Citations

Chronic migraine (CM) is a neurological disease characterized by frequent migraine attacks that prevent affected individuals from performing daily activities of living, significantly diminish quality of life, and increase familial burden. Before onabotulinumtoxinA was approved for CM, there were few treatment options for these seriously disabled patients and none had regulatory approval. The terminology and recognition of CM evolved in parallel with the onabotulinumtoxinA clinical development program. Because there were no globally accepted classification criteria for CM when onabotulinumtoxinA was in development, the patient populations for the trials conducted by Allergan were determined by the Allergan migraine team in collaboration with headache scientists and clinicians. These trials and collaborations ultimately led to improvements in CM classifications. In 2010, onabotulinumtoxinA became the first medication and first biologic approved specifically to prevent headaches in patients with CM. Approval was based on 2 similarly designed phase 3, double-blind, randomized, placebo-controlled, multicenter clinical studies. Both studies showed significantly greater improvements in mean change from baseline in headache-day frequency in patients with CM receiving onabotulinumtoxinA compared with those receiving placebo. The safety and effectiveness of onabotulinumtoxinA have been established globally in >5000 patients with CM with or without medication overuse treated in clinical and observational studies. Benefits also include improvements in quality of life, fewer psychiatric comorbidities, and reduced healthcare resource utilization. Across studies, onabotulinumtoxinA was well tolerated; adverse events tended to be mild or moderate in severity and to decline over subsequent treatment cycles.

Importance Trigeminal autonomic cephalalgias (TACs) comprise a unique collection of primary headache disorders characterized by moderate or severe unilateral pain, localized in in the area of distribution of the first branch of the trigeminal nerve, accompanied by cranial autonomic symptoms and signs. Most TACs are rare diseases, which hampers the possibility of performing randomized clinical trials and large studies. Therefore, knowledge of treatment efficacy must be based only on observational studies, rare disease registries, and case reports, where real-world data and evidence play an important role in health care decisions. Observations Chronic cluster headache is the most common of these disorders, and the literature offers some evidence from randomized clinical trials to support the use of pharmacologic and neurostimulation treatments. Galcanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide, was not effective at 3 months in a randomized clinical trial but showed efficacy at 12 months in a large case series. For the other TACs (ie, paroxysmal hemicrania, hemicrania continua, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing, and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms), only case reports and case series are available to guide physicians in everyday management. Conclusions and Relevance The accumulation of epidemiologic, pathophysiologic, natural history knowledge, and data from case series and small controlled trials, especially over the past 20 years from investigators around the world, has added to the previously limited evidence and has helped advance and inform the treatment approach to rare TACs, which can be extremely challenging for clinicians.

Abstract Objective To evaluate the effect of eptinezumab on patient‐reported outcomes in patients with chronic migraine (CM) and medication‐overuse headache (MOH). Background MOH is a secondary headache disorder commonly occurring in patients with CM and associated with functional and psychological impairments. Medication overuse and monthly headache and migraine days were reduced with eptinezumab compared with placebo as published previously; however, these outcomes do not fully capture the burden of migraine and treatment effect. Methods PROMISE‐2 was a phase 3, randomized, double‐blind, placebo‐controlled trial in adults with CM. Patients were randomized (1:1:1) to receive eptinezumab 100 mg, eptinezumab 300 mg, or placebo (up to 2 doses, 12 weeks apart). Patients completed the following patient‐reported outcomes: 6‐item Headache Impact Test (HIT‐6), Patient Global Impression of Change (PGIC), patient‐identified most bothersome symptom (PI‐MBS), and 36‐item Short‐Form Health Survey (SF‐36). Results A total of 431 CM patients (139, 147, and 145 patients in the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups, respectively) had MOH diagnosed at screening (40.2% of the total PROMISE‐2 population [ n = 1072]). In CM with MOH patients, both doses of eptinezumab were associated with clinically meaningful improvements in mean HIT‐6 total scores by week 4 and remained improved throughout the 24‐week study. Responder rates for individual HIT‐6 items were greater with eptinezumab than with placebo at all time points. At week 12, almost twice as many eptinezumab‐treated patients indicated the PGIC was “much” or “very much” improved (58.5% [79/135, 100 mg] and 67.4% [95/147, 300 mg] vs. 35.8% [48/134, placebo]). Patients in the eptinezumab groups showed numerically greater improvements over placebo in the PI‐MBS and SF‐36 scores. Conclusions This subgroup analysis in patients with CM/MOH at baseline suggests that eptinezumab treatment is associated with early, sustained, and clinically meaningful improvements in patient‐reported outcomes.

In 1995, a committee of the International Headache Society developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Cluster Headache. These have not been revised. With the emergence of new medications, neuromodulation devices and trial designs, an updated version of the International Headache Society Guidelines for Controlled Clinical Trials in Cluster Headache is warranted. Given the scarcity of evidence-based data for cluster headache therapies, the update is largely consensus-based, but takes into account lessons learned from recent trials and demands by patients. It is intended to apply to both drug and neuromodulation treatments, with specific proposals for the latter when needed. The primary objective is to propose a template for designing high quality, state-of-the-art, controlled clinical trials of acute and preventive treatments in episodic and chronic cluster headache. The recommendations should not be regarded as dogma and alternative solutions to particular methodological problems should be explored in the future and scientifically validated.