Low omega-6 vs. low omega-6 plus high omega-3 dietary intervention for Chronic Daily Headache: Protocol for a randomized clinical trial Low-n-6 and low-n-6 plus high-n-3 diets for use in clinical research. Glycemic responses to sweetened dried and raw cranberries in humans with type 2 diabetes. The Effects of Magnesium, l-Carnitine, and Concurrent Magnesium–l-Carnitine Supplementation in Migraine Prophylaxis Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial Vitamins and paediatric migraine: Riboflavin as a preventative medication The effects of sodium valproate with fish oil supplementation or alone in migraine prevention: A randomized single-blind clinical trial Prophylactic Treatment of Migraine with Gamma-Linolenic and Alpha-Linolenic Acids Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools. Failure of Omega-3 Polyunsaturated Fatty Acids in Prevention of Migraine: A Double-Blind Study Versus Placebo Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: A randomized trial Comparison of self-hypnosis and propranolol in the treatment of juvenile classic migraine. Increase in PGE2 and TXA2 in the saliva of common migraine patients. Action of calcium channel blockers. Supplementation with omega-3 polyunsaturated fatty acids in the management of recurrent migraines in adolescents. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial Propranolol and amitriptyline in prophylaxis of migraine. Pharmacokinetic and therapeutic effects. The effects of short- and long-term supplementation with fish oil on the incorporation of n-3 polyunsaturated fatty acids into cells of the immune system in healthy volunteers. Targeted alterations in dietary n-3 and n-6 fatty acids improve life functioning and reduce psychological distress among patients with chronic headache: a secondary analysis of a randomized 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 r and omized 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 r and omized 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 material s complement dietitian advice . Blood and clinical outcome data are collected every 4 weeks . Results Subject recruitment and retention has been excellent ; 35 of 40 r and omized 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 Clinical Trials.gov ( NCT01157208 Few trials have evaluated the metabolic effects and health outcomes of lowering dietary n-6 PUFA . The objectives of the present paper were ( 1 ) to report the methods employed to lower dietary n-6 PUFA , while either increasing or maintaining n-3 PUFA intake and ( 2 ) to vali date our methods with 24 h recalls and erythrocyte fatty acid analyses . A total of sixty-seven subjects were r and omised to either ( 1 ) an average-n-3 PUFA , low-n-6 PUFA ( L6 ) intervention design ed to lower linoleic acid ( LA ; # 2·5 % of energy ( en% ) ) and arachidonic acid ( # 60 mg/d ) , while maintaining an average US intake of n-3 PUFA or ( 2 ) a high-n-3 PUFA , low-n-6 PUFA ( H3-L6 ) intervention design ed to lower n-6 LA , while increasing the n-3 PUFA a-linolenic acid ( ALA ; $ 1·5 en% ) and EPA þ DHA ( $ 1000 mg/d ) . Pre- and intraintervention nutrient intakes were estimated with six 24 h dietary recalls per subject . Both groups achieved the targeted reductions in dietary LA to # 2·5 en% ( median LA 2·45 ( 2·1 , 3·1 ) ; P,0·001 ) . Intakes of n-3 PUFA did not change for the L6 group . Target increases in n-3 ALA ( median 1·6 en% , ( 1·3 , 2·0 ) , P,0·001 ) and EPA þ DHA ( 1482 mg , ( 374 , 2558 ) , P,0·001 ) were achieved in the H3-L6 group . Dietary changes were vali date d by corresponding changes in erythrocyte n-6 and n-3 fatty acid composition . Dietary LA can be lowered to # 2·5 en% , with or without concurrent increases in dietary n-3 PUFA , in an outpatient clinical trial setting using this integrated diet method This study assessed the metabolic response to sweetened dried cranberries ( SDC ) , raw cranberries ( RC ) , and white bread ( WB ) in humans with type 2 diabetes . Development of palatable cranberry preparations associated with lower glycemic responses may be useful for improving fruit consumption and glycemic control among those with diabetes . In this trial , type 2 diabetics ( n= 13 ) received WB ( 57 g , 160 cal , 1 g fiber ) , RC ( 55 g , 21 cal , 1 g fiber ) , SDC ( 40 g , 138 cal , 2.1 g fiber ) , and SDC containing less sugar ( SDC-LS , 40 g , 113 cal , 1.8 g fiber + 10 g polydextrose ) . Plasma glucose ( mmol/L ) peaked significantly at 60 min for WB , and at 30 min for RC , SDC , and SDC-LS at 9.6 ± 0.4 , 7.0 ± 0.4 , 9.6 ± 0.5 , and 8.7 ± 0.5 , respectively , WB remained significantly elevated from the other treatments at 120 min . Plasma insulin ( pmol/mL ) peaked at 60 min for WB and SDC and at 30 min for RC and SDC-LS at 157 ± 15 , 142 ± 27 , 61 ± 8 , and 97 ± 11 , respectively . Plasma insulin for SDC-LS was significantly lower at 60 min than either WB or SDC . Insulin area under the curve ( AUC ) values for RC and SDC-LS were both significantly lower than WB or SDC . Phenolic content of SDC and SDC-LS was determined following extraction with 80 % acetone prior to high-performance liquid chromatography ( HPLC ) and electronspray ionization-mass spectrometry ( ESI-MS ) and found to be rich in 5-caffeoylquinic cid , quercetin-3-galactoside , and quercetin-3-galactoside , and the proanthocyanidin dimer epicatechin . In conclusion , SDC-LS was associated with a favorable glycemic and insulinemic response in type 2 diabetics . Practical Application : This study compares phenolic content and glycemic responses among different cranberry products . The study seeks to exp and the palatable and portable healthy food choices for persons with type 2 diabetes . The novel use of polydextrose as a bulking agent making possible a reduction in caloric content and potential glycemic response is also characterized in this study Given the conflicting results about the positive effects of magnesium and l-carnitine and as there is no report concerning concurrent supplementation of magnesium and l-carnitine on migraine prophylaxis , the effects of magnesium , l-carnitine , and concurrent magnesium – l-carnitine supplementation on migraine indicators were assessed . In this clinical trial , 133 migrainous patients were r and omly assigned into three intervention groups : magnesium oxide ( 500 mg/day ) , l-carnitine ( 500 mg/day ) , and Mg – l-carnitine ( 500 mg/day magnesium and 500 mg/day l-carnitine ) , and a control group . After 12 weeks of supplementation , the checklist of migraine indicators including migraine attacks/month , migraine days/month , and headache severity was completed , and serum concentrations of magnesium and l-carnitine were measured by atomic absorption spectrophotometry and enzymatic UV test , respectively . The results showed a significant reduction in all migraine indicators in all studied groups ( p < 0.05 ) . The ANOVA results showed a significant reduction in migraine frequency across various supplemented and control groups ( p = 0.008 ) . By separating the effects of magnesium supplementation from other confounding factors such as routine treatments using the repeated measures and nested model , it was clarified that magnesium supplementation had a significant effect on all migraine indicators . Oral supplementation with magnesium oxide and l-carnitine and concurrent supplementation of Mg – l-carnitine besides routine treatments could be effective in migraine prophylaxis ; however , larger trials are needed to confirm these preliminary findings BACKGROUND There is conflicting evidence on the benefits of foods rich in vitamin E ( alpha-tocopherol ) , n-3 polyunsaturated fatty acids ( PUFA ) , and their pharmacological substitutes . We investigated the effects of these substances as supplements in patients who had myocardial infa rct ion . METHODS From October , 1993 , to September , 1995 , 11,324 patients surviving recent ( < or = 3 months ) myocardial infa rct ion were r and omly assigned supplements of n-3 PUFA ( 1 g daily , n=2836 ) , vitamin E ( 300 mg daily , n=2830 ) , both ( n=2830 ) , or none ( control , n=2828 ) for 3.5 years . The primary combined efficacy endpoint was death , non-fatal myocardial infa rct ion , and stroke . Intention-to-treat analyses were done according to a factorial design ( two-way ) and by treatment group ( four-way ) . FINDINGS Treatment with n-3 PUFA , but not vitamin E , significantly lowered the risk of the primary endpoint ( relative-risk decrease 10 % [ 95 % CI 1 - 18 ] by two-way analysis , 15 % [ 2 - 26 ] by four-way analysis ) . Benefit was attributable to a decrease in the risk of death ( 14 % [ 3 - 24 ] two-way , 20 % [ 6 - 33 ] four-way ) and cardiovascular death ( 17 % [ 3 - 29 ] two-way , 30 % [ 13 - 44 ] four-way ) . The effect of the combined treatment was similar to that for n-3 PUFA for the primary endpoint ( 14 % [ 1 - 26 ] ) and for fatal events ( 20 % [ 5 - 33 ] ) . INTERPRETATION Dietary supplementation with n-3 PUFA led to a clinical ly important and statistically significant benefit . Vitamin E had no benefit . Its effects on fatal cardiovascular events require further exploration Migraine is a common condition among adults and has become increasingly more recognised as a common condition among children and adolescents . When headaches are frequent or disabling , preventative treatments are indicated . Few studies have addressed the effectiveness of preventative treatments in children and adolescents in a controlled manner . Due to a concern of potential adverse risks , parents are often reluctant to start prophylactic medications and inquire about the use of alternative treatments including vitamin supplementation . Vitamins , in general , are viewed as more ‘ natural ’ and may be involved in the biological pathways underlying migraine . The use of nutraceutical treatment for migraine is a favourable option because they are essentially well tolerated with minimal side effects . Several nutraceuticals have been studied in the literature with some showing positive results in adult patients with migraine ( 1 ) ; however , studies in children and adolescents are scarce with none showing favourable outcomes . As children and adolescents are increasingly diagnosed with migraine , the need for prophylactic or preventative treatment is warranted . Therefore , it is important that headache clinicians and research ers treating paediatric migraine explore therapies that are safe , effective and affordable . Riboflavin , or vitamin B2 , is a co-factor used in mitochondrial function and has been shown to be effective in children with mitochondrial disorders with mild side effects ( 2 ) . In order to achieve this , high doses were required to overcome the mitochondrial impairment . In the pathogenesis of migraine , riboflavin is believed to be a major co-factor in oxidative metabolism as it acts as a precursor to flavin compounds involved in electron transport and generation of energy in the mitochondria ( 3,4 ) . Thus , in theory , low riboflavin levels may be associated with mitochondrial dysfunction linked to migraine . Several studies have shown efficacy and tolerability of riboflavin in migraine prevention in adults ( 5,6 ) ; however . MacLennan et al. ( 7 ) were the first to study the efficacy of high-dose riboflavin ( at least 200mg/day ) in  migraine prevention in children . The results did not show any difference in those who received treatment with riboflavin compared to placebo – although the placebo rate was high . A subsequent , open-label , retrospective study examining high-dose riboflavin in children and adolescents with migraine who failed pharmacological preventative therapy suggested that riboflavin may be effective in migraine , with a more favourable response in boys ( 8) . This sample population was notable for more individuals with severe migraine . A r and omised , placebocontrolled study of a combination of high-dose riboflavin , magnesium and feverfew using low-dose riboflavin ( 25 mg ) , found no difference between high-dose and low-dose riboflavin with equivalent responses ( 9 ) . The study by Bruijn et al. ( 10 ) presented the results of a r and omised , double-blind , placebo-controlled , crossover design ed trial that addressed the effectiveness of a medium dose of riboflavin ( 50mg/day ) in the prevention of  childhood migraine . Subjects were 6–13 years old that met ICHD II criteria for migraine with or without aura and a frequency of at least two headache attacks per month recruited from two hospitals . The study showed no difference in migraine frequency , severity or duration between riboflavin and placebo in each phase . However , there was a reduction in frequency of the tension-type headaches in these children . The reason for this ineffectiveness in contrast to the positive results in adults is likely multifactorial . First , the dose of riboflavin used may not be sufficient to alter mitochondrial metabolism or be clinical ly relevant . The pharmacokinetics of riboflavin suggested that the maximal amount of riboflavin the human body can absorb from a single dose is 27 mg with saturation of absorption reached at doses 30–50 mg decreasing the absorption at higher doses ( 11,12 ) . Furthermore , the half-life of riboflavin is between 1–2 h. This observation of limited absorption with a short half-life suggests that riboflavin therapy may require multiple daily dosing to attain a positive effect . This may explain why the Background Omega-3 polyunsaturated fatty acids ( PUFA ) have beneficial effects on both specific and non-specific inflammatory reactions . The aim of this study was to evaluate the effect of dietary supplementation with fish oil in migraine prevention . Methods A 12-week , r and omized , single-blind clinical trial was conducted from October 2008 to June 2009 . A total of 67 patients ( 52 women , 15 men ) with migraine headache were r and omly allocated to 2 groups . In the first group , 38 patients ( 30 females with a mean age of 35 ± 9 year ) received 400 mg/day sodium valproate . In the second group , 29 patients ( 22 females with a mean age of 36 ± 9 years ) received sodium valproate 400 mg daily plus fish oil supplementation ( 180 mg ) . Response to the treatment was assessed at 0 , 1 , 2 , and 3 months after start of the therapy . Results A significant decrease in duration , monthly frequency , and severity of headache after month 1 , 2 , and 3 in comparison with month 0 occurred in both groups . There was a significant reduction in headache severity ( P = 0.046 ) and frequency ( P = 0.044 ) in the group with fish oil supplementation after month 1 in comparison with sodium valproate alone . In contrast , there was no significant difference between two treatment groups in duration of the headache after month 1 . Mean intensity , mean duration and mean frequency of the attacks after month 2 and 3 were not significantly different between the two groups . Conclusion This study demonstrated that sodium valproate plus fish oil supplementation significantly reduces migraine headache more than sodium valproate alone but only at the beginning of the treatment Polyunsaturated fatty acids ( PUFA ) were administered to 168 patients over a period of 6 months in an open-label uncontrolled study . In 129 patient available for study , 86 % experienced reduction in severity , frequency and duration of migraine attacks , 22 % became free of migraine and more than 90 % had reduced nausea and vomiting . Self-medication changed to simple analgesics in the majority except in 14 % of patients without improvement 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 r and omized trial . Subjects with chronic headache were r and omized 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 Omega-3 polyunsaturated fatty acids ( OPFA ) have beneficial effects on inflammatory reactions and production of cytokines . They decrease the release of 5HT by platelets and possess vasorelaxant activity . This led them to be tried in the prophylactic treatment of migraine . After 4 weeks of a single-blind placebo run-in period , patients were r and omized and treated in double-blind condition by placebo or OPFA 6 g a day for 16 weeks , followed by a 4-week placebo run-out period . The intention to treat population included 196 patients . Those who received all four treatment periods included 96 patients taking OPFA  and 87 taking placebo . The primary efficacy analysis was the number of migraine attacks during the last 4 weeks of treatment . During this period , the mean number of attacks was 1.20 ± 1.40 in the OPFA group and 1.26 ± 1.11 in the placebo group ( NS ) . The total number of attacks during the 4-month period of the study was significantly different between groups : 7.05 in the placebo group , 5.95 in the OPFA group ( P = 0.036 ) . Mean intensity , mean duration of the attacks and rescue medication use , were not significantly different between the two groups . Except for a significant difference against OPFA for eructations , the tolerance was satisfying . Despite a run-in placebo period of 1 month , a very strong placebo effect was observed in this trial : 45 % reduction of the attacks between run-in and 4-month treatment period ( 55 % in the OPFA group , P = 0.058 ) . Finally , this large study did not confirm two previous studies based on a small number of patients Summary A dietary intervention increasing n‐3 and reducing n‐6 fatty acids reduced headache pain , altered antinociceptive lipid mediators , and improved quality of life in a chronic headache population . Abstract Omega‐3 and n‐6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties . We conducted a r and omized , single‐blinded , parallel‐group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n‐3 and n‐6 fatty acids for treatment of chronic headaches . After a 4‐week preintervention phase , ambulatory patients with chronic daily headache undergoing usual care were r and omized to 1 of 2 intensive , food‐based 12‐week dietary interventions : a high n‐3 plus low n‐6 ( H3‐L6 ) intervention , or a low n‐6 ( L6 ) intervention . Clinical outcomes included the Headache Impact Test ( HIT‐6 , primary clinical outcome ) , Headache Days per month , and Headache Hours per day . Biochemical outcomes included the erythrocyte n‐6 in highly unsaturated fatty acids ( HUFA ) score ( primary biochemical outcome ) and bioactive n‐3 and n‐6 derivatives . Fifty‐six of 67 patients completed the intervention . Both groups achieved targeted intakes of n‐3 and n‐6 fatty acids . In intention‐to‐treat analysis , the H3‐L6 intervention produced significantly greater improvement in the HIT‐6 score ( −7.5 vs −2.1 ; P < 0.001 ) and the number of Headache Days per month ( −8.8 vs −4.0 ; P = 0.02 ) , compared to the L6 group . The H3‐L6 intervention also produced significantly greater reductions in Headache Hours per day ( −4.6 vs −1.2 ; P = 0.01 ) and the n‐6 in HUFA score ( −21.0 vs −4.0 % ; P < 0.001 ) , and greater increases in antinociceptive n‐3 pathway markers 18‐hydroxy‐eicosapentaenoic acid ( + 118.4 vs + 61.1 % ; P < 0.001 ) and 17‐hydroxy‐docosahexaenoic acid ( + 170.2 vs + 27.2 ; P < 0.001 ) . A dietary intervention increasing n‐3 and reducing n‐6 fatty acids  reduced headache pain , altered antinociceptive lipid mediators , and improved quality ‐of‐life in this population In a prospect i ve study we compared propranolol , placebo , and self-hypnosis in the treatment of juvenile classic migraine . Children aged 6 to 12 years with classic migraine who had no previous specific treatment were r and omized into propranolol ( at 3 mg/kg/d ) or placebo groups for a 3-month period and then crossed over for 3 months . After this 6-month period , each child was taught self-hypnosis and used it for 3 months . Twenty-eight patients completed the entire study . The mean number of headaches per child for 3 months during the placebo period was 13.3 compared with 14.9 during the propranolol period and 5.8 during the self-hypnosis period . Statistical analysis showed a significant association between decrease in headache frequency and self-hypnosis training ( P = .045 ) . There was no significant change in subjective or objective measures of headache severity with either therapy PGE2 and TXA2 levels and their modulation by nicardipine , a calcium blocking agent , have been studied in patients suffering from migraine . The levels of both metabolites were determined in saliva obtained during the migraine attacks , during the intervals between attacks , and after 2 months of treatment with nicardipine ( 20 mg every 8 h. ) or placebo . The therapeutic response was evaluated on the basis of the number of migraine attacks . The results show a significant increase in the levels of both eicosanoids during the migraine attacks . In contrast to the placebo group , the number of migraine attacks and the levels of both arachidonic acid metabolites are markedly lower in the nicardipine  group . Our results suggest calcium entry into the cytosol as an explanation for the increase in PGE2 and TXA2 .  Nicardipine interferes with calcium mobilization , thereby inhibiting arachidonic acid metabolite synthesis PURPOSE To examine whether dietary supplementation with fish oil rich in very long-chain n-3 polyunsaturated fatty acids might reduce frequency and severity of migraines in adolescents . METHODS Twenty-seven adolescents suffering from frequent migraines for at least 1 year ( mean 4 + /- 1 years since migraine onset ) participated in a r and omized , double-blind , cross-over study consisting of 2 months of fish oil , 1-month washout period , and 2 months of placebo ( olive oil ) . Participants self-assessed severity and duration of headache episodes ( 7-point faces and 10-point visual analog pain scales , 5-point frequency and severity rating scale ) throughout the study . At the end of every 2-month treatment period , participants rated the effectiveness of treatment on a 7-point Likert scale ( 1,"not effective , not worthwhile " ; 4,"moderately effective , moderately worthwhile " ; 7 , " totally effective , totally worthwhile " ) . A score of > or = 4 on the Likert scale was considered as improvement . RESULTS Twenty-three adolescents ( 16 girls , 7 boys , 18 Whites , 3 Hispanics , 1 African-American , 1 Cape Verdean , mean age 15 + /- 1 years ) completed the study . Compared with frequency of headaches before the study ( 31 + /- 4 episodes/2 months ) , there was a significant ( p < .0001 ) reduction in headache frequency during fish oil treatment ( 4 + /- 1 episodes/2 months ) and during placebo ( olive oil ) treatment ( 4 + /- 1 episodes/2 months ) but no significant ( NS ) difference between treatments . Likewise , self- assessment on a 7-point faces pain scale revealed a significant reduction in headache severity during fish oil treatment ( 2.9 + /- 0.5 , p = .01 ) and during placebo ( olive oil ) treatment ( 3.5 + /- 0.4 , < p = .03 ) , compared with headache severity before study ( 5.0 + /- 0.3 ) and no significant difference between treatments . Patients ' ratings of treatments revealed that 87 % experienced reduction in headache frequency , 74 % experienced reduction in headache duration , and 83 % experienced reduction in headache severity during treatment with fish oil , compared with 78 % who experienced reduction in headache frequency , 70 % who experienced reduction in headache duration , and 65 % who experienced reduction in headache severity during treatment with placebo ( olive oil , NS ) . About 91 % stated that they would recommend fish oil to friends or relatives with headaches vs. 91 % who would recommend placebo ( olive oil , NS ) . CONCLUSIONS Patients experienced a similar reduction in frequency , duration , and severity of headaches during treatment with fish oil and during treatment with olive oil . Although there was no significant difference between treatments , the marked improvement from baseline experienced by the patients suggests that the effect should not be dismissed as simply a placebo effect . In fact , results of this preliminary study suggest that both fish oil and olive oil may be beneficial in the treatment of recurrent migraines in adolescents . Further studies are warranted to compare each of these treatments with other interventions BACKGROUND N-3 polyunsaturated fatty acids ( PUFAs ) from oily fish protect against death from cardiovascular disease . We aim ed to assess the hypothesis that incorporation of n-3 and n-6 PUFAs into advanced atherosclerotic plaques increases and decreases plaque stability , respectively . METHODS We did a r and omised controlled trial of patients awaiting carotid endarterectomy . We r and omly allocated patients control , sunflower oil ( n-6 ) , or fish-oil ( n-3 ) capsules until surgery . Primary outcome was plaque morphology indicative of stability or instability , and outcome measures were concentrations of EPA , DHA , and linoleic acid in carotid plaques ; plaque morphology ; and presence of macrophages in plaques . Analysis was per protocol . FINDINGS 188 patients were enrolled and r and omised ; 18 withdrew and eight were excluded . Duration of oil treatment was 7 - 189 days ( median 42 ) and did not differ between groups . The proportions of EPA and DHA were higher in carotid plaque fractions in patients receiving fish oil compared with those receiving control ( absolute difference 0.5 [ 95 % CI 0.3 - 0.7 ] , 0.4 [ 0.1 - 0.6 ] , and 0.2 [ 0.1 - 0.4 ] g/100 g total fatty acids for EPA ; and 0.3 [ 0.0 - 0.8 ] , 0.4 [ 0.1 - 0.7 ] , and 0.3 [ 0.1 - 0.6 ] g/100 g total fatty acids for DHA ; in plaque phospholipids , cholesteryl esters , and triacylglycerols , respectively ) . Sunflower oil had little effect on the fatty acid composition of lipid fractions . Fewer plaques from patients being treated with fish oil had thin fibrous caps and signs of inflammation and more plaques had thick fibrous caps and no signs of inflammation , compared with plaques in patients in the control and sunflower oil groups ( odds ratio 0.52 [ 95 % CI 0.24 - 0.89 ] and 1.19 [ 1.02 - 1.57 ] vs control ; 0.49 [ 0.23 - 0.90 ] and 1.16 [ 1.01 - 1.53 ] vs sunflower oil ) . The number of macrophages in plaques from patients receiving fish oil was lower than in the other two groups . Carotid plaque morphology and infiltration by macrophages did not differ between control and sunflower oil groups . INTERPRETATION Atherosclerotic plaques readily incorporate n-3 PUFAs from fish-oil supplementation , inducing changes that can enhance stability of atherosclerotic plaques . By contrast , increased consumption of n-6 PUFAs does not affect carotid plaque fatty-acid composition or stability over the time course studied here . Stability of plaques could explain reductions in non-fatal and fatal cardiovascular events associated with increased n-3 PUFA intake OBJECTIVES To determine if the effectiveness of propranolol hydrochloride and amitriptyline hydrochloride are correlated with blood levels and /or with st and ardized test of pharmacologic effect and to determine which clinical variables are predictors of response to one or the other medication . DESIGN Three-month modules of treatment with each drug and placebo in a r and omized crossover design . Headache scores from daily diaries were calculated at monthly intervals , as were simultaneous blood levels of drug , supine and st and ing blood pressure , pulse rise with exercise , and salivary flow . SETTING Outpatient headache clinic at the University of Kansas Medical Center , Kansas City . PATIENTS Thirty consecutive patients with a history of frequent migraine . MAIN OUTCOME MEASUREMENTS From headache scores , patients were classified as either propranolol responders , amitriptyline responders , or nonspecific responders . Clinical variables as predictors of response to medications were studied , as were effects on frequency , duration , and /or severity of headache . RESULTS AND CONCLUSIONS No significant correlations were found between changes in headache score and blood level of drug or change in any of the physiologic measurements .  Amitriptyline significantly reduced the severity , frequency , and duration of headache attacks ;  propranolol reduced the severity of attacks only . Amitriptyline response was correlated with female gender and baseline headaches of shortest duration and of highest frequency . Propranolol response was associated with attacks of greatest duration at baseline and with low pulse rise with exercise at baseline . Nonspecific response was associated with male gender and most frequent headaches by history Eight healthy male volunteers supplemented their normal diet with 10 - 15 g/d of a fish oil supplement ( MaxEPA ) to provide 1.4 - 4.2 g/d of eicosapentaenoic acid ( EPA ; C20:5 n-3 ) for a period of 12 weeks . Blood sample s were taken at weeks 0 , 2 and 12 and the fatty acid compositions of the phospholipids of plasma , platelets , neutrophils , monocytes and T- and B-lymphocytes were determined . In all instances the level of EPA increased significantly ( P < 0.05 ) by 2 weeks and remained so without a further increase for the ensuing 10 weeks . Beyond that , few consistent patterns in fatty acid composition were observed . Arachidonic acid ( C20:4 n-6 ) fell significantly ( P < 0.05 ) in plasma , platelets , neutrophils and T- and B-lymphocytes , but generally tended to do so only by week 12 . Given the wide variability in the half-life of these cells ( minutes for neutrophils , months for lymphocytes ) it is evident that uptake of plasma EPA occurs by phospholipid exchange into preformed mature cells and does not require incorporation during cell genesis Abstract Omega-3 and omega-6 fatty acids are precursors of bioactive lipid mediators posited to modulate both physical pain and psychological distress . In a r and omized trial of 67 subjects with severe headaches , we recently demonstrated that targeted dietary manipulation — increasing omega-3 fatty acids with concurrent reduction in omega-6 linoleic acid ( the H3-L6 intervention)—produced major reductions in headache compared with an omega-6 lowering ( L6 ) intervention . Because chronic pain is often accompanied by psychological distress and impaired health-related quality of life ( HRQOL ) , we used data from this trial to examine whether the H3-L6 intervention favorably impacted these domains . Additionally , we examined the effect of the interventions on the number of cases with substantial physical or mental impairments as defined by cutoff values in the Brief Symptom Inventory ( BSI-18 ) , Medical Outcomes Study Short Forms 12 ( SF-12 ) , Headache Impact Test ( HIT-6 ) , and the number of headache days per month . In the intention-to-treat analysis , participants in the H3-L6 group experienced statistically significant reductions in psychological distress ( BSI-18 mean difference : −6.56 ; 95 % confidence interval [ CI ] : −11.43 to −1.69 ) and improvements in SF-12 mental ( mean difference : 6.01 ; 95 % CI : 0.57 to 11.45 ) and physical ( mean difference : 6.65 ; 95 % CI : 2.14 to 11.16 ) health summary scores . At 12 weeks , the proportion of subjects experiencing substantial impairment according to cutoff values in the BSI-18 , SF-12 physical , HIT-6 , and headache days per month was significantly lower in the H3-L6 group . Dietary manipulation of n-3 and n-6 fatty acids , previously shown to produce major improvements in headache , was found to also reduce psychological distress and improve HRQOL and function
The present systematic review with meta- analysis of r and omized controlled trials ( RCTs ) aim ed to analyze the effectiveness of omega-3 fatty acids on the  frequency , severity , and duration of migraine .