Adverse Events Related to Cartiva Hemiarthroplasty of First Metatarsal: An Analysis of Reports to the United States Food and Drug Administration.

Background: The results supporting Cartiva, a synthetic cartilage implant (Wright Medical) in hallux rigidus have come from limited institutions creating observational bias. Complications experienced in community centers are not routinely included in the published literature. To look at a broader range of potential complications, we reviewed the United States Food and Drug Administration's (FDA) voluntary device database and compared that data with published literature. Methods: The Manufacturer and User Facility Device Experience (MAUDE) database of the FDA was retrospectively reviewed between July 2016 and October 2019 using the product code: PNW, assigned for Cartiva. Results: A total of 49 events have been reported and implant subsidence was the most common with 16 reports. Others include fragmentation (9), infection (4), bone erosion (3), foreign body reaction (1) and unspecified (16). Thirty-five events mentioned further surgeries at a mean interval of 4.75 months. Conclusions: The analysis of the MAUDE database disclosed certain device-related dysfunctions that have been underreported in the published literature. Because of the voluntary nature of reporting, the true incidence of each complication is unknown with this data representing a baseline. The MAUDE database could be further strengthened by a more robust reporting mechanism or mandatory reporting of device-related complications.Levels of Evidence: Level IV: Case series from large database analysis.

Adverse events related to total ankle replacement devices: an analysis of reports to the United States Food and Drug Administration.

BACKGROUND: The published outcomes of total ankle replacement (TAR) implants came from limited institutions creating observational bias. For broader perspective, we queried the Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience (MAUDE) voluntary database to explore complications reported outside published literature. METHODS: The database was reviewed retrospectively between November 2011 and April 2019 using two product codes assigned to six TAR devices. RESULTS: Among 648 relevant reports available in the database, common complications were aseptic loosening (19.3%), infection (18.2%), and alignment/mechanical issues (16.5%). Others included instrument/instrumentation complications, impingement, polyethylene problems, fractures, avascular necrosis of talus (AVN), and packaging issues. CONCLUSION: MAUDE database revealed various patterns of device-related malfunctions that have been under-reported in published data. Despite inconsistency in the available reports, it provided opportunities for improvements in quality control, device design, and ultimately patient safety. Database would be further strengthened by more robust reporting mechanism or mandatory reporting of device-related complications.

Instrumented immobilizing boot paradigm quantifies reduced Achilles tendon loading during gait.

Achilles tendon ruptures are common injuries that lead to functional deficits in two-thirds of patients. Progressively loading the healing tendon has been associated with superior outcomes, but the loading profiles that patients experience throughout rehabilitation have not yet been established. In this study, we developed and calibrated an instrumented immobilizing boot paradigm that is aimed at longitudinally quantifying patient loading biomechanics to develop personalized rehabilitation protocols. We used a 3-part instrumented insole to quantify the ankle loads generated by the Achilles tendon and secured a load cell inline with the posterior strut of the immobilizing boot to quantify boot loading. We then collected gait data from five healthy young adults to demonstrate the validity of this instrumented immobilizing boot paradigm to assess Achilles tendon loading during ambulation. We developed a simple calibration procedure to improve the measurement fidelity of the instrumented insole needed to quantify Achilles tendon loading while ambulating with an immobilizing boot. By assessing Achilles tendon loading with the ankle constrained to 0 degrees and 30 degrees plantar flexion, we confirmed that walking with the foot supported in plantar flexion decreased Achilles tendon loading by 60% (P < 0.001). This instrumented immobilizing boot paradigm leverages commercially available sensors and logs data using a small microcontroller secured to the boot and a handheld device, making our paradigm capable of continuously monitoring biomechanical loading outside of the lab or clinic.

Ultrasound echogenicity is associated with fatigue-induced failure in a cadaveric Achilles tendon model.

Achilles tendon disorders are among the most difficult sports-related injuries to predict with current diagnostic tools. The purpose of this study was to identify a clinically useful marker for early tendon damage. We hypothesized that alterations in mean echogenicity are linked with changes in vitro tendon mechanics. To test our hypothesis, we harvested Achilles tendons from 10 fresh-frozen cadaveric feet and cyclically fatigued them using a universal test frame while we continuously acquired ultrasound images. Throughout this fatigue protocol, we applied 2 stress tests every 500 loading cycles to quantify changes in ultrasound imaging echogenicity. We continued this fatigue protocol until each tendon either failed completely or survived 150,000 cycles. Tendons that failed during the fatigue loading (6/10) underwent greater changes in mean echogenicity compared to tendons that did not fail (P = 0.031). These tendons that failed during fatigue loading demonstrated greater changes in mean echogenicity that surpassed 1.0%; whereas survivor tendons exhibited less than 0.5% changes in mean echogenicity. We found that changes in mean echogenicity measured with ultrasound increased proportionally with increased tendon damage. The magnitude of these changes was relatively small (<1.5% change in mean echogenicity) but may be an effective predictor of tendon failure. Mean echogenicity is a promising marker for quantifying fatigue damage in cadaveric Achilles tendons during a stress test. Although these changes cannot be detected with the naked eye, computer-based predictive models may effectively assess risk of tendon damage in physically active adults.

Medial gastrocnemius muscle remodeling correlates with reduced plantarflexor kinetics 14 weeks following Achilles tendon rupture.

Deficits in plantarflexor kinetics are associated with poor outcomes in patients following Achilles tendon rupture. In this longitudinal study, we analyzed the fascicle length and pennation angle of the medial gastrocnemius muscle and the length of the Achilles tendon using ultrasound imaging. To determine the relationship between muscle remodeling and deficits in plantarflexor kinetics measured at 14 wk after injury, we correlated the reduction in fascicle length and increase in pennation angle with peak torque measured during isometric and isokinetic plantarflexor contractions. We found that the medial gastrocnemius underwent an immediate change in structure, characterized by decreased length and increased pennation of the muscle fascicles. This decrease in fascicle length was coupled with an increase in tendon length. These changes in muscle-tendon structure persisted throughout the first 14 wk following rupture. Deficits in peak plantarflexor torque were moderately correlated with decreased fascicle length at 120 degrees per second (R2 = 0.424, P = 0.057) and strongly correlated with decreased fascicle length at 210 degrees per second (R2 = 0.737, P = 0.003). However, increases in pennation angle did not explain functional deficits. These findings suggest that muscle-tendon structure is detrimentally affected following Achilles tendon rupture. Plantarflexor power deficits are positively correlated with the magnitude of reductions in fascicle length. Preserving muscle structure following Achilles tendon rupture should be a clinical priority to maintain plantarflexor kinetics.NEW & NOTEWORTHY In our study, we found that when the Achilles tendon ruptures due to excessive biomechanical loading, the neighboring skeletal muscle undergoes rapid changes in its configuration. The magnitude of this muscle remodeling explains the amount of ankle power loss demonstrated by these patients once their Achilles tendons are fully healed. These findings highlight the interconnected relationship between muscle and tendon. Isolated injuries to the tendon stimulate detrimental changes to the muscle, thereby limiting joint-level function.

Gastrocnemius fascicles are shorter and more pennate throughout the first month following acute Achilles tendon rupture.

The purpose of this study was to characterize the short-term effects of Achilles tendon ruptures on medial gastrocnemius. We hypothesized that the fascicles of the medial gastrocnemius muscle of the injured Achilles tendon would be shorter and more pennate immediately following the injury and would persist throughout 4 weeks post-injury. B-mode longitudinal ultrasound images of the medial gastrocnemius were acquired in 10 adults who suffered acute Achilles tendon ruptures and were treated non-operatively. Ultrasound images were acquired during the initial clinical visit following injury as well as 2 and 4 weeks following this initial clinical visit. Resting muscle structure was characterized by measuring fascicle length, pennation angle, muscle thickness, and muscle echo intensity in both the injured and contralateral (control) limbs. Fascicle length was 15% shorter (P < 0.001) and pennation angle was 21% greater (P < 0.001) in the injured muscle compared to the uninjured (control) muscle at the presentation of injury (week 0). These differences in fascicle length persisted through 4 weeks after injury (P < 0.002) and pennation angle returned to pre-injury levels. Muscle thickness changes were not detected at any of the post-injury visits (difference < 4%, P > 0.026). Echo intensity of the injured limb was 8% lower at the presentation of the injury but was not different compared to the contralateral muscle at 2 and 4 weeks post-injury. Our results suggest that Achilles tendon ruptures elicit rapid changes in the configuration of the medial gastrocnemius, which may explain long-term functional deficits.

Effects of suvorexant on the Insomnia Severity Index in patients with insomnia: analysis of pooled phase 3 data.

OBJECTIVE: Suvorexant is an orexin receptor antagonist that is approved in the US, Japan and Australia for the treatment of insomnia. Using outcomes from the Insomnia Severity Index (ISI) in the core registration studies, we explored suvorexant effects on sleep problems and their impact on daytime function. METHODS: Data were pooled from two similar Phase 3, randomized, double-blind, placebo-controlled, parallel-group, three-month trials in elderly (≥65 years) and non-elderly (18-64 years old) insomnia patients. Age-adjusted (non-elderly/elderly) dose-regimes of 40/30 mg and 20/15 mg were evaluated. The ISI, a 7-item self-rated questionnaire with each item rated on 0-4 scale (higher score corresponds to increasing severity), was administered to patients as an exploratory assessment in both studies at baseline and one and three months after randomization. RESULTS: The analysis included 1824 patients. Suvorexant improved change-from-baseline ISI total scores to a greater extent than placebo (Month three: 20/15 mg = -6.2, 40/30 mg = -6.7, placebo = -4.9, p-values for both active arms vs. placebo <0.001) and resulted in a greater proportion of responders than placebo using a variety of definitions (eg, ≥6-point improvement from baseline at Month three: 20/15 mg = 55.5%, 40/30 mg = 54.9%, placebo = 42.2%, p-values for both active arms vs. placebo <0.001). Additionally, the "impact of insomnia" component, which assesses the impact of insomnia on daytime function/quality-of-life, was improved to a greater extent by suvorexant than placebo. CONCLUSIONS: Suvorexant 20/15 mg and 40/30 mg improved sleep to a greater extent than placebo as assessed by the ISI in patients with insomnia. Improvement in sleep onset/maintenance as well as a reduction of the impact of sleep problems on daytime function contributed to the overall improvement observed in ISI total score. CLINICALTRIALS. GOV IDENTIFIER: NCT01097616, NCT01097629.

Orexin Receptor Antagonism in Painful Diabetic Neuropathy: A Phase 2 Trial With Filorexant.

OBJECTIVES: To evaluate whether orexin receptor antagonism with filorexant provides pain relief in patients with painful diabetic neuropathy (PDN). METHODS: In this double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal proof-of-concept study, patients with PDN (aged 18 to 75 y) entered a 2-week, single-blind active run-in period with filorexant 10 mg nightly, before randomization 1:1 to placebo or filorexant in a 2-week, double-blind treatment period. The primary efficacy endpoint was time to efficacy failure among "primary responders" (≥30% decrease in evening pain intensity during the run-in). Secondary endpoints were time to efficacy failure among "all responders" (≥20% decrease in evening pain intensity during the run-in) and mean change from baseline in evening pain intensity throughout last 3 days of the double-blind period. RESULTS: Of the 182 patients treated during the run-in, 170 were randomized in the double-blind period, including 65 primary responders and 88 responders. There was no significant difference in proportion of patients with efficacy failure during the double-blind period with filorexant versus placebo among primary (24.3% vs. 32.1% [P=0.411]) or all (34.0% vs. 43.9% [nominal P=0.302]) responders or in mean change from baseline in evening pain intensity scores (estimated treatment difference: -0.587 [P=0.269], primary; -0.687 [P=0.108], all). Adverse events were reported by 24.7% of patients during the run-in. A higher proportion of patients treated with filorexant versus placebo reported adverse events during the double-blind period (23.9% vs. 13.4%). DISCUSSION: These data do not provide evidence for the efficacy of nightly filorexant for the treatment of PDN.

Phase II Proof-of-Concept Trial of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Major Depressive Disorder.

Background: We evaluated the orexin receptor antagonist filorexant (MK-6096) for treatment augmentation in patients with major depressive disorder. Methods: We conducted a 6-week, double-blind, placebo-controlled, parallel-group, Phase II, proof-of-concept study. Patients with major depressive disorder (partial responders to ongoing antidepressant therapy) were randomized 1:1 to once-daily oral filorexant 10 mg or matching placebo. Results: Due to enrollment challenges, the study was terminated early, resulting in insufficient statistical power to detect a prespecified treatment difference; of 326 patients planned, 129 (40%) were randomized and 128 took treatment. There was no statistically significant difference in the primary endpoint of change from baseline to week 6 in Montgomery Asberg Depression Rating Scale total score; the estimated treatment difference for filorexant-placebo was -0.7 (with negative values favoring filorexant) (P=.679). The most common adverse events were somnolence and suicidal ideation. Conclusions: The interpretation of the results is limited by the enrollment, which was less than originally planned, but the available data do not suggest efficacy of orexin receptor antagonism with filorexant for the treatment of depression. (Clinical Trial Registry: clinicaltrials.gov: NCT01554176).

Suvorexant in Elderly Patients with Insomnia: Pooled Analyses of Data from Phase III Randomized Controlled Clinical Trials.

OBJECTIVE: Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10-20 mg. Previously reported phase III results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and nonelderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly. METHODS: Prespecified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group trials. In each trial, elderly (≥65 years) patients with insomnia were randomized to suvorexant 30 mg, suvorexant 15 mg, and placebo. By design, fewer patients were randomized to 15 mg. Patient-reported and polysomnographic (subset of patients) sleep maintenance and onset endpoints were measured. RESULTS: Suvorexant 30 mg (N = 319) was effective compared with placebo (N = 318) on patient-reported and polysomnographic sleep maintenance, and onset endpoints at Night 1 (polysomnographic endpoints)/Week 1 (patient-reported endpoints), Month 1, and Month 3. Suvorexant 15 mg (N = 202 treated) was also effective across these measures, although the onset effect was less evident at later time points. The percentages of patients discontinuing because of adverse events over 3 months were 6.4% for 30 mg (N = 627 treated), 3.5% for 15 mg (N = 202 treated), and 5.5% for placebo (N = 469 treated). Somnolence was the most common adverse event (8.8% for 30 mg, 5.4% for 15 mg, 3.2% for placebo). CONCLUSION: Suvorexant generally improved sleep maintenance and onset over 3 months of nightly treatment and was well-tolerated in elderly patients with insomnia (clinicaltrials.gov; NCT01097616, NCT01097629, NCT01021813).

Clinical profile of suvorexant for the treatment of insomnia over 3 months in women and men: subgroup analysis of pooled phase-3 data.

RATIONALE: Sex-related differences in the clinical profiles of some insomnia medications have been previously reported. OBJECTIVE: To evaluate the clinical profile of suvorexant, a novel orexin receptor antagonist approved for treating insomnia at doses up to 20 mg, by sex subgroups. METHODS: Efficacy analyses by sex were based on pooled data from two similar phase 3, randomized, double-blind, placebo-controlled, 3-month trials in elderly (≥65 years) and non-elderly (18-64 years) insomnia patients. Two age-adjusted (non-elderly/elderly) dose regimes of 40/30 and 20/15 mg were evaluated, with fewer patients assigned to 20/15 mg. Efficacy was assessed by patient-reported outcomes (N = 1264 women, 707 men) and by polysomnography endpoints in ~75% of patients. Safety analyses by sex (N = 1744 women, 1065 men) included pooled data from the two 3-month trials plus 3-month data from a safety trial of 40/30 mg. RESULTS: The sex subgroup efficacy analyses mirrored the improvements seen for suvorexant 40/30 and 20/15 mg over placebo on patient-reported outcomes and polysomnography sleep maintenance and onset endpoints in the primary analyses; 95% CIs excluded zero in favor of suvorexant for most endpoints in both sexes, and similar efficacy was observed between sexes (95% CIs overlapped). Suvorexant was well-tolerated in women and men, although women in all treatment groups (including placebo) reported more adverse events than men. The most frequent adverse event was somnolence (women: 11.1% for 40/30 mg, 8.5% for 20/15 mg, 2.3% for placebo; men: 10.1% for 40/30 mg, 3.4% for 20/15 mg, 4.2% for placebo). CONCLUSION: Suvorexant was generally effective and well-tolerated in both women and men with insomnia. ClinicalTrials.gov trial registration numbers: NCT01097616, NCT01097629, NCT01021813.

Effects of suvorexant on sleep architecture and power spectral profile in patients with insomnia: analysis of pooled phase 3 data.

BACKGROUND: The orexin receptor antagonist, suvorexant, is approved for treating insomnia at a maximum dose of 20 mg. We evaluated its effects on sleep architecture. METHODS: The analyses included pooled polysomnography data from two similar randomized, double-blind, placebo-controlled, 3-month trials evaluating two age-adjusted (non-elderly/elderly) dose regimes of 20/15 mg and 40/30 mg in 1482 patients with insomnia. Polysomnography was recorded at baseline and on three nights during the treatment: Night-1, Month-1, and Month-3. Effects on non-REM sleep stages 1 (N1), 2 (N2), 3 (N3)/slow wave sleep (SWS), and REM sleep were evaluated. A power spectral analysis of non-REM sleep was also performed. RESULTS: Suvorexant increased the time (in minutes) spent in all sleep stages compared with placebo. When suvorexant and placebo were compared in terms of changes in percentage of total sleep time spent in each stage, there were small decreases of ≤1%, ≤2.2%, and ≤0.8% for N1, N2, and N3/SWS on average, respectively, and an average increase of ≤3.9% in REM. The largest differences from placebo were observed at Night-1 and generally diminished over time. Suvorexant reduced REM latency (number of non-REM 30-s epochs from lights-off to the first REM epoch) compared with placebo; the reduction was greater at Night-1 (~40-50 non-REM epochs) in comparison to later time points (~12-25 non-REM epochs at Month-3). The spectral analysis of non-REM showed a small decrease in power of 3-6% in the gamma and beta bands, and a small increase of 4-8% in the delta band, at Night-1 for suvorexant relative to placebo; these effects were not apparent at the later Month-1 and Month-3 time points. CONCLUSION: Overall sleep architecture appears to be preserved in insomnia patients taking suvorexant. The power spectral profile of suvorexant is generally similar to placebo.

Clinical and Operative Factors Related to Successful Revision Arthrodesis in the Foot and Ankle.

BACKGROUND: Arthrodesis is a common operative procedure used to manage arthritis and deformity in the foot and ankle. Nonunion is a possible and undesirable outcome in any arthrodesis surgery. Rates of nonunion in the foot and ankle literature range from 0% to 47% depending on the patient population and joint involved. Multiple factors can contribute to developing a nonunion including location, fixation method, tobacco use, diabetes, infection, and others. METHODS: The case logs of 3 foot and ankle surgeons were reviewed from January 2007 to September 2014 to identify nonunion arthrodesis revision cases. The patient factors reviewed included diabetes, inflammatory arthropathy, tobacco use, history of infection, nonunion elsewhere, neuropathy, Charcot arthropathy, posttraumatic arthritis, and prior attempt at revision arthrodesis at the same site. Operative records were reviewed to identify location of the nonunion, instrumention, use of allograft or autograft bone, use of iliac crest bone marrow aspirate (ICBMA) and use of orthobiologics such as bone morphogenetic protein (BMP) during the revision arthrodesis. Successful revision was defined as radiographic union on the final radiograph during follow-up. Eighty-two cases of revision arthrodesis were identified with an average follow-up of 16 months. RESULTS: The overall nonunion rate was 23%. Neuropathy and prior attempts at revision were identified as significant risks (P <.05) for persistent nonunion. Odds ratio calculated based on previous attempts at revision arthrodesis found a 2.8-fold increase in the risk of failure for each attempt at revision. CONCLUSION: Revision arthrodesis for nonunion in the foot and ankle was successful (77%) under a variety of patient and operative conditions. Neuropathy was a significant patient risk factor for persistent nonunions, and we believe it is important to identify even in the nondiabetic patient. As the number of attempts at revisions increases, there is a subsequent 3-fold increase in the risk of persistent nonunion. LEVEL OF EVIDENCE: Level IV, case series.

A Phase II Dose-Ranging Study Evaluating the Efficacy and Safety of the Orexin Receptor Antagonist Filorexant (MK-6096) in Patients with Primary Insomnia.

BACKGROUND: Filorexant (MK-6096) is an orexin receptor antagonist; here, we evaluate the efficacy of filorexant in the treatment of insomnia in adults. METHODS: A double-blind, placebo-controlled, randomized, two 4-week-period, adaptive crossover polysomnography study was conducted at 51 sites worldwide. Patients (18 to <65 years) with insomnia received 1 of 4 doses of oral filorexant (2.5, 5, 10, 20mg) once daily at bedtime during one period and matching placebo in the other period in 1 of 8 possible treatment sequences. Polysomnography was performed on night 1 and end of week 4 of each period. The primary endpoint was sleep efficiency at night 1 and end of week 4. Secondary endpoints included wakefulness after persistent sleep onset and latency to onset of persistent sleep. RESULTS: A total of 324 patients received study treatment, 315 received ≥1 dose of placebo, and 318 ≥1 dose of filorexant (2.5mg, n=79; 5mg, n=78; 10mg, n=80; 20mg, n=81). All filorexant doses (2.5/5/10/20mg) were significantly superior to placebo in improving sleep among patients with insomnia as measured by sleep efficiency and wakefulness after persistent sleep onset on night 1 and end of week 4. The 2 higher filorexant doses (10/20mg) were also significantly more effective than placebo in improving sleep onset as measured by latency to onset of persistent sleep at night 1 and end of week 4. Filorexant was generally well tolerated. CONCLUSIONS: Orexin receptor antagonism by filorexant significantly improved sleep efficiency in nonelderly patients with insomnia. Dose-related improvements in sleep onset and maintenance outcomes were also observed with filorexant.

Correlation of Clinical, Operative, and Histopathologic Diagnosis of Interdigital Neuroma and the Cost of Routine Diagnosis.

BACKGROUND: Diagnosis of an interdigital neuroma (IDN) is clinically based on patient symptoms. During operative excision, it is common to send the excised specimen for routine histopathologic examination. The purpose of this study was to evaluate the accuracy of the clinical and intraoperative diagnosis of IDN and correlate these with the histopathologic results of IDN. METHODS: Case logs of 3 fellowship-trained foot and ankle surgeons were reviewed to identify all neuroma excisions completed between 1997 and 2014. Charts were reviewed to identify the preoperative clinical diagnosis and intraoperative diagnosis as well as concern for pathology besides a neuroma. All results were compared to final histopathology to identify instances of discordance between diagnoses. A total of 123 patients with 133 neuromas were identified. RESULTS: Of the total 133 neuromas, 5 cases included a clinical or intraoperative concern for a diagnosis other than neuroma. In these 5 instances surgeons accurately identified cysts and rheumatoid nodules. 132 of 133 histopathology reports indicated the presence of nerve tissue in their report. There were no reports of malignancy or abnormal nerve tissue. There were no changes to the postoperative protocol based on histopathology. CONCLUSION: The clinical, intraoperative, and histopathologic diagnosis of neuroma was in concordance 100% of the time. With a high level of clinical and intraoperative acumen in identifying a neuroma, we believe it is reasonable not to submit the specimen for histopathologic evaluation. In addition, limiting the amount of routine histopathologic evaluation could have saved approximately $480 per case. LEVEL OF EVIDENCE: Level IV, case series.

Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials.

BACKGROUND: Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials. METHODS: Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in nonelderly (18-64 years) and elderly (≥65 years) patients with insomnia. Suvorexant doses of 40/30 mg (nonelderly/elderly) and 20/15 mg (nonelderly/elderly) were evaluated. The primary focus was 40/30 mg, with fewer patients randomized to 20/15 mg. There was an optional 3-month double-blind extension in trial 1. Each trial included a 1-week, randomized, double-blind run-out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at week 1, month 1, and month 3 by patient-reported subjective total sleep time and time to sleep onset and in a subset of patients at night 1, month 1, and month 3 by polysomnography end points of wakefulness after persistent sleep onset and latency to onset of persistent sleep (LPS). One thousand twenty-one patients were randomized in trial 1 and 1019 patients in trial 2. RESULTS: Suvorexant 40/30 mg was superior to placebo on all subjective and polysomnography end points at night 1/week 1, month 1, and month 3 in both trials, except for LPS at month 3 in trial 2. Suvorexant 20/15 mg was superior to placebo on subjective total sleep time and wakefulness after persistent sleep onset at night 1/week 1, month 1, and month 3 in both trials and at most individual time points for subjective time to sleep onset and LPS in each trial. Both doses of suvorexant were generally well tolerated, with <5% of patients discontinuing due to adverse events over 3 months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued. CONCLUSIONS: Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated.

Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis.

BACKGROUND: This study explored whether antagonism of orexin receptors might be an effective mechanism for migraine prevention. METHODS: We conducted a randomized, double-blind, placebo-controlled, pilot trial. Patients experiencing four to 14 days with migraine during a one-month baseline period were randomized to the orexin receptor antagonist filorexant 10 mg nightly or placebo for three months. Efficacy was assessed by mean monthly migraine days (headache plus at least one associated migraine symptom) and headache days. Safety and tolerability were assessed by adverse event reports and laboratory tests. RESULTS: Of 120 patients treated with filorexant and 115 treated with placebo, 97 (81%) and 101 (88%), respectively, completed the trial. There was no statistically significant difference between treatments for change from baseline in mean monthly migraine days (filorexant = -1.7, placebo = -1.3, difference = -0.4 (95% CI: -1.3, 0.4)) or headache days (filorexant = -1.7, placebo = -1.2, difference = -0.5 (95% CI: -1.4, 0.4)). Filorexant was generally well tolerated but was associated with a higher proportion of patients who reported adverse events than placebo (47% vs 37%), particularly somnolence (13% vs 4%). CONCLUSIONS: These data fail to provide evidence that antagonism of orexin receptors with filorexant, when administered at night, is effective for migraine prophylaxis.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention.

OBJECTIVE: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3-14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥ 1 associated symptom). RESULTS: The trial was terminated following a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥ 1 dose of study medication, and 14 had completed the trial. The mean treatment duration was 48-50 days. Thirteen patients, all in the telcagepant groups, had an alanine aminotransferase (ALT) elevation ≥ 3 × the upper limit of normal and 7 of these also had an aspartate aminotransferase elevation ≥ 3 × the upper limit of normal. Two patients had very high symptomatic transaminase elevations that occurred within 2-6 weeks of treatment initiation and resolved after treatment discontinuation. The originally planned efficacy analysis over 12 weeks was not performed due to limited data at later time points, but there was evidence that telcagepant resulted in a larger reduction from baseline than placebo for mean monthly headache days (month 1: 140 mg = -2.9, 280 mg = -3.1, placebo = -1.7; p < 0.05) and migraine/probable migraine days (month 1: 140 mg = -2.7, 280 mg = -3.0, placebo = -1.6; p < 0.05). CONCLUSIONS: These data suggest a potential role for CGRP receptor antagonism in migraine prophylaxis. However, the observed aminotransferase elevations do not support the use of telcagepant for daily administration. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with migraine, telcagepant taken daily reduces headache days by 1.4 days per month compared to placebo and causes 2.5% of patients to have elevations of serum ALT levels.

The sleep effects of tiagabine on the first night of treatment predict post-traumatic stress disorder response at three weeks.

INTRODUCTION: We sought to test the hypothesis that improvements in sleep might mediate treatment-related improvements in daytime symptoms of post-traumatic stress disorder (PTSD). We evaluated whether changes in sleep occurring on the first night of tiagabine (a gamma-amino butyric acid (GABA) reuptake inhibitor) administration predicted subsequent PTSD response. METHODS: This was an open-label three-week polysomnographic (PSG) study of nightly treatment with tiagabine dosing from 2-12 mg including 20 adults with PTSD with ≥30 min of self-reported and PSG wake time after sleep onset (WASO). RESULTS: A treatment night 1 decrease in self-reported and PSG WASO and an increase in slow-wave sleep (SWS) accounted for 94% of the variance in week 3 Short PTSD Rating Interview (SPRINT) score, the primary outcome measure (p<0.001). Increased night 1 SWS also accounted for 91% of the variance in Work/School Impairment and 45% of the variance in Social Life Impairment as measured with the Sheehan Disability Scale (p<0.001). These relationships were much stronger correlates of three-week outcome than three-week sleep effects. CONCLUSIONS: The initial sleep response to tiagabine may mediate or be an indicator of the subsequent PTSD response. The findings highlight the importance of sleep maintenance and SWS in the treatment of PTSD and also suggest a potential relationship between SWS and daytime function.

A pilot randomized controlled trial with paroxetine for subthreshold PTSD in Operation Enduring Freedom/Operation Iraqi Freedom era veterans.

Subthreshold posttraumatic stress disorder (PTSD) is associated with increased risk for suicidality, depression, and functional impairment. We thus conducted a small (N=12) pilot randomized controlled trial (RCT) with paroxetine for subthreshold PTSD in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) era veterans. Hospital Anxiety and Depression Scale (HADS) scores improved by 30.4% in the paroxetine group. Paroxetine may have promise for subthreshold PTSD.