Drugs targeting 5-hydroxytryptamine receptors in acute treatments of migraine attacks. A review of new drugs and new administration forms of established drugs.

INTRODUCTION: The development of sumatriptan, more than 20 years ago, added substantially to the characterization of 5-hydroxytryptamine (5-HT) receptors and their relevance to acute migraine therapy. Recently, 5-HT1F receptor agonists, with no vascular effects, have shown efficacy in the treatment of migraines. AREAS COVERED: This evaluation reviews the recent advances in acute migraine therapy targeting the 5-HT receptor. Specifically, the authors review the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of 5-HT1F receptor agonists and new formulations of sumatriptan and dihydroergotamine (DHE). EXPERT OPINION: Lasmiditan, a non-vascular acting 5-HT1F receptor agonist, is effective in migraine but causes central nervous system-related adverse events, which may considerably limit its clinical use. The efficacy of transdermal sumatriptan is too low for general use in migraine. Intranasal sumatriptan powder could be a step forward compared with oral sumatriptan, but comparative trials are needed. Orally inhaled DHE has a very quick systemic absorption but the onset of effect in migraine is relatively slow with a maximum effect after 2 h. In contrast, orally inhaled DHE results in a low incidence of recurrence. None of these reviewed treatments are likely to fulfill patients' expectations, and the advancement of acute migraine drugs should likely depend on different mechanisms from current 5-HT-related drugs.

Relatively slow and long-lasting antimigraine effect of dihydroergotamine is most likely due to basic pharmacological attributes of the drug: a review.

INTRODUCTION: If a drug has a slow dissociation from the receptor this can result in a long duration of effect and a slow effect. The long duration of the antimigraine effect of dihydroergotamine (DHE) has been reported previously whereas a possible slow onset of DHE's antimigraine effect, which is the subject of this review, has only rarely been mentioned. METHODS: Eight randomised, controlled trials (RCT) with DHE for acute treatment with migraine were selected from the literature. The speed of the effect of DHE in migraine was evaluated by plotting the effect up to four hours against time. FINDINGS: Subcutaneous DHE 1 mg was inferior to subcutaneous sumatriptan 6 mg for headache relief for the first two hours but equally effective after three hours. After intranasal DHE 2 mg the mean therapeutic gain increased slowly up to four hours. For orally inhaled DHE 0.5 mg there was a considerable time lag between therapeutic gain (maximum after two hours) and plasma concentrations of DHE (Tmax = 12 min). CONCLUSION: DHE has a slow dissociation from the receptor; and this basic attribute of the drug is the most likely cause of the general relatively slow anti-migraine effect of DHE.

Management of cluster headache.

The prevalence of cluster headache is 0.1% and cluster headache is often not diagnosed or misdiagnosed as migraine or sinusitis. In cluster headache there is often a considerable diagnostic delay - an average of 7 years in a population-based survey. Cluster headache is characterized by very severe or severe orbital or periorbital pain with a duration of 15-180 minutes. The cluster headache attacks are accompanied by characteristic associated unilateral symptoms such as tearing, nasal congestion and/or rhinorrhoea, eyelid oedema, miosis and/or ptosis. In addition, there is a sense of restlessness and agitation. Patients may have up to eight attacks per day. Episodic cluster headache (ECH) occurs in clusters of weeks to months duration, whereas chronic cluster headache (CCH) attacks occur for more than 1 year without remissions. Management of cluster headache is divided into acute attack treatment and prophylactic treatment. In ECH and CCH the attacks can be treated with oxygen (12 L/min) or subcutaneous sumatriptan 6 mg. For both oxygen and sumatriptan there are two randomized, placebo-controlled trials demonstrating efficacy. In both ECH and CCH, verapamil is the prophylactic drug of choice. Verapamil 360 mg/day was found to be superior to placebo in one clinical trial. In clinical practice, daily doses of 480-720 mg are mostly used. Thus, the dose of verapamil used in cluster headache treatment may be double the dose used in cardiology, and with the higher doses the PR interval should be checked with an ECG. At the start of a cluster, transitional preventive treatment such as corticosteroids or greater occipital nerve blockade can be given. In CCH and in long-standing clusters of ECH, lithium, methysergide, topiramate, valproic acid and ergotamine tartrate can be used as add-on prophylactic treatment. In drug-resistant CCH, neuromodulation with either occipital nerve stimulation or deep brain stimulation of the hypothalamus is an alternative treatment strategy. For most cluster headache patients there are fairly good treatment options both for acute attacks and for prophylaxis. The big problem is the diagnosis of cluster headache as demonstrated by the diagnostic delay of 7 years. However, the relatively short-lasting attack of pain in one eye with typical associated symptoms should lead the family doctor to suspect cluster headache resulting in a referral to a neurologist or a headache centre with experience in the treatment of cluster headache.

The 5-HT1F receptor agonist lasmiditan as a potential treatment of migraine attacks: a review of two placebo-controlled phase II trials.

Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo-controlled RCT, lasmiditan doses of 2.5-45 mg were used, and there was a linear association between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan 20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used. For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs) emerging from the treatment were reported by 22 % of the patients receiving placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and 400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were moderate or severe. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT(1F) receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients' preferences are necessary to accurately position this new treatment principle in relation to the triptans.

One hundred years of migraine research: major clinical and scientific observations from 1910 to 2010.

Pain research, and headache research in particular, during the 20th century, has generated an enormous volume of literature promulgating theories, questions, and temporary answers. This narrative review describes the most important events in the history of migraine research between 1910 and 2010. Based on the standard textbooks of headache: Wolff's Headache (1948 and 1963) and The Headaches (1993, 2000, and 2006) topics were selected for a historical review. Most notably these included: isolation and clinical introduction of ergotamine (1918); further establishment of vasodilation in migraine and the constrictive action of ergotamine (1938); identification of pain-sensitive structures in the head (1941); Lashley's description of spreading scotoma (1941); cortical spreading depression (CSD) of Leão (1944); serotonin and the introduction of methysergide (1959); spreading oligemia in migraine with aura (1981); oligemia in the wake of CSD in rats (1982); neurogenic inflammation theory of migraine (1987); a new headache classification (1988); the discovery of sumatriptan (1988); migraine and calcitonin gene-related peptide (1990); the brainstem "migraine generator" and PET studies (1995); migraine as a channelopathy, including research from the genetic perspective (1996); and finally, meningeal sensitization, central sensitization, and allodynia (1996). Pathophysiological ideas have evolved within a limited number of paradigms, notably the vascular, neurogenic, neurotransmitter, and genetic/molecular biological paradigm. The application of various new technologies played an important role within these paradigms, in particular neurosurgical techniques, EEG, methods to measure cerebral blood flow, PET imaging, clinical epidemiological, genetic, and molecular biological methods, the latter putting migraine (at least hemiplegic migraine) within a completely new classification of diseases.

The importance of a vibration wave as the trigger for tendon jerks.

Proprioceptive tendon reflexes are traditionally regarded as tendon stretch reflexes. Eliciting reflexes with a sharp blow on a tendon is, however, not a physiological stimulus. Based on clinical experience in eliciting these reflexes and neurophysiological investigations it is suggested that vibration is a relevant stimulus for tendon jerks.

Is there an inherent limit to the efficacy of calcitonin gene-related peptide receptor antagonists in the acute treatment of migraine? A comment.

Calcitonin gene-related peptide (CGRP) receptor antagonists are a new treatment principle in acute migraine attacks. Intravenous olcegepant 2.5 mg resulted in 66% headache relief after 2 h, whereas subcutaneous sumatriptan resulted in 81-92% headache relief after 2 h. The intrinsic activity of a parenteral triptan, a 5HT(1B/1D) receptor agonist, is thus higher than the maximum effect of the parenteral CGRP receptor antagonist olcegepant. For the orally bioavailable CGRP antagonist telcagepant 300 mg, the headache relief was only 55% in one phase III study. These results indicate that CGRP receptor antagonism results in success in the acute treatment of migraine in only a certain fraction of the patients.

Nitroglycerin headache and nitroglycerin-induced primary headaches from 1846 and onwards: a historical overview and an update.

Nitroglycerin (NTG) (glyceryl trinitrate) was synthesized by the Italian chemist Ascanio Sobrero in Paris in 1846. A very unstable explosive, Alfred Nobel while working on explosives, combined it with Kiselguhr and patented it as dynamite in 1867. NTG was introduced in 1879 in medicine in the treatment of angina pectoris by the English doctor William Murrell. NTG-induced headache was quickly recognized as an important adverse event both in the industrial use of NTG, where it was used to produce dynamite, as well as in the use of NTG as drug. This review traces the evolution of our understanding of NTG headache.