Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.

Erenumab administered subcutaneously at a monthly dose of 70 mg or 140 mg significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine-specific medication over a period of 6 months. The long-term safety and durability of the effect of erenumab require further study. (Funded by Amgen and Novartis; STRIVE ClinicalTrials.gov number, NCT02456740 .).

After the introduction of chronic migraine and medication overuse headache as diagnostic entities in The International Classification of Headache Disorders, Second Edition, ICHD-2, it has been shown that very few patients fit into the diagnostic criteria for chronic migraine (CM). The system of being able to use CM and the medication overuse headache (MOH) diagnosis only after discontinuation of overuse has proven highly unpractical and new data have suggested a much more liberal use of these diagnoses. The International Headache Classification Committee has, therefore, worked out the more inclusive criteria for CM and MOH presented in this paper. These criteria are included in the appendix of ICHD-2 and are meant primarily for further scientific evaluation but may be used already now for inclusion into drug trials, etc. It is now recommended that the MOH diagnosis should no longer request improvement after discontinuation of medication overuse but should be given to patients if they have a primary headache plus ongoing medication overuse. The latter is defined as previously, i.e. 10 days or more of intake of triptans, ergot alkaloids mixed analgesics or opioids and 15 days or more of analgesics/NSAIDs or the combined use of more than one substance. If these new criteria for CM and MOH prove useful in future testing, the plan is to include them in a future revised version of ICHD-2.

The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the 'raw patient data' of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post-dose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletripta...

These results provide evidence that will enhance our understanding of the factors driving health care costs and will contribute to development of cost-effective health care strategies.

The trigeminal ganglion was activated, in humans by thermocoagulation as part of the treatment of trigeminal neuralgia and in cats by electrical stimulation, and blood samples were taken from the external jugular vein for estimates of plasma levels of substance P and calcitonin gene-related peptide (CGRP). In those patients who were noted at the time of coagulation to have flushed there were marked elevations of the local (cranial) levels of both peptides. However, in the nonflushing patients no changes in the peptide levels were observed. Parallel experiments in the cat revealed that the levels of substance P-like and CGRP-like immunoreactivity were increased during electrical stimulation of the trigeminal ganglion. The observation of elevation of substance P-like and CGRP-like immunoreactivity after activation of the nociceptive afferent system of the head provides new insights into a putative role of peptides in the pathophysiology of migraine and cluster headache, and suggests new areas of possible therapeutic intervention.

Klatt, J. (2018). Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study. Lancet.Abstract: 299 words excluding Current word count: 4621 (including Research in 24 context) 25 Manuscript LIBERTY-primary manuscript Re-submission draft 2 Summary 26Background: A significant proportion of patients does not respond to, or cannot tolerate, current 27 oral migraine preventives. Erenumab is a novel CGRP-receptor antibody with preventive 28 efficacy in migraine. Here we assessed its efficacy and tolerability in patients with episodic 29 migraine who had previously failed 2-4 migraine preventives (efficacy failure: no meaningful 30 reduction in headache frequency after administration of approved preventive for migraine for at 31 least 2-3 months based on patient history and medical judgment). 32Methods: LIBERTY (NCT03096834) was a 12-week, double-blind, randomised study. 33Participants with migraine symptoms from 4-14 days/month (28-day interval) across the three 34 months prior to screening and during the baseline period were randomised (1:1) to receive 35 erenumab 140 mg or placebo every four weeks subcutaneously for the 12-week double-blind 36 treatment phase. The primary endpoint was proportion of patients achieving ≥50% reduction in 37 monthly migraine days during Weeks 9-12. Additionally, safety and tolerability were also 38 assessed by recording adverse events and by physical examination, vital signs, clinical laboratory 39 assessments, and electrocardiogram. 40 Findings: Of 246 randomised participants (n=121 for erenumab 140 mg and n=125 for placebo), 41 240 completed the double-blind phase. Of these, 95 (38·6%), 93 (37·8%), and 56 (22·8%) had 42 previously failed two, three, and four preventives, respectively. At Week 12, the ≥50% responder 43 rate was observed in 36 (30·3%) patients on erenumab versus 17 (13·7%) patients on placebo 44 (odds ratio, 95% confidence interval [CI]: 2·7 [1·4, 5·2]; p=0·002). The tolerability and safety 45 profiles of erenumab were comparable to placebo. The most frequent treatment-emergent 46 adverse events was injection site pain (7 [5.9%] with erenumab 140 mg, 7 [5.6%] placebo).47 Interpretation: Erenumab was effective in patients with episodic migraine who previously did 48 not respond to/tolerate 2-4 migraine preventives. Erenumab might be an option for patients with 49 difficult-to-treat migraine who have high unmet needs and limited treatment options.50 Funding: Novartis Pharma AG 51 52 LIBERTY-primary manuscript Re-submission draft 3 Research in context 53Evidence before this study 54 We searched PubMed to identify articles published in English language between January 1, 55 2010, and June 18, 2018, using the search terms "episodic migraine", "CGRP OR calcitonin 56 gene-related peptide", and "antibody OR antibodies". The search retrieved 38 articles. Published 57 literature suggests that CGRP is involved in the pathophysiology...

ObjectiveTo evaluate the efficacy and safety of eptinezumab, a humanized anti–calcitonin gene-related peptide monoclonal antibody, in the preventive treatment of chronic migraine (CM).MethodsThe Prevention of Migraine via Intravenous ALD403 Safety and Efficacy–2 (PROMISE-2) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Adults with CM were randomly assigned to receive IV eptinezumab 100 mg, eptinezumab 300 mg, or placebo administered on day 0 and week 12. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over weeks 1 to 12.ResultsAmong treated participants (n = 1,072), baseline mean number of MMDs was ≈16.1 across groups. Treatment with eptinezumab 100 and 300 mg was associated with significant reductions in MMDs across weeks 1 to 12 compared with placebo (placebo −5.6, 100 mg −7.7, p < 0.0001 vs placebo; 300 mg −8.2, p < 0.0001 vs placebo). Treatment-emergent adverse events (TEAEs) were reported by 43.5% (100 mg), 52.0% (300 mg), and 46.7% (placebo) of patients. Nasopharyngitis was the only TEAE reported for >2% of eptinezumab-treated patients at an incidence of >2% over placebo; it occurred in the 300 mg eptinezumab arm (eptinezumab 9.4%, placebo 6.0%).ConclusionIn patients with CM, eptinezumab 100 and 300 mg was associated with a significant reduction in MMDs from the day after IV administration through week 12, was well tolerated, and demonstrated an acceptable safety profile.Classification of evidenceThis study provides Class I evidence that for patients with CM, a single dose of eptinezumab reduces MMDs over 12 weeks of treatment.ClinicalTrials.gov identifierNCT02974153.