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We evaluated whether type of response to the migraine-induction test with a nitroglycerin ointment applied to the frontotemporal head region could predict the efficacy of antimigraine therapy. Forty-two patients with migraine without aura underwent the test before and 2 months after antimigraine therapy. Two and 4 months after treatment withdrawal, most subjects with a negative response to the post-treatment test maintained treatment benefit, whereas benefit was lost in patients with an early onset migraine response.

We have compared the migraine-inducing effect of nitroglycerin ointment applied to the frontotemporal region of the head, which is innervated by the ophthalmic and maxillary divisions of the trigeminal nerve, with that of nitroglycerin applied to the chin (innervated by the mandibular division), the posterolateral region of the neck (innervated by the second and third cervical roots), the lateral surface of the proximal third of the forearm (innervated by the sixth cervical root), and the medial surface of the upper-arm region (second dorsal root). One hundred patients suffering from migraine without aura were randomly divided into five equal groups. Each group received an application of 5 mg nitroglycerin in 2% ointment on a preselected body area for 2 hours. Frontotemporal nitroglycerin induced a significantly greater number of early onset migraine attacks with respect to the arm and forearm regions. In all cases, nitroglycerin applied to the frontotemporal region resulted in subsequent migraine, whereas there was a significant number of negative trials with nitroglycerin applied to the neck, arm, and forearm vs the frontotemporal area. It, therefore, appears that the trigeminal nerve endings in the affected frontotemporal region are particularly sensitive to the migraine-inducing effect of the nitrate. This suggests a peripheral neurogenic hypothesis of migraine genesis.

The hypothesis that alpha-adrenergic receptor blockade accounts for the ability of ergotamine to stop migraine attacks was tested, in migraine patients, in an experimental migraine model based on nitroderivative- induced attacks. In a preliminary single blind, placebo controlled study, thymoxamine, a prevalently post-synaptic alpha adrenergic receptor antagonist, was able to abort migraine attack in 9 out of 10 patients, as opposed to 2 out of 10 by placebo (p < 0.005 Fisher's exact test). In a subsequent randomized, crossover, placebo controlled double blind study, the ability of a selective alpha-1 adrenergic receptor agonist, methoxamine, to block ergotamine antimigraine effect was studied. In 26 patients migraine was induced in two separate tests and then ergotamine was administered once after methoxamine pretreatment and once after placebo; methoxamine was significantly more effective than placebo in blocking antimigraine effect of ergotamine (p = 0.0055 Fisher's exact test). These results support the hypothesis that ergotamine alpha-1 adrenolytic properties may account for its antimigraine effect suggesting that this action takes place outside the blood-brain barrier, since methoxamine can cross it very poorly. Ergotamine target structure could be the trigeminal innervation of the extracranial and/or dural vessels.

Different classes of drugs are used in the pharmacological treatment of headache, both during migraine crisis and migraine prophylaxis. How these drugs exert their therapeutical effect in migraine is not clearly understood. Hypothetical mechanisms of action are discussed by the Authors in regard to the different pathogenetical events relevant to migraine. It is proposed that different pathological events can be modified by one drug and, conversely, one mechanism of action may be common to different drugs.

The responses to work-test in ischemia (tourniquet technique), before and after I.V. injection of naloxone (2 mg) or saline, were investigated in healthy volunteers and patients suffering from various types of headache. The patients were examined during both painful and painless periods. We found that only the subjects suffering from migraine showed a significantly shortened pain tolerance at work-test in ischemia, after injection of naloxone, and only during painful periods. Psychogenic headache patients and migraine patients in painless periods showed responses during work-test similar to those in healthy volunteers, even after injection of naloxone. We believe that hyperalgesic effect of naloxone is due to involvement of beta-endorphin systems only during organic pain.

Twenty common migraine patients received a one sided frontotemporal application of nitroglycerin (10 patients) or placebo ointment (10 patients) in a double blind study. Early onset migraine attacks were induced by nitroglycerin in seven out of 10 patients versus no patient in the placebo group. Subsequently 20 migraine patients, who developed an early onset attack with frontotemporal nitroglycerin, received the drug in a second induction test at other body areas. No early onset migraine was observed. Thus the migraine-inducing effect of nitroglycerin seems to depend on direct stimulation of the habitual site of pain, suggesting that the frontotemporal region is of crucial importance in the development of a migraine crisis. This is not consistent with a CNS origin of migraine attack.