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Recently approved migraine preventive therapies facilitate rapid control of migraine activity, potentially improving patients’ lives and minimizing the societal burden of migraine. This review synthesizes available evidence on rates and timing of early onset of migraine prevention and identifies patient-level outcomes related to early onset prevention. This evidence-based scoping review identified all available clinical trial evidence regarding the early onset of prevention of migraine, under the hypothesis ‘Patients with migraine (episodic or chronic) report additional benefits when receiving an approved migraine preventive treatment that demonstrates an early onset of prevention’. Early onset of prevention was defined as migraine preventive benefits within 30 days post-administration. PubMed, EMBASE, and CINAHL were searched for publications between 1988 and 2020. Overall, 16 publications described 18 studies. All studies were conducted in approved treatments [four anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and one chemodenervation agent] in patients with episodic/chronic migraine; no publications were identified for traditional oral agents for early migraine prevention. Compared to placebo, erenumab (three studies) reduced weekly migraine days within 1 week; fremanezumab (six studies) increased reports of no headache of at least moderate severity on Day 1 and significantly reduced migraine frequency within 1 week; galcanezumab (three studies) significantly reduced the mean number of patients with migraine beginning Day 1 and each day of the first week; eptinezumab (four studies) significantly reduced migraine attack likelihood on Day 1 by > 50% versus baseline; and onabotulinumtoxinA (two studies) reduced headache and migraine days within 1 week. Four publications described function, disability, and quality of life improvements as early as Week 4; none reported cost–benefit. Anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and a chemodenervation agent (onabotulinumtoxinA) provide clinically relevant benefits during the first treatment week. Literature describing clinically relevant benefits regarding early onset of prevention in patients with migraine is limited. [ABSTRACT FROM AUTHOR]

Background: The full utility of an acute treatment requires examination of the entire time course of effect during a migraine attack. Here the time course of effect of ubrogepant is evaluated. Methods: ACHIEVE-I and -II were double-blind, single-attack, Phase 3 trials. Adults with migraine were randomised 1:1:1 to placebo or ubrogepant (50mg or 100mg, ACHIEVE-I; 25 mg or 50 mg, ACHIEVE-II). Pain freedom, absence of most bothersome symptom, and pain relief were assessed at various timepoints. Samples were collected for pharmacokinetic analysis. Data were pooled for this post-hoc analysis. Results: Participants' (n = 912 placebo, n = 887 ubrogepant 50 mg, pooled analysis population) mean age was 41 years, with a majority female and white. Pain relief separated from placebo by 1 h (43% versus 37% [OR, 95% CI: 1.30, 1.0–1.59]), absence of most bothersome symptom by 1.5 h (28% versus 22% [1.42, 1.14–1.77]), and pain freedom by 2 h (20% vs. 13% [1.72, 1.33–2.22]). Efficacy was sustained from 2–24 h (pain relief: 1.71, 1.1–2.6; pain freedom: 1.71, 1.3–2.3) and remained separated at 48 h (pain relief: 1.7, 1.1–2.6; pain freedom: 1.31, 1.0–1.7). Pharmacokinetic analysis demonstrated maximum plasma concentrations were achieved at 1 h, with pharmacologically active concentrations reached within 11 min and remaining above the EC90 for nearly 12 h. Conclusions: Evaluation of the time course of effect of ubrogepant showed pain relief as the most sensitive and earliest measure of clinical effect, followed by absence of most bothersome symptom, and pain freedom. Efficacy was demonstrated out to 48 h, providing evidence of the long-lasting effect of ubrogepant. This evaluation supports the role of examining the entire time course of effect to understand fully the utility of an acute treatment for migraine. Trial registration: ACHIEVE I (ClinicalTrials.gov, NCT02828020) and ACHIEVE II (ClinicalTrials.gov, NCT02867709) [ABSTRACT FROM AUTHOR]

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways. [ABSTRACT FROM AUTHOR]

Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies that target CGRP ligands or receptors, may cause a very rare side effect of reversible cerebral vasoconstriction syndrome (RCVS). This study is a case report of a patient who developed cerebral artery vasoconstriction documented on serial brain magnetic resonance angiography (MRA) scans without the typical manifestations of RCVS following galcanezumab loading dose. Case report: A 40-year-old female patient with high-frequency episodic migraine with visual aura on topiramate 100 mg/day developed transient numbness of the right upper and lower extremities and right face without headache and a normal neurological examination 10 min after a loading dose of galcanezumab, which resolved over the next 2 days. Magnetic resonance angiography brain imaging showed segmental arterial constriction of both middle cerebral arteries in the M1–2 segments and both posterior cerebral arteries in the P1–2 segments, which partial resolved in a subsequent study by the end of 6 months. There were no other supporting examination data, such as transcranial Doppler, which might provide additional information on the progression and improvement of the vasoconstriction. Her differential diagnosis included prolonged migraine sensory aura without headache, RCVS, or cerebral vasoconstriction secondary to the effect of an anti-CGRP monoclonal antibody. Further research needs to be conducted. Plain Language Summary: We report a case with numbness on the right upper and lower extremities and right face without headache 10 min after the loading dose of galcanezumab. These stroke-like symptoms resolved within 2 days. Cerebral blood vessels showed narrowing and then dilatation with residual narrowing of two or more vessels. The differential diagnosis is prolonged migraine aura without headache, reversible cerebral vasoconstriction syndrome, or cerebral vasoconstriction due to the effects of galcanezumab. [ABSTRACT FROM AUTHOR]

The article discusses the concept of combination treatment in managing migraine, which involves using two or more acute or preventive treatments simultaneously. It emphasizes the importance of clear terminology to enhance communication and implementation of treatment strategies, especially in regions with diverse practices. The text highlights the need for a standardized lexicon among clinicians and researchers to improve patient care and reduce ambiguity in the field. The authors suggest a stepwise approach to combining treatments, starting with identifying a baseline treatment and layering subsequent treatments based on individual patient characteristics and disease burden. [Extracted from the article]

Objective Background Methods Results Conclusion To evaluate the safety and tolerability of ubrogepant for the acute treatment of migraine in participants taking atogepant for the preventive treatment of episodic migraine (EM).Atogepant is an oral calcitonin gene‐related peptide (CGRP) receptor antagonist approved for the preventive treatment of migraine in adults and ubrogepant is an oral CGRP receptor antagonist approved for the acute treatment of migraine in adults, with or without aura. The safety and tolerability of the concomitant use of ubrogepant and atogepant have not been previously evaluated in a clinical setting.The TANDEM study, a phase 4, two‐period, multicenter, open‐label study conducted in the United States, enrolled adults with migraine, with or without aura, and <15 headache days/month. In Treatment Period 1, participants took atogepant 60 mg once daily (QD) for 12 weeks and their own non‐gepant acute headache medication for breakthrough migraine attacks. In Treatment Period 2, participants continued taking atogepant 60 mg QD and ubrogepant 100 mg was taken as needed (PRN) for the treatment of breakthrough migraine attacks (up to eight per 4‐week interval) for 12 weeks. In Treatment Period 2, an optional second ubrogepant dose or the participant's own acute medication could be used to rescue headaches that did not resolve within 2–24 h post initial ubrogepant dose. The primary objective evaluated the safety and tolerability of the concomitant use of ubrogepant and atogepant.Of 263 participants enrolled, 262 were treated in Treatment Period 1 (Safety Population 1) and 218 continued and were treated in Treatment Period 2 (Safety Population 2). The mean (standard deviation) number of ubrogepant use days in Treatment Period 2 was 6.6 (5.03) over the 12 weeks. In Treatment Periods 1 and 2, 49.6% and 43.1% of participants experienced a treatment‐emergent adverse event (TEAE), respectively. The most common TEAEs (≥5%) in Treatment Period 1 and Treatment Period 2 were COVID‐19 (8.4%, 3.2%), fatigue (6.5%, 1.4%), nausea (6.1%, 0.9%), decreased appetite (5.7%, 0.9%), and constipation (5.3%, 0.9%). In Treatment Period 2, no increase in the incidence and types of TEAEs in relation to the number of ubrogepant use days or doses taken were identified. During the whole treatment period, 9.9% of participants discontinued atogepant or ubrogepant treatment due to TEAEs. There was one serious TEAE in Treatment Period 1 (ureterolithiasis) and one in Treatment Period 2 (cervical myelopathy), and both were considered not related to study treatment by the study investigators.The use of atogepant 60 mg QD for the preventive treatment of EM and ubrogepant 100 mg PRN for the acute treatment of migraine over the 12‐week open‐label concomitant use treatment period was safe and well tolerated. The overall safety results were consistent with the known safety profiles of atogepant and ubrogepant when used alone and no new safety signals were identified. [ABSTRACT FROM AUTHOR]

The article discusses OnabotulinumtoxinA treatment for preventive treatment in chronic migraine (CM). It mentions combination of calcitonin gene-related peptide (CGRP) targeted monoclonal antibodies (mAbs) and onabotulinumtoxinA in people with migraine is probably effective; and also mentions clinicians add CGRP mAbs to onabotulinumtoxinA, which are the only approved treatments for the prevention of CM.

Objective: To compare effectiveness of onabotulinumtoxinA and topiramate for chronic migraine (CM) prevention. Background: The efficacy* of onabotulinumtoxinA and topiramate has been established in placebo‐controlled randomized clinical trials (*defined as the benefit of treatment under ideal conditions). The effectiveness* of the 2 preventive treatments, however, has not been established (*the benefit of treatment under real‐world conditions, representing a blend of efficacy and tolerability). Methods: In this multicenter, randomized, parallel‐group, post‐authorization, open‐label prospective study (FORWARD; ClinicalTrials.gov, NCT02191579), we randomized adults with CM (1:1) to onabotulinumtoxinA 155 U every 12 weeks for 3 cycles or topiramate "immediate release" 50‐100 mg/day to week 36. Primary outcome measure was proportion of patients achieving ≥50% reduction in headache days (weeks 29‐32). Missing values were imputed using baseline observation carried forward (BOCF) methodology. After 12 weeks, patients initially randomized to topiramate could cross over to onabotulinumtoxinA treatment. We monitored and recorded all adverse events (AEs). Results: We enrolled 282 patients (onabotulinumtoxinA, n = 140; topiramate, n = 142) and 148 patients completed randomized treatment (onabotulinumtoxinA, n = 120 [86%]; topiramate, n = 28 [20%]). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, n = 7 [5%]; topiramate, n = 27 [19%]) and AEs (onabotulinumtoxinA, n = 5 [4%]; topiramate, n = 72 [51%]). Eighty topiramate patients crossed over to onabotulinumtoxinA. In the BOCF analysis, a significantly higher proportion of patients randomized to onabotulinumtoxinA experienced ≥50% reduction in headache frequency compared with those randomized to topiramate (40% [56/140] vs 12% [17/142], respectively; adjusted OR, 4.9 [95% CI, 2.7‐9.1]; P < .001). OnabotulinumtoxinA was superior to topiramate in meeting secondary endpoints. In a post hoc analysis using observed data, the 50% responder rates at week 12 were 45.6% for onabotulinumtoxinA (n = 125) and 29.4% for topiramate (n = 109) (P = .015). AEs were reported by 48% (105/220) of onabotulinumtoxinA and 79% (112/142) of topiramate patients. Results were similar in those who crossed over to onabotulinumtoxinA. Conclusions: While using imputation methods of accounting for differences in discontinuation rates, we found onabotulinumtoxinA to have greater clinical utility than topiramate, largely because of tolerability issues associated with the latter and a relatively higher number of onabotulinumtoxinA patients remaining on treatment. [ABSTRACT FROM AUTHOR]

Introduction: OnabotulinumtoxinA is approved in the USA for the prevention of headache in adults with chronic migraine, a debilitating neurologic disease characterized by headaches occurring on ≥ 15 days per month for > 3 months and including migraine features on ≥ 8 days per month.Objective: The COMPEL Study (NCT01516892), a 108-week, multi-center, open-label study, evaluated the long-term efficacy and safety of onabotulinumtoxinA in adults with chronic migraine. The objective of this subanalysis was to examine the safety and tolerability of onabotulinumtoxinA after each of nine treatment cycles.Methods: OnabotulinumtoxinA 155 U was administered every 12 weeks. Safety and tolerability, overall and by treatment cycle, were assessed. Treatment-emergent adverse events reported between successive treatments were attributed to the preceding treatment. The safety population received one or more doses of onabotulinumtoxinA. The primary efficacy outcome was the reduction in headache days at week 108 compared with baseline.Results: Of 716 patients enrolled, 373 patients (52.1%) completed the study and 343 (47.9%) withdrew; 481 patients (67.2%) received 60 weeks of treatment and 402 (56.1%) received 108 weeks of treatment. In total, 436 (60.9%) patients reported treatment-emergent adverse events; most were mild/moderate in severity. Thirty-two patients (4.5%) discontinued the study after experiencing treatment-emergent adverse events. The incidence of treatment-emergent adverse events typically decreased with repeated onabotulinumtoxinA treatment: first cycle, 24.2%; fourth cycle, 18.4%; ninth cycle, 12.2%. Neck pain (2.7%), eyelid ptosis (1.8%), musculoskeletal stiffness (1.4%), injection-site pain (1.3%), and headache (1.3%) were the most common treatment-emergent adverse events after the first cycle. Seventy-five patients (10.5%) reported serious treatment-emergent adverse events, 13 (1.8%) withdrew. Treatment-related adverse events were reported by 131 patients (18.3%), one was considered serious. OnabotulinumtoxinA significantly reduced headache day frequency by 10.7 (6.4) days per 28-day period (p < 0.0001) at week 108.Conclusions: OnabotulinumtoxinA treatment was well tolerated over 108 weeks; no new safety signals were identified. The overall incidence of treatment-emergent adverse events and the most common individual events decreased with repeated onabotulinumtoxinA administration.Clinical Trial Registration: ClinicalTrials.gov; NCT01516892. [ABSTRACT FROM AUTHOR]