Pain Freedom Research Articles

Real-World Analysis of Remote Electrical Neuromodulation (REN) for the Acute Treatment of Migraine.

Introduction: Migraine is a chronic neurological disease that is the primary cause of years lived with disability in people under the age of 50. Remote electrical neuromodulation (REN) is a novel drug-free acute treatment of migraine, that is FDA cleared for episodic and chronic migraine. As a prescribed digital therapeutic, REN enables large-scale post-marketing research, thus providing real-world information on the use of the intervention in a wide range of populations, environments, and situations.Methods: The REN device (®Nerivio) includes a secured, personal migraine diary, which patients can use to record their symptoms before treatment and 2 h post-treatment. Real-world data on REN treatments were collected via the app from patients across the United States who used Nerivio between October 1st, 2019, and May 24th, 2021. Data analysis focused on four metrics: 1. Per-treatment patterns of REN use as a standalone treatment vs. in combination with medications. 2. Per-user intra-individual efficacy across multiple treatments. 3. Distribution of treatment intensity among users (the electroceutical equivalent to treatment dose). 4. Prevalence and severity of adverse events.Results: 1. Out of 23,151 treatments, in 66.5% of treatments REN was used as a standalone treatment, in 12.9% it was followed by over-the-counter medications, and in 20.6% followed by prescription medications. 2. Out of 2,514 patients, response in at least 50% of treatments was achieved in 66.5% of cases for pain relief, and in 22.6% for pain freedom. 3. Out of 117,583 treatments, in 80% of cases intensity levels were between 18 and 55% of the stimulator's range. The mean intensity was 34.3% of the stimulator's output (±16.6%). 4. Out of 12,368 users (121,947 treatments), there were 59 users (0.48%) who reported device related adverse events, 56 (0.45%) of which were mild, three (0.03%) were moderate, and none were severe.Conclusions: The current analysis of real-world clinical data indicates that REN provides an efficacious, stable, and safe treatment option for acute treatment of migraine in real-world settings, both as a standalone replacement of pharmaceuticals, as well as an adjunct to medications.

Comparison between metamizole and triptans for migraine treatment: a systematic review and network meta-analysis

Objective The aim of this systematic review was to evaluate the efficacy of metamizole and triptans for the treatment of migraine. MethodsRandomized controlled trials including people who received metamizole or triptan by multiple routes of administration and at all doses as treatment compared to subjects who received another treatment or placebo were included in the systematic review. The primary outcomes were freedom from pain at 2 hours; pain relief at 2 hours; sustained headache response at 24 hours; sustained freedom from pain at 24 hours. The statistical analysis of all interventions of interest were based on random effect models compared through a network meta-analysis. Results 209 studies meeting the inclusion and exclusion criteria were analyzed. Of these, 130 had data that could be analyzed statistically. Only 3.0% provided enough information and were judged to have a low overall risk of bias for all categories evaluated; approximately 50% of the studies presented a low risk of selection bias. More than 75% of the studies presented a low risk of performance bias, and around 75% showed a low risk of detection and attrition bias. ConclusionThere is no evidence of a difference between dipyrone and any triptan for pain freedom after 2 hours of medication. Our study suggests that metamizole may be equally effective as triptans in acute migraine treatment.

Ubrogepant Is Safe and Efficacious in Participants Taking Concomitant Preventive Medication for Migraine: A Pooled Analysis of Phase3 Trials.

IntroductionUbrogepant is a calcitonin gene-related peptide receptor antagonist indicated for acute treatment of migraine that can be used to treat breakthrough attacks in individuals taking preventive treatment for migraine. We evaluated the impact of preventive medication use on the efficacy and safety of ubrogepant for the acute treatment of migraine.MethodsThis was an analysis of pooled efficacy data from the ACHIEVE I and ACHIEVE II phase 3 trials, in which efficacy of ubrogepant was assessed at 2 h after taking study medication for pain freedom, absence of most bothersome symptom (MBS), and pain relief. In addition, a long-term safety (LTS) extension trial was completed where safety was assessed on the basis of incidence and severity of treatment-emergent adverse events (TEAEs). Outcomes were compared between participants with or without prior (within 6 months) preventive medication use (anticonvulsants, beta blockers, antidepressants, or onabotulinumtoxinA). For efficacy analyses, data were pooled across ACHIEVE trials for the 50 mg and placebo groups; for safety analyses, data for all dose groups (50 mg and 100 mg) in the LTS trial were pooled.ResultsPreventive treatments were used by 417 of 2247 (18.6%) participants analyzed in the ACHIEVE trials and by 143 of 813 (17.5%) participants in the LTS trial. Responder rates for all outcomes were similar between participants with or without preventive treatment within each dose group (p > 0.05). No significant differences were noted across the different preventive medications. Rates and types of TEAEs were similar between participants with or without preventive treatment. No serious treatment-related adverse events were reported.ConclusionEfficacy and safety of ubrogepant for the acute treatment of migraine were similar between participants with or without prior or current use of concomitant preventive medication.Trial RegistrationClinicalTrials.gov identifiers: NCT02828020 (ACHIEVE I), NCT02867709 (ACHIEVE II), and NCT02873221 (long-term safety trial).Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01923-3.

Efficacy and Safety of Lasmiditan for Acute Treatment of Migraine in Adults: A Meta-Analysis.

Monotherapy with triptans in acute migraine is ineffective in many patients and contraindicated in certain cardiovascular diseases where alternative therapeutic options are necessary to explore. This meta-analysis has evaluated the efficacy and safety of lasmiditan for the treatment of acute migraine in adults. After performing a literature search on MEDLINE/PubMed, Scopus, Cochrane databases, and International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from 4 relevant articles. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed in the selection, analysis, and reporting of findings. A random-effects model was used to estimate effect size. Quality assessment was done using the risk of bias assessment tool and meta-regression for probable variables affecting effect size. Subgroup analysis was done depending on the dose of lasmiditan. Lasmiditan use was associated with a significantly higher percentage of patients with pain freedom (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.72-2.39; P < .00001), sustained pain freedom (OR, 1.93; 95%CI, 1.55-2.39; P <.00001), headache response (OR, 2.05; 95%CI, 1.77-2.36; P < .00001), clinical disability level (OR, 1.36; 95%CI, 1.20-1.55; P < .00001), patients' global impression (OR, 1.88; 95%CI, 1.69-2.10; P < .00001), and significantly lower use of rescue medication (OR, 0.49; 95%CI, 0.38-0.63; P < .00001) compared to placebo. Lasmiditan use was also associated with a higher likelihood of adverse effects like dizziness (OR, 6.54; 95%CI, 4.24-10.07; P < .00001), paresthesia (OR, 4.28; 95%CI, 2.97-6.17; P < .00001), and fatigue (OR, 5.67; 95%CI, 3.78-8.52; P < .00001) compared to placebo. Subgroup analysis showed a dose-dependent effect of lasmiditan on pain freedom, sustained pain freedom, patient's global impression, and occurrence of adverse drug reactions. Prediction probability for effect estimate favoring placebo was calculated to be 0.0017%. Lasmiditan has shown a favorable effect in terms of efficacy and safety in the treatment of an acute attack of migraine in comparison to placebo. Further studies are needed to evaluate long-term safety, efficacy, and use in specific subgroups of patients. PROSPERO Registration Number: CRD42020177838.

P.027 Efficacy and Safety of Eptinezumab Initiated During a Migraine Attack: Results from the RELIEF Study

Background: Eptinezumab is approved for migraine prevention, with demonstrated rapid onset of preventive benefit. RELIEF evaluated the efficacy and safety of eptinezumab initiated during a migraine attack. Methods: RELIEF (NCT04152083; parallel-group, double-blind, placebo-controlled) randomized adults with migraine (4-15d/mo in 3mo prior to screening) to eptinezumab 100mg or placebo, administered IV within 1-6h of qualifying migraine onset. Co-primary efficacy endpoints were time to headache pain freedom and time to absence of most bothersome symptom (MBS). Results: Eptinezumab (n=238) compared with placebo (n=242) achieved significantly faster headache pain freedom (median 4h vs 9h; hazard ratio=1.54, P=0.0006) and absence of MBS (2h vs 3h; 1.75, P&lt;0.0001). At 2h, 23.5% and 12.0% (P=0.0009) of eptinezumab-treated and placebo patients, respectively, reported headache pain freedom, and 55.5% and 35.8% (P&lt;0.0001) reported absence of MBS. Significantly fewer eptinezumab-treated patients used rescue medication within 24h (31.5% vs 59.9%; P&lt;0.0001). Treatment-emergent adverse events occurred in 10.9% eptinezumab-treated and 10.3% placebo patients; no serious adverse events occurred. Conclusions: Infusion of the preventive migraine treatment, eptinezumab, during a migraine resulted in rapid and sustained freedom from headache pain and MBS vs placebo, starting 2h post-infusion, decreasing need for acute medication within 24h post-infusion. No notable safety findings were identified.

Safety and efficacy of remote electrical neuromodulation for the acute treatment of chronic migraine: an open-label study.

Remote electrical neuromodulation (REN) is an acute treatment of migraine. The results from several studies in patients with episodic migraine suggest that REN is an effective and safe acute treatment of migraine. A recent pilot study provided initial support that REN is effective in patients with chronic migraine as well. The current study aimed to validate and provide further evidence for the safety and efficacy of REN in a large sample of patients impacted by chronic migraine. In this open-label, single-arm study, patients with chronic migraine treated their headaches with the REN device (Nerivio, Theranica Bio-Electronics Ltd, Israel) for 4 weeks. Participants used an electronic diary to record their symptoms at treatment initiation, 2 hours after treatment, and 24 hours after treatment. The primary end point was the percentage of subjects who achieved pain relief at 2 hours posttreatment. Secondary end points included pain freedom and improvement of associated symptoms and functional disability. One hundred twenty-six subjects were enrolled into the study, of which 91 subjects had an evaluable treatment with REN. Pain relief and pain disappearance at 2 hours were achieved by 59.3% (54/91) and 20.9% (19/91) of modified intent-to-treat subjects, respectively (with worst-case sensitivity analysis indicating 54.5% and 19.2%, respectively). Sustained pain relief at 24 hours was observed in 64.4% (29/45) of those who achieved pain relief at 2 hours (with worst-case sensitivity analysis indicating 45.6%). The findings of the study show that REN has a favorable effect on nausea, photophobia, and phonophobia and improves functional ability. One device-related adverse event was reported. Remote electrical neuromodulation treatments results in the relief of migraine headaches and associated symptoms, thus offering a drug-free acute treatment option for people with chronic migraine. ClinicalTrials.gov NCT04194008.

Non-invasive neuromodulation in the acute treatment of migraine: a systematic review and meta-analysis of randomized controlled trials.

A systematic review and meta-analysis was performed to determine the efficacy of non-invasive neuromodulation modalities for the treatment of acute migraine. Although pharmacological treatments are the gold standard for the management of acute migraine, some patients may require non-pharmacological treatment options. Non-invasive neuromodulation may provide an alternative, and techniques include transcranial magnetic stimulation (TMS), non-invasive vagal nerve stimulation (nVNS), non-painful remote electrical stimulation (NRES), and external trigeminal nerve stimulation (e-TNS). This systematic review and meta-analysis was performed following PRISMA guidelines. We searched PUBMED, EMBASE, ClinicalTrials.gov, Cochrane Center Register of Controlled Trials, and LILACS databases. We included randomized controlled clinical trials studying patients with migraine treated with any form of non-invasive neuromodulation. Primary outcome was pain freedom within 2h post-treatment. Secondary outcomes were pain relief within 2-h post-treatment and sustained pain freedom and sustained pain relief 48h post-treatment. Pooled analysis demonstrated a significant effect of non-invasive neuromodulation on pain-free rates within 2h (RR, 1.66; 95% CI, 1.35 to 2.05; P < 0.00001) and pain relief rates within 2h (RR, 1.52; 95% CI, 1.13 to 2.05; P = 0.005) post-treatment. Non-invasive neuromodulation had no significant effect on sustained pain freedom at 48h (RR, 1.56; 95% CI, 0.68 to 3.59; P = 0.29) or sustained pain relief at 48h (RR, 1.47; 95% CI, 0.57 to 3.77; P = 0.43) after administration. Neuromodulation has demonstrated some efficacy in acute migraine management and may be considered in the treatment paradigm of acute migraine in patients with contraindications to pharmacological therapies.

Lasmiditan efficacy in the acute treatment of migraine was independent of prior response to triptans: Findings from the CENTURION study.

A significant proportion of triptan users exhibit an insufficient response or inadequate tolerability to a triptan, and some may develop a contraindication. Lasmiditan, a selective 5-HT1F receptor agonist, may be an option for these individuals. We assessed lasmiditan efficacy in a subgroup of patients in CENTURION (Phase 3 migraine consistency study) who exhibited an insufficient response to triptans, including a subgroup with insufficient response due to efficacy only. Patients were randomized to lasmiditan 200 mg for four attacks, lasmiditan 100 mg for four attacks, or placebo for three and lasmiditan 50 mg for one attack. Triptan insufficient responders were pre-defined as patients with insufficient efficacy or tolerability, or who developed a contraindication. In triptan insufficient responders, lasmiditan was superior to placebo (p < 0.05) for pain freedom beginning at 1 h (both doses); pain relief beginning at 0.5 (200 mg) or 1 h (100 mg); migraine-related disability freedom, much/very much better on the Patient Global Impression of Change, and most bothersome symptom freedom at 2 h; sustained pain freedom; and need for rescue medication. Lasmiditan showed benefit for consistency of effect across attacks for 2-h pain freedom and pain relief. Findings were similar in triptan responders and triptan naïve patients and when the triptan insufficient response definition was based on efficacy only. Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans.Trial Registration: CENTURION (NCT03670810); SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Comparison of New Pharmacologic Agents With Triptans for Treatment of Migraine

New therapeutic classes of migraine-specific treatment have been developed, including 5-hydroxytryptamine1F receptor agonists (lasmiditan) and calcitonin gene-related peptide antagonists (rimegepant and ubrogepant). To compare outcomes associated with the use of lasmiditan, rimegepant, and ubrogepant vs triptans for acute management of migraine headaches. The Cochrane Register of Controlled Trials, Embase, and PubMed were searched from inception to March 5, 2020. Double-blind randomized clinical trials examining current available migraine-specific acute treatments were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was applied to extract the data according to a predetermined list of variables of interest, and all network meta-analyses were conducted using a random-effects model. The primary outcome was the odds ratio (OR) for freedom from pain (hereafter referred to as pain freedom) at 2 hours after the dose, and the secondary outcomes were ORs for pain relief at 2 hours after the dose and any adverse events. A total of 64 randomized clinical trials were included (46 442 participants; 74%-87% women; age range, 36-43 years). Most of the included treatments were associated with reduced pain at 2 hours compared with placebo. Most triptans were associated with higher ORs for pain freedom at 2 hours compared with lasmiditan (range: OR, 1.72 [95% CI, 1.06-2.80] to OR, 3.40 [95% CI, 2.12-5.44]), rimegepant (range: OR, 1.58 [95% CI, 1.07-2.33] to OR, 3.13 [95% CI, 2.16-4.52]), and ubrogepant (range: OR, 1.54 [95% CI, 1.00-2.37] to OR, 3.05 [95% CI, 2.02-4.60]). Most triptans were associated with higher ORs for pain relief at 2 hours compared with lasmiditan (range: OR, 1.46 [95% CI, 1.09-1.96] to OR, 3.31 [95% CI, 2.41-4.55]), rimegepant (range: OR, 1.33 [95% CI, 1.01-1.76] to OR, 3.01 [95% CI, 2.33-3.88]), and ubrogepant (range: OR, 1.38 [95% CI, 1.02-1.88] to OR, 3.13 [95% CI, 2.35-4.15]). The comparisons between lasmiditan, rimegepant, and ubrogepant were not statistically significant for both pain freedom and pain relief at 2 hours. Lasmiditan was associated with the highest risk of any adverse events, and certain triptans (rizatriptan, sumatriptan, and zolmitriptan) were also associated with a higher risk of any adverse events than the calcitonin gene-related peptide antagonists. For pain freedom or pain relief at 2 hours after the dose, lasmiditan, rimegepant, and ubrogepant were associated with higher ORs compared with placebo but lower ORs compared with most triptans. However, the lack of cardiovascular risks for these new classes of migraine-specific treatments may offer an alternative to triptans.

The Effect and Safety of 5-HT1F Receptor Agonist Lasmiditan on Migraine: A Systematic Review and Meta-Analysis.

Background Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT1F receptor agonist appears more promising for aborting migraine attacks. Objective To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks. Methods The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model. Results Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75, 95% CI (0.61, 0.92), P = 0.007; 200 mg: RR = 0.81, 95% CI (0.66, 0.99), P = 0.04) at 2-24 h postdose, compared with placebo. Safety data showed that the proportion of patients reporting at least one treatment-emergent adverse event (TEAE) and the incidence of most common TEAEs such as dizziness, paresthesia, fatigue, somnolence, and nausea was higher in the lasmiditan groups (50 mg, 100 mg, and 200 mg), compared with placebo. There was no significant difference between lasmiditan and placebo in terms of cardiovascular-related TEAEs (RR = 2.75, 95% CI (0.81, 9.37), P = 0.11). Compared with lasmiditan 100 mg, lasmiditan 200 mg was more effective in pain freedom at 2 h after the first dose (RR = 0.83, 95% CI (0.74, 0.94), P = 0.004) but associated with a higher risk of reporting at least one TEAE (RR = 0.88, 95% CI (0.81, 0.96), P = 0.006). Conclusions Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term.

Intravenous ibuprofen for acute treatment of migraine: A double-blind, randomized, placebo-controlled pilot study.

To evaluate the efficacy and safety of intravenous (IV) Ibuprofen for acute treatment of migraine. IV nonsteroidal anti-inflammatory drugs (NSAIDs) are an alternative to oral NSAIDs, especially in patients with severe migraine who have emesis or gastroparesis. To date, only three IV NSAIDs (ketorolac, ibuprofen, and meloxicam) are available in the United States for use in moderate and severe pain, but no placebo-controlled trial is available for migraine. We performed a single-center, double-blind, randomized, placebo-controlled pilot study to evaluate the efficacy and safety of IV ibuprofen as an acute treatment of migraine (NCT01230411). Individuals with episodic migraine were screened at the Jefferson Headache Center. Qualified subjects were treated for migraine attacks within 2-72h following the headache onset with either 800mg of IV ibuprofen or placebo in 250ml saline bolus. Migraine pain intensity (4-point Likert scale) and associated symptoms were assessed at predetermined time points (0.25, 0.5, 1, 1.5, 2, 4, 8, 24h). The primary endpoint was pain relief at 2h after infusion. Important secondary endpoints included pain freedom at 2h, sustained relief over 24h, use of rescue therapy, and absence of associated symptoms. Adverse events (AEs) were also collected. Seventy-four participants were enrolled between 2011 and 2017. Forty-four subjects (female 33/44; 75.0%) with mean (SD) age 41.0 (11.2) 11.2 years came for the treatment. All treated subjects (n=44) were included in the analysis. Among them, 23 were randomized to receive IV ibuprofen. Both groups were demographically similar except for longer migraine duration (i.e., years lived with disease) in the active treatment than in the placebo group. At 2h posttreatment, pain relief was found in 74% (17/23) and 48% (10/21) after IV ibuprofen and placebo, respectively (odds ratio [OR] 3.12, 95% CI: 0.88-11.0; p=0.078). Other secondary endpoints at 2 and 24h were not significant. The longitudinal repeated-measures analysis within 2h on ibuprofen treatment showed significant pain relief (OR 2.47, 95% CI 1.08-5.7; p=0.033) and absence of associated symptoms: photophobia (OR 4.0, 95% CI 1.57-10.3; p=0.004), phonophobia (OR 3.12, 95% CI 1.16-8.4; p=0.025), and osmophobia (OR 3.45, 95% CI 1.01-11.8; p=0.048). AEs were observed in seven subjects in both groups, with arm pain being the most common. No serious AE was reported. This study did not meet the primary endpoint but showed pain relief and elimination of several associated symptoms within 2h on repeated-measures analysis. Although limited by small sample size and high placebo response, our results indicate that IV ibuprofen may be a safe and effective option for acute treatment of migraine, but more extensive studies are necessary.

New Gepants Against Acute Migraine

Objectives: Recently two calcitonin gene-related peptide receptor antagonists (ubrogepant and rimegepant) were approved for the acute attack of migraine. This systematic review and network meta-analysis was performed, so as to evaluate and comprehend the effectiveness of both ubrogepant and rimegepant in alleviating the acute attack of migraine. Materials and Methods: An in-depth search was performed through Cochrane library, Pub Med, and clincialtrials.gov, for the period 2015–2019, using the key words: ubrogepant; rimegepant; and acute migraine. The randomized double-blind phase III clinical trials that explored the efficacy of these drugs were considered for inclusion in this review. The outcomes for this review were considered as the proportion of patients who had to resort to rescue medication within 24 h of taking either of the gepant, and the proportion of patients who had achieved sustained pain freedom and relief. In addition, an indirect meta-analysis was also conducted to establish the comparative effectiveness of these drugs. In addition, risk of bias and heterogeneity among the trials were also assessed to ascertain the strength of the trials. Results: A total of five placebo-controlled RCTs were included in this review. Altogether, both drugs demonstrated well in the parameters assessed. Rimegepant was better than ubrogepant, as a lesser proportion of patients used rescue medication by 3.4%, and a significantly higher number of patients achieved sustained pain freedom by 2.1% at 2–24 h. In sustained pain relief at 2–24 h, rimegepant was slightly better than ubrogepant by 0.5%. Hence, rimegepant 75 mg emerged to be better in all outcomes. Conclusions: Both gepants proved to be efficacious in alleviating the acute attack of migraine. Rimegepant displayed superiority over the ubrgepant.

A Review of Eptinezumab Use in Migraine.

We present a review of the efficacy and safety profile of eptinezumab (also known by the brand name Vyepti), a calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) developed by Lundbeck Seattle BioPharmaceuticals, Inc., that received its first approval in the USA on 21 February 2020 for the preventive treatment of migraine in adults. It is administered by an intravenous infusion at a 100 mg dose every 3 months and shows no drug interactions.Studies have shown that eptinezumab is an effective preventative medication in migraine which starts showing its effect from day 1 of its administration, which maintains a consistent level of efficacy through a year of its treatment at doses 100 mg and 300 mg. It was found to be effective at reducing time to headache pain freedom during acute migraine attacks as well.Eptinezumab is a relatively safe drug for the prevention of migraines with treatment-related adverse events occurring at a low frequency. They bear a safe profile in patients with comorbidities like obesity and type 1 diabetes. The most frequent adverse events observed were nasopharyngitis, upper respiratory tract infections (URTIs), and sinusitis and were usually mild. The development of anti-drug antibodies was common, but they declined to undetectable levels with continued dosing and did not appear to impact the overall safety profile of the drug. Further studies are needed to assess long-term safety, use in different patient populations, and to compare its efficacy to other drugs of its class.

A close association of freedom from pain, migraine-related functional disability, and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN

BackgroundWhile pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing.MethodsPatient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom.ResultsPatients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time.ConclusionsThis study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint.Trial RegistrationSAMURAI (NCT02439320); SPARTAN (NCT02605174).

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Tolerability, and Safety of Celecoxib Oral Solution (ELYXYB) in Acute Treatment of Episodic Migraine with or without Aura.

BackgroundSafe, effective, oral therapies are needed for acute treatment of migraine. This clinical trial assessed the efficacy, tolerability, and safety of celecoxib oral solution (ELYXYB) in a single migraine attack associated with moderate-to-severe pain.MethodsThis was a phase III, randomized (1:1), double-blind, placebo-controlled trial, conducted at 41 US centers from December 2016 to October 2017. Adults with episodic migraine (with or without aura) for ≥1 year were treated with a single 4.8 mL dose of 120-mg celecoxib oral solution or placebo. Co-primary endpoints were the proportion of patients who were pain-free and free from the most bothersome migraine symptom (MBS) at 2 hours post-dose. The MBS was identified at screening from among nausea, photophobia, or phonophobia.ResultsSix hundred thirty-one patients were randomized (celecoxib oral solution, n=316; placebo, n=315; mean age 41 years, range 18–75; 84.3% female). One study site met prespecified outlier criteria (defined as a treatment effect estimate that was at least twice as large as all other sites) and was excluded from efficacy analyses. This site had a mean 2-hour pain freedom placebo response rate of 75% vs a combined mean of 23.5% for all other sites. In subsequent analysis, 2-hour post-dose pain freedom response rates were significantly higher in the celecoxib oral solution group vs placebo (32.8%, [27.2%, 38.8%]) vs 23.5%, [18.5%, 29.2%]; P=0.020). For 2-hour post-dose MBS freedom, response rates were significantly higher in the celecoxib oral solution group vs placebo (58.1% [51.4%, 64.5%] vs 43.9% [37.2%, 50.7%]; P=0.003). A total of 10.7% (31/289) of patients treated with celecoxib oral solution and 9.9% (28/283) of placebo-treated patients reported a treatment-emergent adverse event (TEAE). Study drug-related TEAEs were reported by 7.3% (21/289) and 7.4% (21/283) of celecoxib oral solution and placebo patients, respectively; the most common were nausea (celecoxib oral solution: 1.4% [4/289] vs placebo: 1.8% [5/283]) and dysgeusia (celecoxib oral solution: 1.7% [5/289] vs placebo: 1.1% [3/283]). No serious TEAEs, deaths, or drug-related TEAEs leading to withdrawal were reported.ConclusionCelecoxib oral solution is a safe, effective COX-2-selective nonsteroidal anti-inflammatory drug for the treatment of acute migraine. In this analysis, celecoxib oral solution was significantly more effective than placebo and was also associated with a low rate of gastric TEAEs. Celecoxib oral solution may provide a convenient, alternate option to currently available treatments.Trial RegistrationClinicalTrials.gov Identifier: NCT03009019; registered January 4, 2017; retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03009019.

가족해체 결혼이주여성의 가족재구성 경험에 관한 질적연구

This study is to examine the family dissolution and reconstruction experiences of marriage migrant women. To this end, in-depth interviews were conducted with seven marriage migrant women who got divorced and then formed new couple relationships in Korea. The data were analyzed by a phenomenological analysis method. As a result, the analysis identified 146 meaningful statements and 28 sub-categories resulting in 9 core categories: ‘getting off on the wrong foot,’ ‘mounting conflict and distrust,’ ‘expressions of deepening conflict and increasing anxiety,’ ‘escape from pain and incomplete freedom,’ ‘becoming a Korean as a mother for Korean children,’ ‘desire for happiness,’ ‘crack of happiness,’ ‘repositioning’ and ‘exercising embedded agency.’ The nature of marriage migrant women’s experience derived from these categories could be described as ‘surviving beyond the barrier behind the barrier.’ Based on the main findings, this paper discusses the practical implications for marriage migrants.

Comparison of Remote Electrical Neuromodulation and Standard-Care Medications for Acute Treatment of Migraine in Adolescents: A Post Hoc Analysis.

There is an unmet need for new, efficacious, well-tolerated, acute treatments for migraine in adolescents. Remote electrical neuromodulation (REN) is a novel, nonpharmacological treatment that provides significant symptom relief with good tolerability. The current post hoc analysis compared the efficacy of REN to that of standard-care medications for the acute treatment of migraine in adolescents. Within-participant post hoc analysis of data from a clinical trial. Data from a clinical trial. Data from 35 adolescent participants were analyzed. Efficacy was compared between a run-in phase, in which attacks were treated with standard-care medications (triptans or over-the-counter medications), and an intervention phase, in which attacks were treated with REN. Efficacy was compared within participants through the use of McNemar's test at four endpoints (2 hours after treatment): single-treatment pain freedom and pain relief, and consistency of pain freedom and pain relief (defined as response in at least 50% of the available first four treatments). At 2 hours after treatment, pain freedom was achieved by 37.1% of the participants with REN, vs 8.6% of the participants with medications (P = 0.004). Pain relief was achieved by 71.4% with REN, vs 57.1% with medications (P = 0.225). Consistency of pain freedom was achieved by 40% with REN, vs 8.6% with medications (P < 0.001). Consistency of pain relief was achieved by 80.0% with REN, vs 57.2% with medications (P = 0.033). Our results suggest that REN may have higher efficacy than certain standard-care medications for the acute treatment of migraine in adolescents. A larger-scale, blinded comparative-effectiveness and tolerability study is needed.

Acute Treatments for Episodic Migraine in Adults

Migraine is common and can be associated with significant morbidity, and several treatment options exist for acute therapy. To evaluate the benefits and harms associated with acute treatments for episodic migraine in adults. Multiple databases from database inception to February 24, 2021. Randomized clinical trials and systematic reviews that assessed effectiveness or harms of acute therapy for migraine attacks. Independent reviewers selected studies and extracted data. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction or by using a fixed-effect model based on the Mantel-Haenszel method if the number of studies was small. The main outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. The strength of evidence (SOE) was graded with the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Evidence on triptans and nonsteroidal anti-inflammatory drugs was summarized from 15 systematic reviews. For other interventions, 115 randomized clinical trials with 28 803 patients were included. Compared with placebo, triptans and nonsteroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day (moderate to high SOE) and increased risk of mild and transient adverse events. Compared with placebo, calcitonin gene-related peptide receptor antagonists (low to high SOE), lasmiditan (5-HT1F receptor agonist; high SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), acetaminophen (moderate SOE), antiemetics (low SOE), butorphanol (low SOE), and tramadol in combination with acetaminophen (low SOE) were significantly associated with pain reduction and increase in mild adverse events. The findings for opioids were based on low or insufficient SOE. Several nonpharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation (moderate SOE), transcranial magnetic stimulation (low SOE), external trigeminal nerve stimulation (low SOE), and noninvasive vagus nerve stimulation (moderate SOE). No significant difference in adverse events was found between nonpharmacologic treatments and sham. There are several acute treatments for migraine, with varying strength of supporting evidence. Use of triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited.

Effects of Intravenous Eptinezumab vs Placebo on Headache Pain and Most Bothersome Symptom When Initiated During a Migraine Attack

Intravenous eptinezumab, an anti-calcitonin gene-related peptide antibody, is approved for migraine prevention in adults. It has established onset of preventive efficacy on day 1 after infusion. To evaluate the efficacy of and adverse events related to eptinezumab when initiated during a migraine attack. Phase 3, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial conducted from November 4, 2019, to July 8, 2020, at 47 sites in the United States and the country of Georgia. Participants (aged 18-75 years) with a greater than 1-year history of migraine and migraine on 4 to 15 days per month in the 3 months prior to screening were treated during a moderate to severe migraine attack. Eptinezumab, 100 mg (n = 238), or placebo (n = 242), administered intravenously within 1 to 6 hours of onset of a qualifying moderate to severe migraine. Co-primary efficacy end points were time to headache pain freedom and time to absence of most bothersome symptom (nausea, photophobia, or phonophobia). Key secondary end points were headache pain freedom and absence of most bothersome symptom at 2 hours after start of infusion. Additional secondary end points were headache pain freedom and absence of most bothersome symptom at 4 hours and use of rescue medication within 24 hours. Of 480 randomized and treated patients (mean age, 44 years; 84% female), 476 completed the study. Patients treated with eptinezumab vs placebo, respectively, achieved statistically significantly faster headache pain freedom (median, 4 hours vs 9 hours; hazard ratio, 1.54 [P < .001]) and absence of most bothersome symptom (median, 2 hours vs 3 hours; hazard ratio, 1.75 [P < .001]). At 2 hours after infusion, in the respective eptinezumab and placebo groups, headache pain freedom was achieved by 23.5% and 12.0% (between-group difference, 11.6% [95% CI, 4.78%-18.31%]; odds ratio, 2.27 [95% CI, 1.39-3.72]; P < .001) and absence of most bothersome symptom by 55.5% and 35.8% (between-group difference, 19.6% [95% CI, 10.87%-28.39%]; odds ratio, 2.25 [95% CI, 1.55-3.25]; P < .001). Results remained statistically significant at 4 hours after infusion. Statistically significantly fewer eptinezumab-treated patients used rescue medication within 24 hours than did placebo patients (31.5% vs 59.9%, respectively; between-group difference, -28.4% [95% CI, -36.95% to -19.86%]; odds ratio, 0.31 [95% CI, 0.21-0.45]; P < .001). Treatment-emergent adverse events occurred in 10.9% of the eptinezumab group and 10.3% of the placebo group; the most common was hypersensitivity (eptinezumab, 2.1%; placebo, 0%). No treatment-emergent serious adverse events occurred. Among patients eligible for preventive migraine therapy experiencing a moderate to severe migraine attack, treatment with intravenous eptinezumab vs placebo shortened time to headache and symptom resolution. Feasibility of administering eptinezumab treatment during a migraine attack and comparison with alternative treatments remain to be established. ClinicalTrials.gov Identifier: NCT04152083.

Ubrogepant: An Oral Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist for Abortive Migraine Treatment.

To review the pharmacology, efficacy, and safety of ubrogepant as an abortive migraine treatment. A literature search of MEDLINE and PubMed was performed (January 2006 through May 2021) using the following search terms: ubrogepant, calcitonin gene related peptide, and abortive migraine therapy. Relevant studies evaluating ubrogepant's pharmacology, efficacy, and safety in humans for the treatment of migraine were considered. Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved by the Food and Drug Administration for the acute treatment of migraine via data from ACHIEVE I and II. From ACHIEVE I, ubrogepant demonstrated superiority to placebo in freedom from migraine pain at 2 hours postdose (50-mg dose: odds ratio [OR] = 1.83, 95% CI = 1.25-2.66; 100-mg dose: OR = 2.04, 95% CI = 1.41-2.95) and freedom from most bothersome symptom (MBS; 50-mg dose: OR = 1.70, 95% CI = 1.27-2.28; 100-mg dose: OR = 1.63, 95% CI = 1.22-2.17). ACHIEVE II trial demonstrated efficacy of ubrogepant 50 mg compared with placebo (2-hour pain freedom: OR = 1.62, 95% CI = 1.14-2.29; 2-hour MBS freedom: OR = 1.65, 95% CI = 1.25-2.20). Ubrogepant is a viable option for patients who are unable to tolerate nonsteroidal anti-inflammatory drug or triptan therapy because of ineffective relief or contraindications that limit use. Ubrogepant is a well-tolerated effective abortive migraine treatment that bridges a gap in therapy for many patients who previously could not tolerate other first-line treatments.