Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine

Background: Calcitonin gene–related peptide (CGRP) may have a causative role in migraine. We therefore hypothesized that a CGRP-receptor antagonist might be effective in the treatment of migraine attacks. Methods: In an international, multicenter, double-blind, randomized clinical trial of BIBN 4096 BS, a highly specific and potent nonpeptide CGRP-receptor antagonist, 126 patients with migraine received one of the following: placebo or 0.25, 0.5, 1, 2.5, 5, or 10 mg of BIBN 4096 BS intravenously over a period of 10 minutes. A group-sequential adaptive treatment-assignment design was used to minimize the number of patients exposed. Results: The 2.5-mg dose was selected, with a response rate of 66 percent, as compared with 27 percent for placebo (P=0.001). The BIBN 4096 BS group as a whole had a response rate of 60 percent. Significant superiority over placebo was also observed with respect to most secondary end points: the pain-free rate at 2 hours; the rate of sustained response over a period of 24 hours; the rate of recurrence of headache; improvement in nausea, photophobia, phonophobia, and functional capacity; and the time to meaningful relief. An effect was apparent after 30 minutes and increased over the next few hours. The overall rate of adverse events was 25 percent after the 2.5-mg dose of the drug and 20 percent for the BIBN 4096 BS group as a whole, as compared with 12 percent for placebo. The most frequent side effect was paresthesia. There were no serious adverse events. Conclusions: The CGRP antagonist BIBN 4096 BS was effective in treating acute attacks of migraine

Effect of erenumab on functional outcomes in patients with episodic migraine in whom 2-4 preventives were not useful: results from the LIBERTY study

Objective To evaluate the effect of erenumab on patient-reported, functional outcomes in patients with episodic migraine (EM) in whom 2-4 preventives were not useful from the Phase 3b LIBERTY study.MethodsAs previously reported, 246 patients with EM with 2-4 prior failed preventives were randomised 1:1 to subcutaneous erenumab 140 mg or placebo every 4 weeks for 12 weeks. This analysis evaluated Migraine Physical Function Impact Diary (MPFID), Headache Impact Test (HIT-6) and Work Productivity and Activity Impairment (WPAI) scores at Week 12. P values were nominal without multiplicity adjustment.ResultsErenumab significantly improved MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores versus placebo (treatment difference (TD) (95% CI) MPFID-PI: -3.5 (-5.7 to -1.2) (p=0.003); MPFID-EA: -3.9 (-6.1 to -1.7)) (p= 5-point reduction in MPFID score (OR vs placebo (95% CI) MPFID-EA: 2.1 (1.2 to 3.6); MPFID-PI: 2.5 (1.4 to 4.5)). A similar trend was observed for HIT-6 (TD: -3.0; p= 5-point reduction (OR (95% CI): 2.4 (1.4 to 4.1)). In three out of four WPAI domains, erenumab showed improvement versus placebo.ConclusionAt 12 weeks, erenumab was efficacious on functional outcomes in patients with EM in whom 2-4 preventives were not useful.Paroxysmal Cerebral Disorder

Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study

Background Clinical observations and results from recent studies support the use of non-invasive vagus nerve stimulation (nVNS) for treating cluster headache (CH) attacks. This study compared nVNS with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH). Methods After completing a 1-week run-in period, subjects were randomly assigned (1:1) to receive nVNS or sham therapy during a 2-week double-blind period. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 minutes after treatment initiation, without rescue treatment. Results The Full Analysis Set comprised 48 nVNS-treated (14 eCH, 34 cCH) and 44 sham-treated (13 eCH, 31 cCH) subjects. For the primary endpoint, nVNS (14%) and sham (12%) treatments were not significantly different for the total cohort. In the eCH subgroup, nVNS (48%) was superior to sham (6%;p<0.01). No significant differences between nVNS (5%) and sham (13%) were seen in the cCH subgroup. Conclusions Combing both eCH and cCH patients, nVNS was no different to sham. For the treatment of CH attacks, nVNS was superior to sham therapy in eCH but not in cCH. These results confirm and extend previous findings regarding the efficacy, safety, and tolerability of nVNS for the acute treatment of eCH

A review of diagnostic and functional imaging in headache

The neuroimaging of headache patients has revolutionised our understanding of the pathophysiology of primary headaches and provided unique insights into these syndromes. Modern imaging studies point, together with the clinical picture, towards a central triggering cause. The early functional imaging work using positron emission tomography shed light on the genesis of some syndromes, and has recently been refined, implying that the observed activation in migraine (brainstem) and in several trigeminal-autonomic headaches (hypothalamic grey) is involved in the pain process in either a permissive or triggering manner rather than simply as a response to first-division nociception per se. Using the advanced method of voxel-based morphometry, it has been suggested that there is a correlation between the brain area activated specifically in acute cluster headache — the posterior hypothalamic grey matter — and an increase in grey matter in the same region. No structural changes have been found for migraine and medication overuse headache, whereas patients with chronic tension-type headache demonstrated a significant grey matter decrease in regions known to be involved in pain processing. Modern neuroimaging thus clearly suggests that most primary headache syndromes are predominantly driven from the brain, activating the trigeminovascular reflex and needing therapeutics that act on both sides: centrally and peripherally

Long-term efficacy and safety of erenumab results from 64 weeks of the LIBERTY study

ObjectiveTo report the efficacy and safety of erenumab among patients with episodic migraine (EM) whowere unsuccessful on 2 to 4 preventive treatments observed at week 64 of the open-label extension phase (OLEP) of A Study Evaluating the Effectiveness of AMG 334 Injection in Preventing Migraines in Adults Having Failed Other Therapies (LIBERTY) study (ClinicalTrials.gov NCT03096834).MethodsTheOLEP, evaluatingmonthly erenumab 140 mg for 3 years, enrolled 240 patients who completed the double-blind treatment phase (DBTP) of 12 weeks during which they received placebo or erenumab 140 mg subcutaneous injections every 4 weeks as monotherapy. Efficacy outcomes were evaluated through the initial 52weeks ofOLEP (fromDBTP baseline to total 64weeks) in the overall population, patients receiving erenumab in DBTP, and patients from the DBTP placebo arm who switched to erenumab in OLEP. Endpoints included reduction of >= 50% in monthly migraine days (MMD) from DBTP baseline and change inMMDfrom DBTP baseline, Headache Impact Test score, and Migraine Physical Function Impact Diary score (Physical Impairment and Everyday Activities).ResultsAltogether, the week 52 visit of theOLEP was completed by 204 of 240 (85.0%) patients. Among patients continuing erenumab, the 50% responder rate increased from 29.9% at weeks 9 to 12 to 44.3% at weeks 61 to 64. The 50% responder rate in patientswho initiated erenumab in theOLEP remained higher in the OLEP (50.0% at week 61-64) than during DBTP (14.2% at weeks 9-12) compared to patients in continuous erenumab arm. In the OLEP, the 50% responder rate for the overall population increased from weeks 13 to 16 until weeks 37 to 40 and then remained stable through weeks 61 to 64. Patients treated with erenumab in DBTP showed sustained effects on all efficacy outcomes; those initiating erenumab in theOLEP demonstrated continued improvement from week 13 onward. Adverse events (AEs) were reported, considering both treatment groups, by approximate to 80.8% (serious AEs by 6.7%), 76.3% (5.9%) in the continuing erenumab arm, and 85.2% (7.4%) in those starting erenumab in OLEP. No deaths were reported.ConclusionsIn patients with EM who were unsuccessful on 2 to 4 prior preventive treatments, the LIBERTY study demonstrated sustained efficacy on erenumab monotherapy treatment through 64 weeks in both treatment arms. Safety of erenumab was consistent with that observed in previous clinical trials.Paroxysmal Cerebral Disorder

Guidelines of the International Headache Society for clinical trials with neuromodulation devices for the treatment of migraine

BackgroundAlthough the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine.MethodsAn international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine.ResultsKey terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created.ConclusionsAdoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment.Paroxysmal Cerebral Disorder

Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: a comprehensive review.

ObjectiveThe objective is to summarize the knowledge on the epidemiology, pathophysiology and management of secondary headache attributed to SARS-CoV-2 infection and vaccination; as well as to delineate their impact on primary headache disorders.MethodsThis is a narrative review of the literature regarding primary and secondary headache disorders in the setting of COVID-19 pandemic. We conducted a literature search in 2022 on PubMed, with the keywords “COVID 19” or “vaccine” and “headache” to assess the appropriateness of all published articles for their inclusion in the review.ResultsHeadache is a common and sometimes difficult-to-treat symptom of both the acute and post-acute phase of SARS-CoV-2 infection. Different pathophysiological mechanisms may be involved, with the trigeminovascular system as a plausible target. Specific evidence-based effective therapeutic options are lacking at present. Headache attributed to SARS-CoV-2 vaccinations is also common, its pathophysiology being unclear. People with primary headache disorders experience headache in the acute phase of COVID-19 and after vaccination more commonly than the general population. Pandemic measures, forcing lifestyle changes, seemed to have had a positive impact on migraine, and changes in headache care (telemedicine) have been effectively introduced.ConclusionsThe ongoing COVID-19 pandemic is a global challenge, having an impact on the development of secondary headaches, both in people with or without primary headaches. This has created opportunities to better understand and treat headache and to potentiate strategies to manage patients and ensure care.Paroxysmal Cerebral Disorder

The differential diagnosis of chronic daily headaches: an algorithm-based approach

Chronic daily headaches (CDHs) refers to primary headaches that happen on at least 15 days per month, for 4 or more hours per day, for at least three consecutive months. The differential diagnosis of CDHs is challenging and should proceed in an orderly fashion. The approach begins with a search for “red flags” that suggest the possibility of a secondary headache. If secondary headaches that mimic CDHs are excluded, either on clinical grounds or through investigation, the next step is to classify the headaches based on the duration of attacks. If the attacks last less than 4 hours per day, a trigeminal autonomic cephalalgia (TAC) is likely. TACs include episodic and chronic cluster headache, episodic and chronic paroxysmal hemicrania, SUNCT, and hypnic headache. If the duration is ≥4 h, a CDH is likely and the differential diagnosis encompasses chronic migraine, chronic tension-type headache, new daily persistent headache and hemicrania continua. The clinical approach to diagnosing CDH is the scope of this review