Remote electrical neuromodulation for migraine prevention: A double-blind,randomized, placebo-controlled clinical trial

Objective

To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine.

Background

Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine.

Methods

We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary.

Results

Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval −3.9 to −1.5], p < 0.001). The significance was maintained when analyzing the episodic (−3.2 ± 3.4 vs. −1.0 ± 3.6, p = 0.003) and chronic (−4.7 ± 4.4 vs. −1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group.

Conclusion

Applied every other day, REN is effective and safe for the prevention of migraine.     

Early intervention in migraine with sumatriptan tablets 50 mg versus 100 mg: a pooled analysis of data from six clinical trials

BACKGROUND: In clinical trials evaluating sumatriptan in the treatment of moderate or severe migraine pain, the 50- and 100-mg doses have been comparably effective and well tolerated. OBJECTIVE: To assess the dose-efficacy relationship of sumatriptan tablets given early for mild pain, data from 6 randomized, double-blind, placebo-controlled, early-intervention studies of sumatriptan tablets 50 mg and 100 mg (5 of which have been published) were pooled for analysis. These constitute all the studies conducted to date of sumatriptan tablets prospectively given early for mild pain. METHODS: The primary efficacy end point in all the studies was the proportion of patients reporting a pain-free result (ie, mild, moderate, or severe pain reduced to none) 2 hours postdose. Other efficacy end points included the proportion of patients who were migraine free (ie, no pain and no associated symptoms of nausea, vomiting, photophobia, or phonophobia) 2 hours postdose; the proportion reporting worsening of pain (ie, moderate or severe pain) 2 hours postdose; and the proportion with a sustained pain-free result (ie, pain free from 2-24 hours postdose with no use of a second dose of study medication or of rescue medication). Tolerability was assessed by evaluating the incidence of individual adverse events. The investigators assessed each adverse event's relationship to study medication. RESULTS: The number of patients in the intent-to-treat population was 2297 (771 sumatriptan 50 mg, 759 sumatriptan 100 mg, 767 placebo). Patients' mean age ranged from 39.4 to 39.8 years across groups, and most patients were female (90%-92%) and white (89%-90%). A pain-free result 2 hours post dose was reported by significantly more patients who took either dose of sumatriptan tablets compared with placebo and by significantly more patients who took the 100-mg dose compared with the 50-mg dose (50 mg, 49%; 100 mg, 58%; placebo, 24%; P < 0.001, both sumatriptan doses vs placebo, and 100 mg vs 50 mg). A similar pattern was observed for migraine-free results 2 hours postdose (50 mg, 42%; 100 mg, 47%; placebo, 20%; P < 0.05, both sumatriptan doses vs placebo, and 100 mg vs 50 mg), worsening of pain 2 hours postdose (50 mg, 26%; 100 mg, 21%; placebo, 46%; P < 0.05, both sumatriptan doses vs placebo, and 100 mg vs 50 mg), and sustained pain-free results from 2 through 24 hours postdose (50 mg, 30%; 100 mg, 35%; placebo, 12%; P < 0.05, both sumatriptan doses vs placebo, and 100 mg vs 50 mg). Both doses of sumatriptan were well tolerated, and no dose-related trends in the incidence of individual drug-related adverse events were observed. CONCLUSIONS: In this analysis of pooled data from 6 clinical trials, sumatriptan tablets 50 mg and 100 mg administered early in a migraine attack while the pain was mild were well tolerated and significantly more effective than placebo. The 100-mg dose of sumatriptan was significantly more effective than the 50-mg dose.     

Muscle endurance and cervical electromyographic activity during submaximal efforts in women with and without migraine

BackgroundDespite previous reports supporting cervical muscle weakness and altered motor control in migraine, the endurance under standardized submaximal loads has not been investigated. Therefore, this study aimed to assess the endurance and muscle activity of the cervical musculature during submaximal isometric contractions in women with migraine and those without headache.MethodsCervical muscle endurance tests were performed for flexors and extensors at 25%, 50%, and 75% of the output force during maximal isometric contraction using the Multi-Cervical Rehabilitation Unit with customized biofeedback. Initial values and relative rates of changes in root mean square and median frequency were calculated using cervical muscle superficial electromyography.FindingsWomen with chronic migraine presented significantly shorter flexor endurance time in all load tests than controls (25%, P = .001, 50%, P = .005; 75%, P = .013), while episodic migraine only differed from controls at 75% (P = .018). The frequency of neck pain and/or pain referred to the head after the endurance test was up 12% in the control group, 40% in the episodic migraine group and 68% of the chronic migraine group. Few differences between groups were observed in the electromyographic variables and none of them was related to a worse performance in the endurance tests.InterpretationCervical flexor endurance was reduced in women with chronic migraine when independent of the load, whereas it was reduced to 75% of the maximal force in those with episodic migraine. No difference in the electromyographic variables could be related to this reduced flexor endurance. Also, no differences were detected in extensors endurance.     

MAP0004, orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late treatments

OBJECTIVETo evaluate the efficacy of MAP0004, an orally inhaled dihydroergotamine, for acute treatment of migraine when administered at various time points from within 1 hour to more than 8 hours after migraine onset.PATIENTS AND METHODSThis post hoc subanalysis was conducted using data from 902 patients enrolled in a randomized, double-blind, placebo-controlled, 2-arm, phase 3, multicenter study conducted from July 14, 2008, through March 23, 2009. End points were 2-hour pain relief and pain-free rates in patients who treated a migraine in ≤1 hour, from >1 hour to ≤4 hours, from >4 to ≤8 hours, or in >8 hours after onset of migraine, given that patients may be unwilling or unable to initiate treatment at headache inception.RESULTSTreatment with MAP0004 was significantly more effective than placebo in relieving pain at all treatment points (≤1 hour after start of migraine: 66% [74/112] for MAP0004 vs 41% [48/118] for placebo, P<.001; >1 to ≤4 hours: 60% [91/153] vs 35% [58/168], P<.001; >4 to ≤8 hours: 53% [36/68] vs 30% [16/54], P=.008; and >8 hours: 48% [25/52] vs 24% [11/46], P=.007). Pain-free rates were also significantly higher with MAP0004 than placebo for treatment within 8 hours after migraine onset (≤1 hour: 38% [43/112] for MAP0004 vs 13% [15/118] for placebo, P<.001; >1 to ≤4 hours: 28% [43/153] vs 10% [17/168], P<.001; >4 to ≤8 hours: 22% [15/68] vs 7% [4/54], P<.025) but not at >8 hours (19% [10/52] vs 9% [4/46], P=.106).CONCLUSIONThis post hoc subanalysis shows that MAP0004 was effective in treating migraine irrespective of the time of treatment, even more than 8 hours after onset of migraine pain.     

Eptinezumab for the Prevention of Episodic Migraine: Sustained Effect Through 1 Year of Treatment in the PROMISE-1 Study

PurposeThe Prevention of Migraine via Intravenous ALD403 Safety and Efficacy 1 (PROMISE-1) study was a phase III, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, tolerability, and pharmacokinetic properties of repeat intravenous (IV) doses of the calcitonin gene–related peptide‒targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with episodic migraine. Here we present the results of PROMISE-1 through 1 year of treatment (up to 4 doses).MethodsPatients received up to 4 IV administrations of eptinezumab 30 mg, 100 mg, 300 mg, or placebo every 12 weeks. Patients recorded migraine and headache in an electronic diary daily. Additional assessments, including the patient-reported outcomes, were performed at regularly scheduled clinic visits throughout the 56-week study period.FindingsA total of 888 adults (mean age, 39.8 years; 84.3% female; 83.8% white) received treatment: eptinezumab 30 mg, n = 219; eptinezumab 100 mg, n = 223; eptinezumab 300 mg, n = 224; and placebo, n = 222. During the primary 12-week study evaluation period, single doses of eptinezumab 100 mg and 300 mg led to significant reductions in mean monthly migraine-days versus placebo, beginning as early as the first day after the initial dose. The reduction in mean monthly migraine-days was maintained throughout the study (100 mg, −3.9, −4.5, −4.7, and −4.5 days; 300 mg, −4.3, −4.8, −5.1, and −5.3 days; and placebo, −3.2, −3.8, −4.0, and −4.0 days during weeks 1–12, 13–24, 25–36, and 37–48, respectively). Overall, the number of patients with a ≥50% or ≥75% reduction in migraine for each 12-week interval during the entire study was consistently numerically higher in the eptinezumab groups than in the placebo group. The proportions of patients with ≥50% reduction in migraine were similar across the eptinezumab groups. Eptinezumab was well tolerated throughout the study. Adverse events were similar across dosing periods, and there were no serious tolerability signals identified with continued dosing.ImplicationsIV eptinezumab administered every 12 weeks for up to 4 doses was associated with early and sustained migraine-preventive effects and a favorable safety profile in adults with episodic migraine. ClinicalTrials.gov identifier: NCT02559895.     

A phase 2, double-blind,randomized, placebo-controlled,dose-escalation study to evaluate the efficacy,safety, and tolerability of naloxegol in patients with opioid-induced constipation

Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n = 207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30–1000 mg/day morphine equivalents for ?2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50 mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P = 0.0020] and 3.3 vs 0.5 [P = 0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25 mg (3.0 vs 0.8 [P = 0.0022]) and 50 mg (3.5 vs 1.0 [P < 0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25 mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC.     

Pain-free results with sumatriptan taken at the first sign of migraine pain: 2 randomized, double-blind, placebo-controlled studies

OBJECTIVE: To evaluate the efficacy and tolerability of sumatriptan, 50-mg and 100-mg tablets, compared with placebo for treatment of migraine at the first sign of pain. PATIENTS AND METHODS: Two identical multicenter randomized, double-blind, placebo-controlled, single-attack studies were conducted from May through November 2000 in adults (aged 18-65 years). Patients treated migraine at the first sign of pain, while pain was mild, but not more than 2 hours after onset with oral sumatriptan, 50 mg or 100 mg, or matching placebo. The primary end point was pain-free relief at 2 hours after treatment with 50 mg of sumatriptan compared with placebo. RESULTS: There were 354 patients in study 1 and 337 patients in study 2. Significantly more patients treated with sumatriptan, 50 mg and 100 mg, were completely free from pain 2 and 4 hours after treatment vs patients treated with placebo (at 2 hours, 50% and 57% vs 29%; at 4 hours, 61% and 68% vs 30%; for both, P < .001). Also, significantly more patients treated with sumatriptan, 50 mg and 100 mg, were migraine-free (no pain or associated symptoms) vs those treated with placebo at 2 and 4 hours after treatment (at 2 hours, 43% and 49% vs 24%; at 4 hours, 54% and 63% vs 28%; for both, P < .001). The incidence of overall adverse events was low with the 50- and 100-mg dose of sumatriptan (placebo, 7%; sumatriptan at 50 mg, 14%; sumatriptan at 100 mg, 16%). CONCLUSIONS: Treatment of migraine at the first sign of pain with sumatriptan, 50-mg and 100-mg tablets, provides superior pain-free relief at 2 and 4 hours after treatment compared with placebo. Results of these studies suggest that sumatriptan at 100 mg may be more efficacious than at 50 mg when used in the early treatment paradigm. Because these studies were not powered to detect statistical differences between active doses, studies to investigate this finding are warranted.     

Effect of Cardamom Inhalation Therapy on Intra-and Postoperative Nausea and Vomiting of Mothers Undergoing Spinal Anesthesia for Elective Cesarean Section

PurposeThis study aimed to determine the effect of cardamom inhalation on intra and postoperative nausea and vomiting (IONV/PONV) of mothers undergoing spinal anesthesia for elective cesarean section.DesignA single-blind, randomized, placebo-controlled clinical trial study.MethodsSeventy eligible participates were equally randomized to the intervention or placebo group. The demographic and clinical characteristics questionnaire, a 100 mm Visual Analogue Scale (VAS) to measure the severity of nausea; and the mothers' emetic episodes checklist were used. Upon the first episode of nausea, participants inhaled through a plastic bag containing distilled gauze pads in normal saline with or without Cardamom essential oil.FindingsFollowing the intervention, nausea severity in placebo (25.28 ± 32.38) and cardamom (13.14 ± 19.96) groups declined (P < .001), however after controlling the initial severity of nausea, the declining extent was more noticeable in the intervention group than in the placebo group. The episodes of nausea (37.1% vs 65.7%, P = .006), and retching (20% vs 45.7%, P = .028) were significantly lower in the intervention group than in the placebo group. Administration of antiemetic medications was lower in the intervention than the placebo group (37.1% vs 65.7%, P = .009).ConclusionsCardamom aromatherapy was effective in alleviating mothers’ experience of nausea and retching across the cesarean surgical continuum. As such, it can be considered as a palliative treatment for IONV/PONV in Cesarean section surgeries.     

Treatment with sumatriptan 50 mg in the mild phase of migraine attacks in patients with infrequent attacks: a randomised, double-blind, placebo-controlled study

Most migraine patients with infrequent attacks are currently not treated with migrainespecific medication such as triptans. The response of these patients to triptans is unknown. The objective of this study was to investigate the efficacy and tolerability of sumatriptan 50 mg vs. placebo in migraine patents with infrequent migraine attacks when medication is taken during the mild phase of an attack. The study design was double-blind, placebocontrolled, parallel-group and randomised. Migraine patients were recruited by general practitioners and referred to one of 4 study centres. Additional patients were recruited by advertising. The patients were eligible for the study if they had between 6 and 12 migraine attacks with or without aura per year. The patients were instructed to take the medication during the mild phase of a single attack. The primary efficacy measure was the percentage of patients pain-free after 2 h. Fortysix percent of treated attacks were moderate or severe. In the intention-to-treat analysis, sumatriptan was superior (20/51 patients were pain-free) to placebo (8/47 patients pain-free) (p=0.03). Adverse events (AEs) occurred more frequently after sumatriptan (40%) than after placebo (13%) (p=0.003) and most AEs were mild or moderate. In this migraine population with infrequent attacks, sumatriptan was superior to placebo and was generally well tolerated.     

Almotriptan in migraine patients who respond poorly to oral sumatriptan: a double-blind, randomized trial

OBJECTIVE: To investigate the efficacy and tolerability of almotriptan 12.5 mg in migraine patients who respond poorly to sumatriptan 50 mg. BACKGROUND: Poor response to sumatriptan therapy for acute migraine attacks has been documented in the literature, but few controlled trials have investigated the efficacy of an alternative triptan in this subgroup of patients. METHODS: Patients with an International Headache Society diagnosis of migraine who self-described as experiencing at least two unsatisfactory responses to sumatriptan treated their first migraine attack with open-label sumatriptan 50 mg. Patients who did not achieve 2-hour pain relief (improvement of headache from moderate/severe to mild/no headache) were then randomized to treat their second attack with almotriptan 12.5 mg or placebo under double-blind conditions. RESULTS: In the first attack, 221 of 302 participants (73%) did not achieve 2-hour pain relief with sumatriptan and were randomized to treatment of their second attack with almotriptan 12.5 mg or placebo. Of the 198 sumatriptan nonresponders who treated their second attack (99 almotriptan; 99 placebo), 70% had severe headache pain at baseline. Two-hour pain-relief rates were significantly higher with almotriptan compared to placebo (47.5% vs 23.2%; P<.001). A significant treatment effect for almotriptan was also seen in pain-free rates at 2 hours (33.3% vs 14.1%; P<.005) and sustained freedom from pain (20.9% vs 9.0%; P<.05). In the second attack, 7.1% of patients in the almotriptan group experienced adverse events compared to 5.1% in the placebo group (P=.77). CONCLUSIONS: Almotriptan 12.5 mg is an effective and well-tolerated alternative for patients who respond poorly to sumatriptan 50 mg. A poor response to one triptan does not predict a poor response to other agents in that class.     

Efficacy and tolerability of almotriptan in adolescents: a randomized, double-blind, placebo-controlled trial

Objectives.— To assess the efficacy and safety of almotriptan 6.25 mg, 12.5 mg, and 25 mg vs placebo for acute migraine treatment in adolescents. Patients and Methods.— In this double‐blind, placebo‐controlled, parallel‐group, multicenter trial, 866 patients aged 12 to 17 years with a >1 year history of migraine (per International Headache Society criteria) were randomized to treat one migraine headache with almotriptan 6.25 mg, 12.5 mg, 25 mg, or placebo. The primary efficacy endpoint was headache pain relief 2 hours after dosing, adjusted for baseline severity, with absence of nausea, photophobia, and phonophobia 2 hours after dosing as coprimary endpoints. Results.— The 2‐hour pain‐relief rate was significantly higher with almotriptan 25 mg compared with placebo (66.7% vs 55.3%; P = .022). The incidence of nausea, photophobia, and phonophobia at 2 hours (adjusted for baseline pain intensity) for the almotriptan 25 mg and placebo groups was not significantly different. The 2‐hour pain‐relief rates (unadjusted) were significantly higher with almotriptan 6.25 mg (71.8%), 12.5 mg (72.9%), and 25 mg (66.7%) than with placebo (55.3%; P = .001, P < .001, and P = .028, respectively). Rates for sustained pain relief also were significantly greater with almotriptan 6.25 mg (67.2%), 12.5 mg (66.9%), and 25 mg (64.5%) than with placebo group (52.4%), P < .01 for the 6.25‐ and 12.5‐mg doses and P < .05 for the 25‐mg dose. Age group subanalysis demonstrated significantly greater 2‐hour pain‐relief rates with all 3 doses of almotriptan compared with placebo for patients aged 15 to 17 years, a significantly lower incidence of photophobia and phonophobia at 2 hours with almotriptan 12.5 mg compared with placebo for patients aged 15 to 17 years, and a significantly lower incidence of photophobia with almotriptan 12.5 mg compared with placebo for those aged 12 to 14 years. Almotriptan treatment was well tolerated, with the most common adverse events (>2%) of nausea, dizziness, and somnolence. Conclusions.— Oral almotriptan was efficacious for relieving migraine headache pain in adolescents, with the 12.5‐mg dose associated with the most favorable efficacy profile with respect to relieving headache pain and associated symptoms of migraine (photophobia and phonophobia). Almotriptan treatment was well tolerated in this adolescent population.     

Two replicate randomized, double-blind, placebo-controlled trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets

BACKGROUND: The gastric stasis that commonly accompanies migraine headache may impair absorption of conventional oral tablets in the stomach. A fast-disintegrating/rapid-release formulation of sumatriptan has been developed to enhance tablet disintegration and drug dispersion and potentially improve absorption. OBJECTIVE: Two studies were conducted comparing the time to onset of relief from moderate or severe migraine pain with the fast-disintegrating/rapid-release formulation of sumatriptan tablets 50 and 100 mg and placebo. METHODS: These were 2 identically designed randomized, double-blind, parallel-group studies. Sumatriptan 50 or 100 mg or placebo was taken on an outpatient basis to treat a single moderate or severe migraine attack. Using a personal digital assistant, patients recorded the time of dosing and the time at which pain severity reached none or mild (ie, pain relief) or none (ie, pain free) in real time so that the time to onset of relief could be measured as a continuous variable. Onset of relief was defined as the earliest time point at which a statistically significant difference in pain relief compared with placebo was achieved and maintained through 2 hours after dosing. Before dosing and at pre-determined time points after dosing, patients also provided an assessment of migraine pain as none, mild, moderate, or severe. At a clinic visit within 1 week after treatment of the migraine attack, patients were queried about adverse events. For each adverse event, investigators recorded whether study medication was considered the cause. Data analyses were undertaken for each study individually and, in post hoc analyses of the primary and key secondary end points, on pooled data from both studies. RESULTS: The 2 studies comprised 2696 patients: 902 received sumatriptan 50 mg, 902 received sumatriptan 100 mg, and 892 received placebo. Patients' mean age ranged from 40.2 to 40.8 years across treatment groups, and most patients were female (83%-87%) and white (92%-93%). In the analysis of pooled data, sumatriptan tablets provided significantly more effective pain relief compared with placebo as early as 20 minutes after dosing with the 100-mg dose and as early as 30 minutes after dosing with the 50-mg dose (P < or = 0.05). Similar results were observed for the individual studies: in study 1, sumatriptan tablets were significantly more effective than placebo at 25 minutes with the 100-mg dose and at 50 minutes with the 50-mg dose; in study 2, sumatriptan tablets were significantly more effective than placebo at 17 minutes for the 100-mg dose and at 30 minutes for the 50-mg dose (P < or = 0.05). In the pooled data, the cumulative percentages of patients with pain relief by 2 hours after dosing were 72% for the 100-mg dose and 67% for the 50-mg dose, compared with 42% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). The cumulative percentages of patients with a pain-free response by 2 hours were 47% for the 100-mg dose, 40% for the 50-mg dose, and 15% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). In the individual studies, significantly more patients receiving either sumatriptan dose were migraine free 2 hours after dosing and had sustained pain relief and a sustained pain-free response over 24 hours compared with placebo (P < or = 0.001, both sumatriptan doses vs placebo). The only drug-related adverse events reported in >2% of patients in any treatment group in either study were nausea (both studies: 3% sumatriptan 100 mg, 2% sumatriptan 50 mg, 1% placebo) and paresthesia (study 1: <1% sumatriptan 100 mg, <1% sumatriptan 50 mg, 0% placebo; study 2: 3% sumatriptan 100 mg, 1% sumatriptan 50 mg, <1% placebo). CONCLUSIONS: In these studies, sumatriptan tablets in a fast-disintegrating/rapid-release formulation were effective for the acute treatment of moderate to severe migraine pain, were generally well tolerated, and achieved an onset of pain relief as early as 20 minutes for 100 mg and as early as 30 minutes for 50 mg.     

Efficacy, speed of action and tolerability of almotriptan in the acute treatment of migraine: pooled individual patient data from four randomized, double-blind, placebo-controlled clinical trials

A meta-analysis of pooled individual patient data from four randomized, placebo-controlled, double-blind trials comparing several doses of almotriptan (n = 1,908) with placebo (n = 386) was used to investigate the efficacy, speed of onset and tolerability of almotriptan in the acute treatment of migraine. As early as 30 min after dosing, almotriptan 12.5 mg was significantly more effective than placebo for pain relief (14.9% vs. 8.2%; P < 0.05) and pain free (2.5% vs. 0.7%; P < 0.05). At 2 h, pain-relief rates were 56.0%, 63.7% and 66.0% for almotriptan 6.25, 12.5 and 25 mg, respectively, compared with 35% for placebo; 2-h pain-free rates were 26.7%, 36.4% and 43.4% compared with 13.9% for placebo. All almotriptan dosages were significantly more effective than placebo in eliminating migraine-associated symptoms (P < 0.05) and in achieving sustained pain relief up to 24 h (P < 0.05). The incidence of adverse events after almotriptan 6.25 mg and 12.5 mg was not significantly different from that of placebo. This meta-analysis confirms the findings of individual clinical trials, while demonstrating for the first time, significant pain-free efficacy at 30 min compared with placebo.     

The efficacy of ginger for the treatment of migraine: A meta-analysis of randomized controlled studies

IntroductionThe efficacy of ginger for migraine remains controversial. We conduct a systematic review and meta-analysis to explore the influence of ginger versus placebo on treatment in migraine patients.MethodsWe have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through September 2020 for randomized controlled trials (RCTs) assessing the effect of ginger versus placebo on treatment efficacy in migraine patients. This meta-analysis is performed using the random-effect model.ResultsThree RCTs are included in the meta-analysis. Overall, compared with control group in migraine patients, ginger treatment is associated with substantially improved pain free at 2 h (RR = 1.79; 95% CI = 1.04–3.09; P = 0.04) and reduced pain scores at 2 h (MD = −1.27; 95% CI = −1.46 to −1.07; P < 0.00001), but reveals no obvious impact on treatment response (RR = 2.04; 95% CI = 0.35–11.94; P = 0.43) or total adverse events (RR = 0.80; 95% CI = 0.46–1.41; P = 0.44). The incidence of nausea and vomiting is obviously lower in ginger group than that in control group.ConclusionsGinger is safe and effective in treating migraine patients with pain outcomes assessed at 2 h.     

High-dose regimen to achieve novel target trough concentration in teicoplanin

In the treatment of severe MRSA infections such as endocarditis, more than 20 mg/L of plasma trough concentration (C_min) is recommended for teicoplanin; however, in the treatment of common MRSA infections, recommended C_min remains more than 10 mg/L. In this study, we set C_min as 15–30 mg/L to obtain a favorable clinical outcome in the treatment of common MRSA infections, and investigated the optimal loading regimen that achieved the target C_min in patients with normal renal function. Seventy-eight patients received the high-dose regimen A (6 mg/kg every 12-h for initial two days) and 60 patients received the high-dose regimen B (the first five loading doses of 10–12 mg/kg at 12-h intervals for initial three days, followed by 6 mg/kg once daily). The mean C_min on the 4th day was 13.7 ± 5.3 mg/L in regimen A, and 20.0 ± 6.6 mg/L in regimen B (P < 0.001), and the proportion of patients achieving the 15–30 mg/L was 25.6% and 68.3% (P < 0.001). Clinical response at end-of treatment were 66.7% and 85.0% (P = 0.014). The patients of initial C_min with ≥15 mg/L had tended to be higher clinical response than those with <15 mg/L (80.9% vs 68.6%, P = 0.084). There were no significant differences in the occurrence of adverse effects in regimen A and B (nephrotoxicity; 1.3% vs 3.3%, P = 0.413, hepatotoxicity; 5.1% vs 3.3%, P = 0.608). In conclusion, to obtain C_min 15–30 mg/L, the first five loading doses of 10–12 mg/kg at 12-h intervals was required in patients with normal renal function.     

Feasibility of Using Detuned Laser as a Placebo In Manual Therapy Research: An Analysis of Participant Perceptions

ObjectiveThe purpose of this study was to determine the feasibility of using detuned laser as a placebo intervention in manual therapy research.MethodsWe performed a secondary data analysis of a randomized controlled trial. In our analysis, 30 participants with chronic ankle instability (manual therapy group: n = 13, age = 33.1 ± 8.1 years, female participants = 50%; detuned laser group: n = 17, age = 31.9 ± 11.8 years, female participants = 72%) were asked to indicate which intervention (manual therapy [active] or detuned laser [placebo]), they thought they had received and to give a confidence rating on their response regarding the received intervention at the conclusion of the course of intervention. Independent t tests were used to compare the groups. Participants in both groups were asked the following open-ended question: “What did you think of the intervention?”.ResultsThere were 52.9% participants in the detuned laser group and 53.8% participants in the manual therapy group who perceived that they had received the active intervention. The confidence ratings about their perceptions (6.7 ± 2.0, detuned laser group; 6.3 ± 2.4, manual therapy group) (P = .66) and the self-reported recovery ratings (1.9 ± 1.5 and 1.8 ± 1.2, respectively) (P = .77) were similar.ConclusionsParticipants in this study confidently perceived that detuned laser was an active intervention. They positively rated their recovery following the course of the placebo intervention and perceived that detuned laser was effective in treating their condition. Therefore, it is feasible for detuned laser to be used as a placebo for manual therapy trials.     

Functionality,satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: a post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials

BackgroundTriptans are the first-line option for the acute treatment of migraine attacks; however, triptans are contraindicated in people with certain underlying cardiovascular risk factors and are associated with inadequate efficacy or poor tolerability in some individuals. Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine.MethodsThis post hoc analysis of the phase 3 ACHIEVE trials examined the impact of ubrogepant on the Functional Disability Scale (FDS), satisfaction with medication, and Patient Global Impression of Change (PGIC) in participants who were self-reported triptan insufficient responders (TIRs), defined as those who are unable to take triptans due to contraindications, tolerability issues, or insufficient efficacy. Responder definitions for the FDS, satisfaction measures, and PGIC were based on qualitative interpretation of the respective response options for the pooled ubrogepant 50 mg and placebo groups.ResultsIn the pooled analysis population (n = 1799), 451 (25%) participants were TIRs, with most (80%) reporting insufficient efficacy with triptan use. A significantly higher proportion of TIRs treated with ubrogepant vs placebo reported being able to function normally from 2 to 8 h post dose (P < 0.05). Notably, significance was demonstrated at the time of the primary outcome assessments (2 h post dose), where rates of normal function were 38% for ubrogepant vs 29% for placebo (P = 0.048). A greater proportion of TIRs in the ubrogepant arm vs the placebo arm were satisfied with treatment at 2 (33% vs 21%, P = 0.006) and 24 h (58% vs 28%, P < 0.001) and indicated that their migraine improved at 2 h vs placebo (30% vs 18%, P = 0.006). Results were generally similar in the insufficient efficacy subpopulation of TIRs as in the overall TIRs group. Ubrogepant was safe and well tolerated in TIRs, with no new safety signals identified.ConclusionsIn people with migraine who are TIRs, individuals treated with ubrogepant had favorable 2-h outcomes, as measured by the FDS, satisfaction with medication, and PGIC, compared with placebo.Trial registrationClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02828020","term_id":"NCT02828020"}}NCT02828020 (ACHIEVE I), registered July 11, 2016; {"type":"clinical-trial","attrs":{"text":"NCT02867709","term_id":"NCT02867709"}}NCT02867709 (ACHIEVE II), registered August 16, 2016.     

Identification of negative predictors of pain-free response to triptans: analysis of the eletriptan database

Thirty to forty percent of migraineurs do not respond to any given triptan treatment. We identified clinical variables that significantly predict therapeutic non-response and evaluated the efficacy of eletriptan (20, 40 and 80 mg) and sumatriptan (100 mg) vs. placebo in a subgroup of patients with all predictor variables. First-attack data were pooled from 10 randomized, double-blind, placebo-controlled migraine trials ( n  = 8473). Multivariate regression analyses identified three significant baseline predictors of failure to achieve 2-h pain-free response: severe headache pain, presence of photophobia/phonophobia and presence of nausea. Time of dosing following headache onset did not influence 2-h pain-free response. Among patients with all three risk factors ( n  = 2010; 24% of total sample), 2-h pain-free response was significantly higher in patients receiving all three doses of eletriptan or sumatriptan vs. placebo (all P  < 0.01). Thus, eletriptan and sumatriptan are efficacious in difficult-to-treat patients at high risk for non-response to triptans.     

Empagliflozin Monotherapy in Japanese Patients with Type 2 Diabetes Mellitus: a Randomized, 12-Week,Double-Blind,Placebo-Controlled,Phase II Trial

Introduction

This study was designed to determine the efficacy and tolerability of empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus (T2DM).

Methods

Patients with glycosylated hemoglobin (HbA1c) ≥7.0–≤10% were randomized via an interactive web response system, and treated double-blind with empagliflozin 5, 10, 25, 50 mg, or placebo once daily for 12 weeks. The primary endpoint was change from baseline in HbA1c at week 12. Other endpoints included percentage of patients with HbA1c <7.0% and changes from baseline in fasting plasma glucose (FPG), body weight, and systolic blood pressure (SBP) at week 12.

Results

A total of 547 patients were randomized and treated with empagliflozin 5 mg (n = 110), 10 mg (n = 109), 25 mg (n = 109), 50 mg (n = 110), or placebo (n = 109) for 12 weeks. Adjusted mean [95% confidence interval (CI)] differences vs. placebo in changes from baseline in HbA1c were ?0.72% (?0.87, ?0.57) with empagliflozin 5 mg, ?0.70% (?0.85, ?0.55) with 10 mg, ?0.95% (?1.10, ?0.80) with 25 mg, and ?0.91 (?1.06, ?0.76) with 50 mg (all p < 0.001). More patients with HbA1c ≥7.0% at baseline reached HbA1c <7.0% with empagliflozin (19–33%) than placebo (3%). Compared with placebo, empagliflozin reduced FPG, body weight (p < 0.001 for all doses for both endpoints) and SBP (p = 0.001, p = 0.014 and p = 0.003 for empagliflozin 10, 25, and 50 mg, respectively). Adverse events were reported by 42% of patients receiving placebo and 33–38% of patients receiving empagliflozin. There were few reports of confirmed hypoglycemic adverse events or events consistent with urinary tract infection or genital infection in any treatment group.

Conclusions

Empagliflozin monotherapy for 12 weeks in Japanese patients with T2DM reduced HbA1c, FPG, body weight and SBP, and was well tolerated.     

2000 Wolfe Award. Sumatriptan for the range of headaches in migraine sufferers: results of the Spectrum Study

BACKGROUND: Migraineurs experience a spectrum of headaches: migraine, migrainous, and episodic tension-type as defined by the International Headache Society (IHS). OBJECTIVE: To evaluate the effectiveness of sumatriptan, 50-mg tablets, in treating the spectrum of headaches in IHS-diagnosed migraineurs. DESIGN/METHODS: Migraineurs with severe disability (Headache Impact Questionnaire score 250 or greater) were enrolled in a randomized, double-blind, placebo-controlled, crossover study. Patients treated up to 10 headaches with sumatriptan, 50 mg, or placebo (4:1). Headache features, recorded prior to treatment, were used to classify each headache using IHS criteria. Headache response (moderate or severe pain reduced to mild or no pain) and pain-free response were recorded at 2 and 4 hours postdose (primary endpoint). Because patients treated multiple attacks, statistical methods controlling for within-subject correlation were used. RESULTS: Two hundred forty-nine migraineurs treated 1576 moderate or severe headaches: migraine (n = 1110), migrainous (n = 103), and tension-type (n = 363). Sumatriptan was superior to placebo for headache response 4 hours postdose (primary endpoint) across all headache types (migraine, 66% versus 48%; P<.001; migrainous, 71% versus 39%; P<.01; tension-type, 78% versus 50%, P<.001). Sumatriptan was also superior to placebo for pain-free response 4 hours postdose for migraine (41% versus 24%, P<.001) and tension-type headaches (56% versus 36%, P =.001). Sumatriptan provided superior pain-free response 2 hours postdose for migraine (18% versus 7%, P<.0001) and tension-type headache (28% versus 14%, P =.0005) compared with placebo. CONCLUSION: Sumatriptan, 50-mg tablets, are effective for the full spectrum of headaches experienced by patients with disabling migraine due to a sumatriptan-responsive mechanism.