Lessons from triptans in migraine treatment

Research for a new antimigraine compound started at Glaxo in 1972 and led to the discovery of the first triptan drug, sumatriptan, a 5-HT1-like receptor agonist with an indolic structure identical to neurotransmitter 5-HT. On November 14th, 1991, SISC organised in some Italian Headache Centres the “Migraine Day”, officially starting the sumatriptan “revolution”, followed by the “age of triptans”. The availability of sumatriptan, a specific analgesic for migraine pain, had opened new prospects of migraine treatment, which up to then had only used non-specific analgesics, such as FANS, paracetamol, and ergotamine, an agonist drug of various receptors, with important side effects and contraindications. Research was immediately directed towards the synthesis of triptans with better pharmacokinetic and pharmacodynamic characteristics and less side effects. Six triptans were synthesized, 5 of which had the same indolic structure as sumatriptan and were therefore defined as “me-too”, while one had a carbazolic structure. Like all revolutions, the triptans’ was a complete one. The congresses, courses, and conferences were practically all about the research of the triptan with the highest therapeutic index. However, the physiopathology of migraine pain implies, besides 5-HT, noradrenaline, the formation of NO, GABA, enkephalins, and the release of neurotransmitters (SP and CGRP) and neuropeptides. The proof that an agonist of receptor CGRP is effective in migraine pain treatment when taken by mouth opens new prospects. If there are available different types of antimigraine drugs and their associations, subtypes of patients shall be identified, according to the different treatments or associations they need. The methodological elements which can be deduced from research on the clinical efficacy of triptans, opening new prospects of research about the physiopathology and clinical aspects of migraine, are the following: 1°) detecting premonitory symptoms that may increase the awareness of migraine; 2°) detecting the onset time of migraine aura and its signs and symptoms; 3°) deciding when the drug must be administered in clinical trials; 4°) detecting pain intensity (light, moderate, or severe) and the possible autonomic symptoms when administering the drug and afterwards, after established periods of time, and assessing the following primary end points: - pain relief and pain free after 30 and 60 minutes - pain free after 2 hours (not pain relief) - sustained pain free after 24 hours - sustained pain free and no side effects after 24 hours and the following secondary end points: - presence and intensity of possible other symptoms (osmophobia, phonophobia, photophobia, nausea, vomiting) - recurrence after 24 hours - disability time per treated attack - consistency across multiple attacks. The criteria of inclusion of migraine patients in clinical trials must consider the severity of migraine, assessing the progress and characteristics of the last 5-10 attacks, in order to divide into groups the subjects included in the studies. The efficacy of a drug is different in episodic migraine patients with attacks lasting 3-4 hours and in patients with attacks lasting 4-8 hours or previously treated with drugs causing pain relief for a few hours, with the reappearance of pain, for example, after 4-6 hours. Patients’ selection contributes to the disparity between clinical trials and clinical practice; it is fundamental that patients in clinical trials are as similar as possible to the patients who are then going to take the drugs in clinical practice. Drugs should be used as research tools and clinical records should be created on these bases, in order to know more about the mechanism of pain generation subsequent to the activation of the trigeminal vascular system and about the role played by vasodilatation and plasma protein extravasation.