Translation from German to English (Publication "Der Freie Arzt" Sept. 1993)
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Migraine Prevention

Omega-3 and Omega-6 Fatty Acids and their co-enzymes as an alternative to established therapies.
Prof. Dr. W. Wagner, Nootbaar-Wagner, U Prof. Dr. M. Hamm, Prof. Dr. Dr. M. Brandl.

The causes of migraine have never been conclusively explained. There area only hypothetical approaches. The pathogenic mechanism in the first diagram shows that the headache symptomatic for migraine is caused by a multitude of mechanisms, in particular an extra cranial vaso-dilation together with a lowered pain threshold. The key substance is serotonin, 95% of which is stored in the thrombocytes. It is released at the onset of a migraine episode. This release is favored by an increase of the arachidonic acid and pro staglandin as well as increased amounts of tyramine etc. Free fatty acids also activate the aggregation of thrombocytes.

Reduced levels of prostacycline and increased levels of thrombaxane influence the balance between vaso-dilation and vaso-constriction and may contribute to an increased release of serotonine. Another probability for this to happen is a primary thrombocytic dysfunction (9, pp. 84-91). 5-hydroxy-tryptophane (5-HT) from XX and prostaglandin E2 cause a direct extracranial vaso-dilation with prostaglandin E2 reducing the pain threshold at the noziceptor even more, thereby increasing the pain triggered by vaso-dilation. The serotonine level increased by high amounts of thrombocytes starts to cause an intra cerebral vaso-constriction which in turn may produce an aura and then causes an increase of free fatty acid which in turns raises the level of serotonine. Moreover, this higher level causes an increased sensitivity to pain. However, serotonine is quickly metabolized and eliminated and the level diminishes. This mechanism is responsible for extra cranial vaso diliation. The serotonine metabolism causes the tryptophane level to increase which may trigger the reflex to vomit together with the notorious nausea.

Established migraine therapy is essentially an attenuation of the attack using mainly ergotamine, di-hydro-ergotamine in a combination with non-steroid anti-phlogistic analgesic (NSAA) or high doses of NSAA like aspirin or low-potency opiates. The risk with all registered drugs so far has been the danger of dependence with a consecutive chronic migraine or chronic headache. Another therapy for the attenuation of attacks is a treatment with a serotonine agonist called surnatryptane. The first diagram gives evidence to the fact that at present there exists no efficient preventative therapy low effects are outweighed by considerable side effects (9, pp. 100-117 10, pp. 85-99).

Migraine prevention - an alternative to established therapy:
Wolfgang Wagner M.D. and wife Ursula.

Taking into consideration the present migraine theories and the ranking of serotonine and prostaglandin, the question arises whether there exists a combination of active ingredients that will influence the levels of prostaglandin and arachidonic acid as well as of serotonine including precursor phases and metabolites. It should not have any of the above-mentioned side effects and yet be efficient in preventing migraine attacks.

Working hypothesis

The combination of active ingredients in the migraine relief balm consisting of evening primrose, wheatgerm oil, linseed oil (Omega-3 and Omega-6 fatty acids), soybean phosphatides, magnesium, vitamin E, and vitamin C, increases the absorption of alpha and Gamma linoleic acid and thereby influences the eicosanoid metabolism. This in turn may lower the level of prostaglandin E2 and at the same time raise that of prostacycline. If this hypothesis is correct in principle, a reduced release of serotonine together with a lower level of prostaglandin E2 would stabilize the pain threshold at the noziceptor and preclude any hypersensitivity. This mechanism then would represent an efficient preventative migraine therapy.

Material and methods

We researched the preventative effectiveness of the N2 Migraine Nutrition supplements in an open, prospective study with 33 patients who had been suffering from migraine for at least 3 years. The tests were asked to provide a thorough medical history and were instructed how to use a visual analogous scale (VAS) (6). They were then told to take 2 x 2 capsules of the supplements per day. Female tests were allowed to increase the dosage during menstruation. If medication with the supplements was not giving satisfactory results, the patients received an additional 2 x 50 mg acetylsalicylic acid (low dose ASS) per day. Patients were told to keep their mode of attenuation (MOA). In the case of reduced intensity and duration of attacks they could switch to only NSAA or also reduce the dose of the supplements.

Statistical tools

Verification of statistical significance or frequency of attacks and change of VAS was conducted using the Wilcoxon test for tied and paired random tests. The same procedure was used for the change in MOA (ref. to annex, chart of statistical procedures).

Results

Distribution by age and sex, migraine history

The study included 33 patients (30 female, 3 male). 30 suffered from classical migraine, 3 from simple migraines. The youngest patient was 23 years old, the oldest 69. The largest age segment (n= 20 = 60%) was between 30 to 50 years. The medical histories revealed that 29 patients (88%) had had attacks for at least 10 years. One patient had a history of 50 years. The average history was of 22 years.

Time of improvement

First signs of improvement (criteria were reduced severity of attacks and/or no attack at certain critical moments) were reported by 19 patients after 1 to 2 months. Two patients (6%) reported improvements after 2 to 3 months, 7 patients (21%) after 3 to 4 months. Five patients did not notice any significant changes within 5 to 6 months. (ref to graph 2)

Reduction of frequency

At the start of the treatment all patients had a severity rating of 65% = 100% with a frequency varying between 2 attacks/week (app 70/year) and 4/year. The majority had 10 to 30 attacks/year (n = 24 = 73%), three patients had fewer than 10 attacks per year

(9%), and six patients had more than 30/year (18%) At the end of the trial period of six months the patients were asked to make a statement whether they felt clearly that the frequency of attacks had noticeably decreased (ref. to graph 3) Moreover we evaluated the patients'' pain records. They corroborated the statements. Twenty seven patients (82%) had noted a reduction of frequency of more than 50% , four patients (12%) still noted a reduction of 10 to 50%. These results are significant.

For 2 patients (6%) there was no reduction, i.e. a reduction of less than 10%. Two patients who obtained a reduction of frequency of more than 50% compared to before the start of the treatment also took regular 2 x 50 mg low dose ASS in addition to the supplements (ref to graph 4). In total 4 patients among the 33 tests took an additional ASS dose regularly.

Reduction of severity

Twenty-four out of 33 patients (73%) attested to a VAS reduction by at least 30% due to the use of the supplements alone. On average the reduction was 45 VAS % points wth a range of 0 - 80% points. With 3 patients (9%) this result could only be obtained by a combination of the supplements and low dose ASS (ref. to graph no 5) For these patients the reduction was of 35% points. One patient, using only the supplements, reported a VAS reduction of only 25%, and 5 patients (15%) including one test who also took low dose

ASS obtained a reduction of an average of 13% points. Although the total results were significant on the 0.01% we considered these partial results as nil, since the reduction was not subjectively satisfactory for the patients.

Improvement of condition

Parallel to improvement of the evaluation of VAS, the patients were asked about their subjective appreciation of any changes with regard to their migraine (ref. to graph 7). Out of 33 patients 28 (85%) reported an improvement with the supplements alone, another three (9%) obtained this result only with additional low dose ASS (2 x 50 mg/day). Two patients reported no improvement at all, although one patient received additional low dose ASS (2 x 50 mg/day).

Change in MOA after six months of the nutritional supplement treatment. The MOA of patients changed as follows (ref. to graph 8). Three patients had not taken medication prior to treatment with the supplements, two did not take any medication after the end of the treatment. Thirteen patients had taken combination treatment (NSAA + ergotamine) prior to the therapy. The number of these patients decreased to six patients at the end of the therapy. Nine patients had used acetylsalicylic acid for attenuation of attacks prior to the nutritional therapy, with a dose of 1 to 3 mg per attack for six of them. After six months of treatment with the supplements, 23 patients attenuated exclusively with ASS, with a dose between 500 to max. 1,000 mg. No patient took in excess of 1,000 mg. Another attenuation approach was a combination of NSAA + spasmolytics or low potency opiates such as codeine. Prior to the therapy eight patients used these drugs, after six months of therapy only two did so. All results (excepting "no medication") are significant on the 0.01% level.

Daily dose

The dose sufficient for 1 day varied with each patient. (ref. to graph 9) Thirteen patients (39%) took 2 capsules/day, another six (18%) took three capsules/day. For 13 patients (39%) four capsules were the correct dose, whereas one patient had to take six capsules of the supplements per day.

Side Effects

None of the 33 patients reported any side effects. Some patients had the impression their appetite had increased. However there was no certainty as to the causal link with the supplements.

Experience with other preventative drug therapies

While establishing a medical history, we also inquired about the efficiency of other preventative drugs and methods such as beta blockers or calcium single current blockers or other therapies like acupuncture or massage. Seventy-five % of the patients had had experience with such drugs and procedures. On the average, they had applied them for six months, but had discontinued due to lack of results or considerable side effects. They were not ready to submit to any of these therapies again.

Discussion

The central point where the migraine headache is triggered is the noziceptor and pain afference in the brain''s vascular wall (2). According to Soyka, there is a special mechanism typical for migraine patients which, in certain circumstances, releases high amounts of 5-hydroxy-trypatamine (5-HT) and subsequently deploys partly central, partly peripheral effects at these pain threshold of migraine patients with the spasm threshold of epileptics. With epileptic patients a seizure occurs when the spasm threshold is lowered. The situation with migraine patients could be similar. However, there exists as yet no clinical evidence (10 p.93) A desirable effect would therefore be to either block the noziceptor by direct receptor blockers (yet to be developed) or to raise or at least stabilize the pain threshold.

Another therapeutic success would be to prevent or at least to reduce an increase of the prostaglandin level. These were the considerations that led to a combination of active ingredients that would influence the eicosandoid metabolism. In this context, Berg researched the amounts of free fatty acids in food and came to the conclusion that mainstream nutrition with its high intake of animal products causes an above-normal level of arachidonic acids. (3) This may lead to an increased production o prostaglandin E2 which in turn had the above mentioned effects on the brain''s vascular wall.
Arachidonic acid, moreover, is metabolized into thromboxane (TXA), considered as initiator of thrombocyte aggregation ad intracerebral vascular constrictor. If one were capable to decrease arachidonic acid, PGE2 and TXA2 and to increase prostaglandin E2 and PGE, some essential factors for the release of 5-HT would be eliminated.

For this it is necessary to reduce the intake of animal fats and at the same time to block the synthesis of cyclo-oxigenase inhibitors, e.g. ASS. This would result in an efficient preventative migraine treatment.

According to Berg a diet with alpha- and Gamma linoleic acid causes a reduction of the effects of arachidonic acid, i.e. an increase in PGE2 and PGI production together with a substantial decrease in TXA2 and PGE2 results in a positive effect with women suffering from PMS. (3)2Supportive factors are vital, however, increasing the effect of the free fatty acids (FFS). Vitamin B6 for example is a co-enzyme in the metabolism of poly-unsaturated FSS and of the amino-acid tryptophane, a predecessor of serotonine (1) Niacin, together with some polyene acids, has an anti-aggregative effect. Our findings support the above-mentioned hypothesis. Of particular interest were two cases out of four, where the supplements was not effective. However, a combination of the supplements and low dose ASS produced the desired results. This could be attributable to a decreased aggregation tendency, produced by low dose ASS together with a change in diet.

The high preventative success rate (73% reduced VAS, 82% reduced attack frequency, 85% improved condition, significant MOA changes) without supplementary low dose ASS may be explained by the fact that the increased dietary intake of omega fatty acids was sufficient by itself. Berg noted in this context (4) that in comparison with the endogenous synthesis of arachidonic acid the amount from food intake was significantly higher. If the absorption of alpha-linoleic and gamma-linoleic acid is insufficient, there seems to occur a higher production of arachidonic acid together with a tendency towards a subsequent production of PGE2.

Another hypothesis for the therapeutic mechanism of the supplements was established by Adam (ref to graph 10) as early as 1985 (1). He showed that alpha-linoleic acid is capable to inhibit the synthesis of linoleic acid to arachidonic acid. An explanation for some patients to have results with low doses (13 patients took 2 capsules/day) while others had to take 4 to 6 capsules/day in order to obtain a satisfactory preventative result could be that these patients had different basic levels of alpha and Gamma linoleic acid, caused by differences in the patients'' nutrition.

Another interesting change occurred in the MOA of the patients. Whereas at the beginning of the treatment additional combination drugs such as ergotamine, ergotamine + NSAA, NSAA + spamolytics or codeine and very high doses of NSAA were necessary in order to obtain even a partially satisfactory result. Significant change towards low single doses of max 1 g ASS occurred after six months of treatment . The reason for this sudden decrease of ASS doses and ergotamine lies in the fact that during the therapy the substrate level was raised with the result that an additional cyclo-oxygenase inhibition with low single doses was sufficient to raise the pain threshold at the noziceptor during an attack.

We would like to make a statement why this study was not conducted as a double blind study: The patients who participated in the study had suffered from migraine for an average of 22 years, varying from 3 to 50 years. Seventy-six % of the patients had experience with classical preventative therapies. They approached us for help in their hopeless condition. Although we did not know in the beginning whether the results from two random case observations could be applicable to a larger population, we renounced to conduct a double blind study for ethical reasons.

Placebo effect

It is common knowledge that in any given pain treatment there is a placebo effect in the order of 20 VAS points (5). This effect decreases however after three months at the most, i.e. patients will have reappearing pains after an apparently successful acupuncture treatment. Therefore any study should last a minimum of six months. None of the patients showed an immediate effect which would have been indicative of a placebo effect: the first results came only after one to two months, in some cases after three to four months. All patients were to be examined at the end of a 1 year treatment and the results were to be evaluated.

Conclusion

We researched in an open prospective study the preventative effects of the dietary nutrient compound the supplements. In 85% of cases a significant improvement was obtained within a period of six months. Omega-3 and Omega-6 fatty acids, together with their co-enzymes of fat metabolism, are therefore an efficient preventative measure, not producing any of the common side effects, and should be considered first choice.

Dr. Michael Hamm, nutrition scientist, Hamburg (Germany)

Our present eating habits with their biased selection, predominant high calorie intake with low contents in essential nutrients and high alcohol consumption combine with a high decree of processed foods and soil depletion to create a food supply that is not devoid of deficiencies. Another aspect has to be taken into account as well: with the decreased calorie intake e.g. during slimness diets or due to biased ideals of slimness or reduced calorie intake later in life (the latter is actually quite desirable) one encounters increasing difficulties to have a balanced nutrition. This makes it clear that food supplements become important in many cases insuring the provision with vital nutrients and preventative substances such as anti-oxidants. Equally important for our modern diet are poly-unsaturated fatty acids which participate in various ways in metabolic processes, e.g. as precursors of prostaglandin. A useful nutrient supplementation should always be considered as a long term program: the intake should correspond to daily recommended doses and should exclude any over-dosage. Only a regular intake of nutrients will lead to the desired results, in particular the water-soluble and fat-soluble anti-oxidants vitamin C and E, provitamin A (= beta-carotene) and all poly-unsaturated essential fatty acids. The sophisticated balance of dietary nutrients in the supplements produce multiple benefits on a long term basis, protecting and regulating the cellular and vascular metabolism, skin and immune system. Regular intake of the supplements benefits in particular women, people with high stress exposure and consumers of recreational foods and drinks, high performance athletes, senior citizens, and patients for whom a dietary plan has been laid out for Neurodermitis and herpes.