, researchers found that most of the participants from both groups had significant resolution of daily headaches. In fact, they reported that 62.5% of the control group and 85.2% of the omega 3 group experienced at least 75% fewer headaches. These results assume that all participants experienced headaches daily, which will be discussed in the next section.

The majority study participants experienced relief of headache frequency regardless of study arm. However, people taking the omega-3 supplements experienced significantly greater improvements, with 66.7% of omega-3 participants reporting fewer than 5 headaches over the 60-day trial. In comparison, only 33.3% of the control group experienced improvement of that magnitude.

What does the study really tell us?

The greater improvement of the migraineurs using omega-3 supplements implies that these anti-inflammatory supplements provide some prophylaxis for sufferers of chronic migraine. In the discussion, the study authors posit that the effect of EPA and DHA could cause greater serotonin receptor expression. Another possible mechanism is that omega-3 fatty acids decrease inflammation associated with migraines.

However, some limitations of the study make it more difficult to cast a clear verdict. The use of the baseline interview assumed that all patients who came to the headache clinic were experiencing daily headache. There is no mention that participants admitted to the study had completed headache diaries prior to enrollment, or that they were asked to do a baseline headache diary prior to their supplement intervention. Improvement in migraine status was measured by comparing the frequency of headaches during the trial with the assumption that patients were experiencing headaches every day.

It is possible that every patient enrolled experienced headaches daily prior to enrollment. Certainly, headaches must be very intrusive to warrant appointments at a headache clinic. However, it is also possible that patients suffered from difficulty recalling the exact number of days they experienced headaches in the previous month, and that they just knew that the headaches occurred extremely frequently.

Without having a better measurement for patient headache frequency at baseline—which could have been ascertained with a one or two-month run-in period requiring patients to take amitriptyline and keep a headache diary—it is difficult to know exactly what the true magnitude in change was for each group. And so, while the omega-3 group did show significantly fewer headaches at the end of 60 days, we don’t know whether there may have been a significant difference in headache frequency between groups at baseline.

That being said, members of the group receiving the omega-3 supplement were twice as likely to experience fewer than five headaches over sixty days compared to the control group, a striking difference.

The article did not mention what if any treatments participants were using prior to enrolling in the study. Most of the patients enrolling noted that they had experienced onset of headaches for greater than 10 years, so it seems unlikely that all the participants were previously untreated. If the low dose amitriptyline monotherapy in participants created a significant shift in their previous treatment regimen, this could confound the results.

Ultimately, the study did show that the experimental arm experienced fewer total headaches over 60 days than the control arm, which gives ample reason to continue examining the potential effects of omega-3 fatty acids on migraine. However, due to study limitations (especially a lack of rigor in data analysis), it is difficult to assess the true magnitude or significance of the effects seen.

The authors suggest that omega-3 fatty acids increase the density of serotonin receptors and reduce inflammation, therefore decreasing the frequency of headaches in participants with chronic migraine. However, the study had some major limitations that weakened its conclusions. For example, the authors did not account for or did not have a reliable enough count of headache frequency for participants at baseline. The researchers also did not account for participants’ previous migraine treatments prior to enrollment. These factors limit the value of the findings, and should be accounted for in future studies evaluating the effects of DHA and EPA on migraine frequency.

The big picture

While this study had interesting findings, it certainly does not close the book on the usefulness of omega-3 for migraine prevention. Other literature has examined the possible effects of omega-3 fatty acids on migraines. Overall, these findings are less impressive than the current study.

A 2012 study with 67 participants[8] assessed possible differences in migraine frequency, duration, and headaches in an experimental arm given omega-3 fatty acids and valproate (another medication for migraine) compared to valproate alone. This study, which ran over three months, found that all patients had reductions in headaches and that the omega-3 group showed greater improvement, but only for the first month. Months two and three of the study showed no difference between the two arms.

Other studies show similarly unimpressive results. A 2002 trial in the Journal of Adolescent Health found that participants supplementing omega-3 oil had no effect compared to olive oil on migraine management. A 2001 trial showed no difference between omega-3s and placebos. And a recent 2016 review on the evidence for nutraceuticals[7] in migraine concluded that evidence for omega-3 supplementation for migraine was poor.

Interestingly, a 2013 trial[9] examined effects on chronic migraine of increasing dietary intake of omega-3 fatty acids with reduction of omega-6 fatty acids compared to reduction of omega-6 fatty acids alone. This trial, which took more of a “whole foods” approach to the issue, did find that the participants assigned to the high omega-3, low omega-6 diet had greater improvement in headache frequency, duration, and intensity compared to the control group as well as compared to baseline.

At this point, the literature does not suggest that there is a clear cut benefit to supplementing omega-3 fatty acids if the goal is migraine management, but there is always potential for better-powered, well-designed studies to further the body of knowledge on the subject.

While the current study suggests that omega-3 fatty acids might help reduce the frequency of migraine, the findings have significant limitations. The wider body of literature suggests that there is weak evidence for including omega-3 fatty acids as a supplementary treatment for migraine, though including more food sources of omega-3, like fish, might show a stronger effect.

Frequently Asked Questions

Q. The omega-3 and placebo supplements in this study both had artificial sweeteners. Aren’t those migraine triggers in some people?

The most common migraine triggers are shown in Figure 3. Generally, it appears that artificial sweeteners aren’t strongly associated with migraine in people who have them. However, triggers can vary based on the individual. The addition of sweeteners to the omega-3 fatty acids and placebo in this trial were likely crucial to double-blinding the study, since the taste of fish oils would be distinct in a powdered supplement.

Figure 3: Top 6 triggers of migraines

Q. What about herbal supplements for migraine?

Feverfew and butterbur are often used to manage migraine. In a 2004 Cochrane Review, five trials examining feverfew with a total of 343 patients were assessed. The review concluded that there was insufficient evidence of an effect of feverfew on migraine.

Butterbur is a more controversial supplement. While the evidence is slightly stronger for butterbur as a prophylactic for migraine, supplementation has been associated with serious side effects in some case reports, including 40 reported cases of hepatotoxicity, with two requiring liver transplants[7]. Furthermore, since dietary supplements have little regulation, one recent assessment in the United States found that only one-third of butterbur supplements contained the amount of active ingredient advertised and one-third contained hepatotoxic alkaloids.

What do I need to know?

Despite the results of the reviewed study, there is not a strong body of evidence suggesting that omega-3 fatty acid supplementation is effective for reducing frequency of migraine. The current study found a statistically significant improvement in headache frequency in the experimental arm but was hampered by several limitations. Additionally, the author’s suggested mechanism—increased serotonin receptor expression in the brain—is still unproven.

Migraine is a major cause of disability[10] across the globe and research into better treatment options are very necessary. While the use of natural or nutraceutical products in the treatment of migraine do not show strong results thus far, individuals still may still find relief when finding something that works for them.

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See other articles with similar topics: Migraine, Omega 3.

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References

  1. ^ a b Goadsby PJ, et al. Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. (2017)
  2. ^ H J Engels, J C Wirth. No ergogenic effects of ginseng (Panax ginseng C.A. Meyer) during graded maximal aerobic exercise. J Am Diet Assoc. (1997)
  3. ^ Richard B Lipton, Stephen D Silberstein. Episodic and chronic migraine headache: breaking down barriers to optimal treatment and prevention. Headache. (2015)
  4. ^ H J Engels, J C Wirth. No ergogenic effects of ginseng (Panax ginseng C.A. Meyer) during graded maximal aerobic exercise. J Am Diet Assoc. (1997)
  5. ^ H J Engels, J C Wirth. No ergogenic effects of ginseng (Panax ginseng C.A. Meyer) during graded maximal aerobic exercise. J Am Diet Assoc. (1997)
  6. ^ Marcelo E Bigal, et al. Chronic migraine in the population: burden, diagnosis, and satisfaction with treatment. Neurology. (2008)
  7. ^ a b c d Thilinie Rajapakse, Tamara Pringsheim. Nutraceuticals in Migraine: A Summary of Existing Guidelines for Use. Headache. (2016)
  8. ^ Marzieh Tajmirriahi, et al. The effects of sodium valproate with fish oil supplementation or alone in migraine prevention: A randomized single-blind clinical trial. Iran J Neurol. (2012)
  9. ^ Christopher E Ramsden, et al. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Pain. (2013)
  10. ^ Todd A Smitherman, et al. The prevalence, impact, and treatment of migraine and severe headaches in the United States: a review of statistics from national surveillance studies. Headache. (2013)