Association of diet and headache.

The global prevalence of migraine as a primary headache has been estimated as 14.4% in both sexes. Migraine headache has been ranked as the highest contributor to disability in under 50 years old population in the world. Extensive research has been conducted in order to clarify the pathological mechanisms of migraine. Although uncertainties remains, it has been indicated that vascular dysfunction, cortical spreading depression (CSD), activation of the trigeminovascular pathway, pro-inflammatory and oxidative state may play a putative role in migraine pain generation. Knowledge about pathophysiological mechanisms of migraine should be integrated into a multimodal treatment approach to increase quality of life in patients. With respect to this, within the integrative health studies growing interest pertains to dietary interventions. Although the number of studies concerning effects of diet on headache/migraine is not yet very large, the current article will review the available evidence in this area. All publications on headache/migraine and dietary interventions up to May 2019 were included in the present review through a PubMed/MEDLINE and ScienceDirect database search. According to the current findings, Ketogenic diet and modified Atkins diet are thought to play a role in neuroprotection, improving mitochondrial function and energy metabolism, compensating serotoninergic dysfunction, decreasing calcitonin gene-related peptide (CGRP) level and suppressing neuro-inflammation. It can also be speculated that prescription of low glycemic diet may be promising in headache/migraine control through attenuating the inflammatory state. Moreover, obesity and headaches including migraine could be attributed to each other through mechanisms like inflammation, and irregular hypothalamic function. Thereby, applying dietary strategies for weight loss may also ameliorate headache/migraine. Another important dietary intervention that might be effective in headache/migraine improvement is related to balance between the intake of essential fatty acids, omega-6 and omega-3 which also affect inflammatory responses, platelet function and regulation of vascular tone. Regarding elimination diets, it appears that targeted these diets in migraine patients with food sensitivities could be effective in headache/migraine prevention. Taken together, dietary approaches that could be considered as effective strategies in headache/migraine prophylaxis include weight loss diets in obese headache patients, ketogenic and low-calorie diets, reducing omega-6 and increasing omega-3 fatty acid intakes.

Effect of exclusion of frequently consumed dietary triggers in a cohort of children with chronic primary headache.

BACKGROUND: Although dietary factors are known to trigger headaches, the relationship between food and headache in children remains unclear. This prospective, observational case series aimed to evaluate the effect of exclusion of frequently-consumed foods in a cohort of children with headache. METHODS: One hundred and fifteen children aged 3-15 (mean 10.5) years with primary headache were followed in a paediatric outpatient clinic. Patients who frequently consumed foods or food additives known to trigger headaches were advised to exclude them for six weeks and to return for follow-up with headache and food diary. RESULTS: One hundred patients attended follow-up. Of these 13 (13%) did not respond to dietary exclusion; 87 (87%) achieved complete resolution of headaches by exclusion of 1-3 of the identified food(s). Caffeine was the most common implicated trigger (28), followed by monosodium glutamate (25), cocoa (22), aspartame (13), cheese (13), citrus (10) and nitrites (six). One patient was sensitive to tomatoes. CONCLUSIONS: This study demonstrates the potential scale and significance of seven frequently consumed foods or food additives as triggers for primary headache in children. Also this is the first study to show that headaches can be triggered by the cumulative effect of a food that is frequently consumed, rather than by single time ingestion.

Lower Sodium Intake and Risk of Headaches: Results From the Trial of Nonpharmacologic Interventions in the Elderly.

OBJECTIVES: To determine the effect of sodium (Na) reduction on occurrence of headaches. METHODS: In the Trial of Nonpharmacologic Interventions in the Elderly, 975 men and woman (aged 60-80 years) with hypertension were randomized to a Na-reduction intervention or control group and were followed for up to 36 months. The study was conducted between 1992 and 1995 at 4 clinical centers (Johns Hopkins University, Wake Forest University School of Medicine, Robert Wood Johnson Medical School, and the University of Tennessee). RESULTS: Mean difference in Na excretion between the Na-reduction intervention and control group was significant at each follow-up visit (P < .001) with an average difference of 38.8 millimoles per 24 hours. The occurrence of headaches was significantly lower in the Na-reduction intervention group (10.5%) compared with control (14.3%) with a hazard ratio of 0.59 (95% confidence interval = 0.40, 0.88; P = .009). The risk of headaches was significantly associated with average level of Na excretion during follow-up, independent of most recent blood pressure. The relationship appeared to be nonlinear with a spline relationship and a knot at 150 millimoles per 24 hours. CONCLUSIONS: Reduced sodium intake, currently recommended for blood pressure control, may also reduce the occurrence of headaches in older persons with hypertension.

Diet and Headache: Part 2.

BACKGROUND: Comprehensive diets do not require the exclusion of a specific provocative food or ingredient, but regulate the quantities of core components of foods such as vitamins, ions, proteins, carbohydrates, and fats. OBJECTIVES: To review the evidence supporting the use of comprehensive diets in the prevention of migraine and other headache disorders and to discuss the mechanisms through which food, and ingredients within foods and beverages might trigger attacks of headache METHODS: This represents Part 2 of a narrative review of the role of diet in the prevention of migraine and other headache disorders. A PubMed search was performed with the following search terms: "folate," "vitamin D," "low fat diet," "omega-3 and omega-6 fatty acid diet," "ketogenic diet," "Atkins diet," and "sodium." Each of these search terms was then crossreferenced with "headache" and "migraine" to identify relevant studies. Only studies that were written in English were included in this review. RESULTS: Low fat and high omega-3/low omega-6 fatty diets decrease the frequency of attacks of migraine and/or other headache disorders as demonstrated in two separate randomized controlled trials. A ketogenic diet was more effective than a standard diet in reducing the frequency of migraine in a single nonrandomized clinical study. An observation study found that dietary consumption of folate was inversely associated with the frequency of migraine attacks in persons with migraine with aura that have the C variant of the methylene tetrahydrofolate reductase gene. The mechanisms though which diets may precipitate headache include their effects on neuropeptides, neuro-receptors and ion channels, inflammation, sympathetic nervous system, release of nitric oxide, vasodilation, and cerebral glucose metabolism. CONCLUSIONS: Evidence exists to support the use of comprehensive diets in the prevention of migraine and other headache disorders. However, the results of these studies should be considered preliminary until replicated in larger randomized controlled clinical trials.

Dietary intake patterns and diet quality in a nationally representative sample of women with and without severe headache or migraine.

OBJECTIVE/BACKGROUND: The role of diet in migraine is not well understood. We sought to characterize usual dietary intake patterns and diet quality in a nationally representative sample of women with and without severe headache or migraine. We also examined whether the relationship between migraine and diet differs by weight status. METHODS: In this analysis, women with migraine or severe headache status was determined by questionnaire for 3069 women, ages 20-50 years, who participated in the National Health and Nutrition Examination Study, 1999-2004. Women who experienced severe headaches or migraines were classified as migraine for the purposes of this analysis. Dietary intake patterns (micro- and macronutrient intake and eating frequency) and diet quality, measured by the Healthy Eating Index, 2005, were determined using one 24-hour dietary recall. RESULTS: Dietary intake patterns did not significantly differ between women with and without migraine. Normal weight women with migraine had significantly lower diet quality (Healthy Eating Index, 2005 total scores) than women without migraine (52.5 ± 0.9 vs. 45.9 ± 1.0; P < .0001). CONCLUSIONS: Whereas findings suggest no differences in dietary intake patterns among women with and without migraine, dietary quality differs by migraine status in normal weight women. Prospective analyses are needed to establish how diet relates to migraine onset, characteristics, and clinical features in individuals of varying weight status.

A randomized trial on the effects of regular water intake in patients with recurrent headaches.

BACKGROUND: Previously published investigations suggest a positive effect of increased water intake on headache, but a randomised controlled trial has not been done. OBJECTIVE: To investigate the effects of increased water intake on headache. METHODS: Randomised controlled trial in primary care with two groups and a follow-up period of 3 months. Patients were included if they had at least two episodes of moderately intense headache or at least five mildly intense episodes per month and a total fluid intake of less than 2.5 l/day. Both groups received written instructions about stress reduction and sleep improvement strategies. The intervention group additionally received the instruction to increase the daily water intake by 1.5 l. The main outcome measures were Migraine-Specific Quality of Life (MSQOL) and days with at least moderate headache per month. RESULTS: We randomised 50 patients to the control group and 52 patients to the intervention group. Drinking more water resulted in a statistically significant improvement of 4.5 (confidence interval: 1.3-7.8) points on MSQOL. In addition, 47% in the water group reported much improvement (6 or higher on a 10-point scale) on perceived intervention effect against 25% in the control group. However, drinking more water did not result in relevant changes in days with at least moderate headache. CONCLUSIONS: Considering the observed positive subjective effects, it seems reasonable to recommend headache patients to try this non-invasive intervention for a short period of time to see whether they experience improvement.

Applications of Ketogenic Diets in Patients with Headache: Clinical Recommendations.

Headaches are among the most prevalent and disabling neurologic disorders and there are several unmet needs as current pharmacological options are inadequate in treating patients with chronic headache, and a growing interest focuses on nutritional approaches as non-pharmacological treatments. Among these, the largest body of evidence supports the use of the ketogenic diet (KD). Exactly 100 years ago, KD was first used to treat drug-resistant epilepsy, but subsequent applications of this diet also involved other neurological disorders. Evidence of KD effectiveness in migraine emerged in 1928, but in the last several year's different groups of researchers and clinicians began utilizing this therapeutic option to treat patients with drug-resistant migraine, cluster headache, and/or headache comorbid with metabolic syndrome. Here we describe the existing evidence supporting the potential benefits of KDs in the management of headaches, explore the potential mechanisms of action involved in the efficacy in-depth, and synthesize results of working meetings of an Italian panel of experts on this topic. The aim of the working group was to create a clinical recommendation on indications and optimal clinical practice to treat patients with headaches using KDs. The results we present here are designed to advance the knowledge and application of KDs in the treatment of headaches.

Effects of food on physical and sleep complaints in children with ADHD: a randomised controlled pilot study.

Attention deficit/hyperactivity disorder (ADHD), a common behavioural disorder in children, may be associated with comorbid physical and sleep complaints. Dietary intervention studies have shown convincing evidence of efficacy in reducing ADHD symptoms in children. In this pilot study, we investigated the effects of an elimination diet on physical and sleep complaints in children with ADHD. A group of 27 children (3.8-8.5 years old), who all met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD, were assigned randomly to either a diet group (15/27) or a control group (12/27). The diet group followed a 5-week elimination diet; the control group adhered to their normal diet. Parents of both groups had to keep an extended diary and had to monitor the behaviour and the physical and sleep complaints of their child conscientiously. The primary endpoint was the clinical response, i.e. a decrease of physical and sleep complaints, at the end of the trial, based on parent ratings on a Physical Complaints Questionnaire. The number of physical and sleep complaints was significantly decreased in the diet group compared to the control group (p < 0.001), with a reduction in the diet group of 77% (p < 0.001, effect size = 2.0) and in the control group of 17% (p = 0.08, effect size = 0.2). Specific complaints that were significantly reduced were in three domains: headaches or bellyaches, unusual thirst or unusual perspiration, and sleep complaints. The reduction of complaints seemed to occur independently of the behavioural changes (p = 0.1). However, the power of this comparison was low. A positive correlation existed between the reduction of physical and behavioural symptoms (p < 0.01). The reduction did not differ between children with or without an atopic constitution (p = 0.7). An elimination diet may be an effective instrument to reduce physical complaints in children with ADHD, but more research is needed to determine the effects of food on (functional) somatic symptoms in children with and without ADHD. This trial was registered as an International Standard Randomised Controlled Trial, ISRCTN47247160.

A Single Institution's Experience of Primary Headache in Children With Celiac Disease.

BACKGROUND: Few studies exist examining the frequency of primary headache in children with celiac disease and the impact of a gluten-free diet on primary headache symptomology. This study explores characteristics and frequency of headaches in children with celiac disease and response to gluten-free diet at a single institution. METHODS: Medical records were reviewed for children with celiac disease confirmed by the presence of elevated tissue transglutaminase IgA levels and histologic changes consistent with the diagnosis of celiac disease on small bowel biopsy. Eligible participants were contacted via letter for participation in a phone survey regarding headaches. Phone interviews were conducted 2 weeks after notification and lasted approximately 10 minutes. Headaches were classified according to ICHD-3 criteria. RESULTS: 247 eligible patients or their families were contacted. A total of 132 (53.44%) agreed to participate. One participant was excluded due to insufficient information provided. Overall, 51 of 131 participants had recurrent headache defined as at least 1 episode per month (39%, 95% confidence interval [CI]: 31%-47%) and 33 had migraine with or without aura (25%, 95% CI: 18%-33%). Twenty-eight had frequent tension-type headache (22%, 95% CI: 15%-29%). Thirty-two participants noted headaches before a confirmed diagnosis of celiac disease. Twenty-two of 32 participants (68.75%) noticed decreased headache frequency or intensity, or both, after starting the gluten-free diet. CONCLUSION: This study suggests that at least one-third of children and adolescents with celiac disease have recurrent headaches at the time of diagnosis. A gluten-free diet led to improved headache symptomology in a significant number of these patients.

Complementary and alternative medicine (CAM) in headache of children and adolescents: open-label Italian study.

OBJECTIVE: The aim of the present research is to evaluate and to compare various nutraceuticals and food supplements in the headaches prophylaxis. BACKGROUND: Recently the use of complementary and alternative medicine, nutraceuticals and food supplements, in prophylaxis and attack therapy of headaches is spreading both in adulthood and in childhood age. MATERIALS AND METHODS: 99 children, 6-17 years, females 44 and males 55, suffering from primary headaches and admitted to Headache Center in the years 2016- 2017 are the sample. 7 patients were excluded because they did not adhere to the study due to lack of therapeutic compliance and because they did not return to clinical controls. The patients referred to the Headache Center are selected consecutively. The open-label study evaluating clinical trial concerns the evaluation of the following parameters: headache diagnosis according to International Headache Society criteria (ICHD-III, 2013 beta version), migraine index; the prophylaxis and attack therapies at time zero and after 12 months. The compounds used to prophylaxis therapy are: Mg citrate, Mg oxide and Mg aspartate (compound n°1), Bisglycinate Mg + L-Tryptophan + Niacin + B2 Vitamin + D Vitamin (compound n°2), Oxide Mg + Partenium + Andrographis paniculata + coenzyme Q10, B2 Vitamin (compound n°3). Each compound was compared with the other to evaluate clinical efficacy. Attack therapy: Paracetamol, Ibuprofen, ketoprofen, Indomethacin. Informed consent was obtained for participation in the study by the parents of the children. Statistical analysis is made by Kruskal -Wallis test and analysis post hoc Conover. RESULT: 22 females and 24 males suffer from Migraine without aura, 9 females and 12 males from Migraine with Aura, 11 females and 14 males from Tension Type Frequent Headache. The therapy as with compounds n°1, 2 and 3 is effective in reducing migraine index and reduces the use of attack therapy in all the cases very significantly (p=0.000001). In MwoA the compound n° 1 is less effective than compounds n° 2 and 3(p=0.00089).In MA compound n° 3 is less effective than compounds n° 2 and 1 (p=0.0044). In FETTH, compound n° 3 is less effective compared to compound n° 2 (p=0.052). CONCLUSION: The use of nutraceuticals and food supplements appears to be effective and also encouraging as it is well accepted by parents and children themselves.

Is an "Epigenetic Diet" for Migraines Justified? The Case of Folate and DNA Methylation.

Migraines are a common disease with limited treatment options and some dietary factors are recognized to trigger headaches. Although migraine pathogenesis is not completely known, aberrant DNA methylation has been reported to be associated with its occurrence. Folate, an essential micronutrient involved in one-carbon metabolism and DNA methylation, was shown to have beneficial effects on migraines. Moreover, the variability of the methylenetetrahydrofolate reductase gene, important in both folate metabolism and migraine pathogenesis, modulates the beneficial effects of folate for migraines. Therefore, migraine could be targeted by a folate-rich, DNA methylation-directed diet, but there are no data showing that beneficial effects of folate consumption result from its epigenetic action. Furthermore, contrary to epigenetic drugs, epigenetic diets contain many compounds, some yet unidentified, with poorly known or completely unknown potential to interfere with the epigenetic action of the main dietary components. The application of epigenetic diets for migraines and other diseases requires its personalization to the epigenetic profile of a patient, which is largely unknown. Results obtained so far do not warrant the recommendation of any epigenetic diet as effective in migraine prevention and therapy. Further studies including a folate-rich diet fortified with valproic acid, another modifier of epigenetic profile effective in migraine prophylaxis, may help to clarify this issue.

Behavioral disorders in children with idiopathic intracranial hypertension.

The purpose of this research was to evaluate the association between idiopathic intracranial hypertension and behavior, attention, and learning abilities in children. Parents of school-age children with idiopathic intracranial hypertension were asked to fill out a questionnaire and to rank the child's behavioral patterns before and after the diagnosis and treatment of the disease. The questionnaire was based on Conners' test. Ten children were included in the study. Mean age at diagnosis was 11.5 years. Mean follow-up time was 25 months. Six patients (60%) met the definition of attention- and concentration-deficit disorders before diagnosis of idiopathic intracranial hypertension; 1 patient was treated with methylphenidate (Ritalin) before referral to eye examination. After the diagnosis was made and treatment was established, 5 patients (83%) reported an improvement in their attention and behavior. Of these 6 patients, 2 (33%) reported marked improvement. We conclude that attention- and concentration-deficit disorder might be an early sign for pediatric idiopathic intracranial hypertension. Diagnosis and treatment of idiopathic intracranial hypertension in these children may improve the child's behavior, attention, and achievements in school, without the need to resort to other modes of therapy.

Headache Associated with Coeliac Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this systematic review was to explore the relationship between coeliac disease (CD) and headache. The objectives were to establish the prevalence of each entity amongst the other, to explore the role of gluten free diet (GFD), and to describe the imaging findings in those affected by headaches associated with CD. METHODOLOGY: A systematic computer-based literature search was conducted on the PubMed database. Information regarding study type, population size, the age group included, prevalence of CD amongst those with headache and vice versa, imaging results, the nature of headache, and response to GFD. RESULTS: In total, 40 articles published between 1987 and 2017 qualified for inclusion in this review. The mean pooled prevalence of headache amongst those with CD was 26% (95% CI 19.5⁻33.9%) in adult populations and 18.3% (95% CI 10.4⁻30.2%) in paediatric populations. The headaches are most often migraine-like. In children with idiopathic headache, the prevalence of CD is 2.4% (95% CI 1.5⁻3.7%), whereas data for adult populations is presently unavailable. Brain imaging can be normal, although, cerebral calcifications on CT, white matter abnormalities on MRI and deranged regional cerebral blood flow on SPECT can be present. GFD appears to be an effective management for headache in the context of CD, leading to total resolution of headaches in up to 75% of patients. CONCLUSIONS: There is an increased prevalence of CD amongst idiopathic headache and vice versa. Therefore, patients with headache of unknown origin should be screened for CD, as such patients may symptomatically benefit from a GFD.

[Gluten migraine].

OBJECTIVE: to study the prevalence of migraine among patients with celiac disease (CD) and clinical features of «gluten migraine¼ syndrome and to assess the efficacy of gluten diet in its treatment. MATERIAL AND METHODS: Authors examined 200 CD patients (main group) and 100 patients with reflux esophagitis and without CD (control group). All patients fulfilled the headache diary during three months before the diagnosis of migraine was made and six months during gluten diet. RESULTS AND CONCLUSION: CD group had migraine syndrome four times more often than the control group (48.5%; p<0.001). In CD group migraine attacks were 2.5 times more frequent than in the control group (р=0.004), but the duration of the attacks was less long, 8 hours in average. The migraine attacks measured by the Visual Analog Scale were less intensive, 55% in average, and had a later onset. The attacks were more frequent in CD patients who were older than 50 years old (р<0.05). The attacks disappeared in 25% of patients with migraine syndrome who were on the gluten diet and the reduction in the intensity and/or frequency of attacks was observed in 38% of patients. We revealed the clear association between migraine syndrome and CD and the high efficacy of gluten diet in the treatment of migraine symptoms.

Role of the gluten-free diet on neurological-EEG findings and sleep disordered breathing in children with celiac disease.

PURPOSE: To determine whether celiac children are at risk for EEG-neurological features and sleep disordered breathing (SDB), and whether an appropriate gluten-free diet (GFD) influences these disorders. METHODS: We consecutively enrolled 19 children with a new biopsy-proven celiac disease (CD) diagnosis. At CD diagnosis and after 6 months of GFD, each patient underwent a general and neurological examination, an electroencephalogram, a questionnaire about neurological features, and a validated questionnaire about SDB: OSA (obstructive sleep apnea) scores<0 predict normality; values>0 predict OSA. RESULTS: At CD diagnosis, 37% of patients complained headache that affected daily activities and 32% showed positive OSA score. The EEG examinations revealed abnormal finding in 48% of children. After 6 months of GFD headache disappeared in 72% of children and EEG abnormalities in 78%; all children showed negative OSA score. CONCLUSION: According to our preliminary data, in the presence of unexplained EEG abnormalities and/or other neurological disorders/SDB an atypical or silent CD should also be taken into account.

Diet-induced changes in n-3- and n-6-derived endocannabinoids and reductions in headache pain and psychological distress.

UNLABELLED: Omega-3 and omega-6 fatty acids are biosynthetic precursors of endocannabinoids with antinociceptive, anxiolytic, and neurogenic properties. We recently reported that targeted dietary manipulation-increasing omega-3 fatty acids while reducing omega-6 linoleic acid (the H3-L6 intervention)-reduced headache pain and psychological distress among chronic headache patients. It is not yet known whether these clinical improvements were due to changes in endocannabinoids and related mediators derived from omega-3 and omega-6 fatty acids. We therefore used data from this trial (N = 55) to investigate 1) whether the H3-L6 intervention altered omega-3- and omega-6-derived endocannabinoids in plasma and 2) whether diet-induced changes in these bioactive lipids were associated with clinical improvements. The H3-L6 intervention significantly increased the omega-3 docosahexaenoic acid derivatives 2-docosahexaenoylglycerol (+65%, P < .001) and docosahexaenoylethanolamine (+99%, P < .001) and reduced the omega-6 arachidonic acid derivative 2-arachidonoylglycerol (-25%, P = .001). Diet-induced changes in these endocannabinoid derivatives of omega-3 docosahexaenoic acid, but not omega-6 arachidonic acid, correlated with reductions in physical pain and psychological distress. These findings demonstrate that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids in humans and suggest that 2-docosahexaenoylglycerol and docosahexaenoylethanolamine could have physical and/or psychological pain modulating properties. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01157208) PERSPECTIVE: This article demonstrates that targeted dietary manipulation can alter endocannabinoids derived from omega-3 and omega-6 fatty acids and that these changes are related to reductions in headache pain and psychological distress. These findings suggest that dietary interventions could provide an effective, complementary approach for managing chronic pain and related conditions.

Toward an understanding of the rationale for the use of dietary supplementation for chronic pain management: the serotonin model.

The use of dietary metabolic precursors to neurotransmitter in the management of chronic pain patients has received critical attention for several years. As pain evolves from acute to chronic, different neuronal pathways are used and diverse areas of the brain become involved in pain perception and modulation. The serotonergic system serves as a useful model for understanding the effect of metabolic precursors. Oral L-tryptophan administration decreases the perception of pain, appearing to act synergistically with the enkephalins and endorphins. Drugs that either increase the serotonin level or block reuptake are associated with decreased pain perception, increased pain threshold, and improved sleep. From a therapeutic standpoint, dietary modification would appear to be attractive, due to its low economic basis, decreased risk of addiction and dependence, as well as simplicity. However, potential risk from toxicity is only recently being recognized, along with difficulty in reliability of analgesic effect from one patient to another. Currently, L-tryptophan is unavailable for therapeutic use in the United States and is not recommended implicitly or explicitly by the author because of its potential health risk.

Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools.

BACKGROUND: Dietary linoleic acid (LA, 18:2n-6) lowering in rats reduces n-6 polyunsaturated fatty acid (PUFA) plasma concentrations and increases n-3 PUFA (eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)) concentrations. OBJECTIVE: To evaluate the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, alters unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache. DESIGN: Secondary analysis of a randomized trial. Subjects with chronic headache were randomized for 12 weeks to (1) average n-3, low n-6 (L6) diet; or (2) high n-3, low n-6 LA (H3-L6) diet. Esterified and unesterified plasma fatty acids were quantified at baseline (0 weeks) and after 12 weeks on a diet. RESULTS: Compared to baseline, the L6 diet reduced esterified plasma LA and increased esterified n-3 PUFA concentrations (nmol/ml), but did not significantly change plasma arachidonic acid (AA, 20:4n-6) concentration. In addition, unesterified EPA concentration was increased significantly among unesterified fatty acids. The H3-L6 diet decreased esterified LA and AA concentrations, and produced more marked increases in esterified and unesterified n-3 PUFA concentrations. CONCLUSION: Dietary n-6 PUFA lowering for 12 weeks significantly reduces LA and increases n-3 PUFA concentrations in plasma, without altering plasma AA concentration. A concurrent increase in dietary n-3 PUFAs for 12 weeks further increases n-3 PUFA plasma concentrations and reduces AA.

Lowering dietary linoleic acid reduces bioactive oxidized linoleic acid metabolites in humans.

Linoleic acid (LA) is the most abundant polyunsaturated fatty acid in human diets, a major component of human tissues, and the direct precursor to the bioactive oxidized LA metabolites (OXLAMs), 9- and 13 hydroxy-octadecadienoic acid (9- and 13-HODE) and 9- and 13-oxo-octadecadienoic acid (9- and 13-oxoODE). These four OXLAMs have been mechanistically linked to pathological conditions ranging from cardiovascular disease to chronic pain. Plasma OXLAMs, which are elevated in Alzheimer's dementia and non-alcoholic steatohepatitis, have been proposed as biomarkers useful for indicating the presence and severity of both conditions. Because mammals lack the enzymatic machinery needed for de novo LA synthesis, the abundance of LA and OXLAMs in mammalian tissues may be modifiable via diet. To examine this issue in humans, we measured circulating LA and OXLAMs before and after a 12-week LA lowering dietary intervention in chronic headache patients. Lowering dietary LA significantly reduced the abundance of plasma OXLAMs, and reduced the LA content of multiple circulating lipid fractions that may serve as precursor pools for endogenous OXLAM synthesis. These results show that lowering dietary LA can reduce the synthesis and/or accumulation of oxidized LA derivatives that have been implicated in a variety of pathological conditions. Future studies evaluating the clinical implications of diet-induced OXLAM reductions are warranted.

Low omega-6 vs. low omega-6 plus high omega-3 dietary intervention for chronic daily headache: protocol for a randomized clinical trial.

BACKGROUND: Targeted analgesic dietary interventions are a promising strategy for alleviating pain and improving quality of life in patients with persistent pain syndromes, such as chronic daily headache (CDH). High intakes of the omega-6 (n-6) polyunsaturated fatty acids (PUFAs), linoleic acid (LA) and arachidonic acid (AA) may promote physical pain by increasing the abundance, and subsequent metabolism, of LA and AA in immune and nervous system tissues. Here we describe methodology for an ongoing randomized clinical trial comparing the metabolic and clinical effects of a low n-6, average n-3 PUFA diet, to the effects of a low n-6 plus high n-3 PUFA diet, in patients with CDH. Our primary aim is to determine if: A) both diets reduce n-6 PUFAs in plasma and erythrocyte lipid pools, compared to baseline; and B) the low n-6 plus high n-3 diet produces a greater decline in n-6 PUFAs, compared to the low n-6 diet alone. Secondary clinical outcomes include headache-specific quality-of-life, and headache frequency and intensity. METHODS: Adults meeting the International Classification of Headache Disorders criteria for CDH are included. After a 6-week baseline phase, participants are randomized to a low n-6 diet, or a low n-6 plus high n-3 diet, for 12 weeks. Foods meeting nutrient intake targets are provided for 2 meals and 2 snacks per day. A research dietitian provides intensive dietary counseling at 2-week intervals. Web-based intervention materials complement dietitian advice. Blood and clinical outcome data are collected every 4 weeks. RESULTS: Subject recruitment and retention has been excellent; 35 of 40 randomized participants completed the 12-week intervention. Preliminary blinded analysis of composite data from the first 20 participants found significant reductions in erythrocyte n-6 LA, AA and %n-6 in HUFA, and increases in n-3 EPA, DHA and the omega-3 index, indicating adherence. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01157208).