Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trial.

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), known for its role in migraine pathogenesis, has been identified as a novel drug target. Given the clinical parallels between post-traumatic headache (PTH) and migraine, we explored the possible role of PACAP-38 in the pathogenesis of PTH. To this end, we conducted a randomized, double-blind, placebo-controlled, two-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-min continuous intravenous infusion of either PACAP-38 (10 pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week washout period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-h observational period post-infusion. The secondary outcome was the difference in the area under the curve (AUC) for baseline-corrected median headache intensity scores during the same 12-h observational period. Of 49 individuals assessed for eligibility, 21 were enrolled and completed the trial. The participants had a mean age of 35.2 years, and 16 (76%) were female. Most [19 of 21 (90%)] had a migraine-like phenotype. During the 12-h observational period, 20 of 21 (95%) participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with two (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-h observational period was higher after PACAP-38 than placebo (P < 0.001). These compelling results demonstrate that PACAP-38 is potent inducer of migraine-like headache in people with persistent PTH. Thus, targeting PACAP-38 signalling might be a promising avenue for the treatment of PTH.

Activation of ATP-sensitive potassium channels triggers migraine attacks independent of calcitonin gene-related peptide receptors: a randomized placebo-controlled trial.

BACKGROUND: The present study aimed to investigate whether levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine pre-treated with erenumab, a monoclonal CGRP receptor antibody. METHODS: In this double-blind, placebo-controlled, two-way cross-over study, adults with migraine without aura received a subcutaneous injection of 140 mg of erenumab on day 1. Subsequently, they were randomized to receive a 20-minute infusion of 0.05 mg/ml levcromakalim or placebo on two experimental days separated by at least one week (between days 8 and 21). The primary endpoint was the difference in the incidence of migraine attacks between levcromakalim and placebo during the 12-hour post-infusion period. RESULTS: In total, 16 participants completed the study. During the 12-hour observation period, 14 (88%) of 16 participants experienced migraine attacks after levcromakalim, compared to two (12%) after placebo (p < 0.001). The area under the curve for median headache intensity was greater after levcromakalim than placebo (p < 0.001). Levcromakalim elicited dilation of the superficial temporal artery during the first hour after infusion, a response absent following placebo (p < 0.001). CONCLUSIONS: The induction of migraine attacks via opening of KATP channels appears independent of CGRP receptor activation.Trial Registration: ClinicalTrials.gov, Identifier NCT05889442.

No wearing-off effect of erenumab or fremanezumab for chronic migraine prevention: a single-center, real-world, observational study.

BACKGROUND: The present study investigates the wearing-off effect in adults with chronic migraine treated with erenumab or fremanezumab. METHODS: This real-world observational study was based on pre-collected headache diaries from chronic migraine patients in treatment with either monthly injections of 140 mg of erenumab or 225 mg of fremanezumab. Consistent wearing-off was defined as an increase of ≥2 weekly migraine days in the last week compared to the second week over two consecutive 4-week treatment periods. The primary endpoint was wearing-off in the total population. The secondary endpoints were difference in wearing-off in (i) a subgroup of patients treated with erenumab and fremanezumab and (ii) consistent wearing-off in patients with a ≥30% reduction in monthly migraine days, compared to baseline, in the two consecutive treatment months. RESULTS: In total, 100 patients (erenumab: n = 60, fremanezumab: n = 40) were included. Sixty-two out of 100 (62%) patients had consistent ≥30% treatment response on antibody therapy in both months (erenumab: n = 36, fremanezumab: n = 26). There was no consistent wearing-off over the two consecutive months from week 2 to week 4 (3.04%, p = 0.558). There was no wearing-off within the erenumab (p = 0.194) or the fremanezumab (p = 0.581) groups. Among the ≥30% treatment responders, there was no consistent wearing-off over the two consecutive months (2.6%, p = 0.573). CONCLUSIONS: There was no wearing-off in treatment responders, which is in alignment with premarketing data from placebo-controlled phase III studies. These data suggest that patients should be informed upfront that no wearing-off effect is expected because anxiety for attacks at the end of the month per se may generate migraine attacks.

Hypersensitivity to BKCa channel opening in persistent post-traumatic headache.

BACKGROUND: Large conductance  calcium-activated potassium (BKCa) channels have been implicated in the neurobiological underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to examine whether MaxiPost (a BKCa channel opener) could induce migraine-like headache in persons with PPTH. METHODS: This is a randomized double-blind, placebo-controlled, two-way crossover study from September 2023 to December 2023. Eligible participants were adults with PPTH after mild traumatic brain injury who reported having no personal history of migraine. The randomized participants received a single dose of either MaxiPost (0.05 mg/min) or placebo (isotonic saline) that was infused intravenously over 20 minutes. The two experiment sessions were scheduled at least one week apart to avoid potential carryover effects. The primary endpoint was the induction of migraine-like headache after MaxiPost as compared to placebo within 12 hours of drug administration. The secondary endpoint was the area under the curve (AUC) values for headache intensity scores between MaxiPost and placebo over the same 12-hour observation period. RESULTS: Twenty-one adult participants (comprising 14 females and 7 males) with PPTH were enrolled and completed both experiment sessions. The proportion of participants who developed migraine-like headache was 11 (52%) of 21 participants after MaxiPost infusion, in contrast to four (19%) participants following placebo (P = .02). Furthermore, the median headache intensity scores, represented by AUC values, were higher following MaxiPost than after placebo (P < .001). CONCLUSIONS: Our results indicate that BKCa channel opening can elicit migraine-like headache in persons with PPTH. Thus, pharmacologic blockade of BKCa channels might present a novel avenue for drug discovery. Additional investigations are nonetheless needed to confirm these insights and explore the therapeutic prospects of BKCa channel blockers in managing PPTH. GOV IDENTIFIER: NCT05378074.

Effects of PDE-3 inhibition in persistent post-traumatic headache: evidence of cAMP-dependent signaling.

BACKGROUND: Phosphodiesterase 3 (PDE-3) inhibition have been implicated in the neurobiologic underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to ascertain whether PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. METHODS: We tested cilostazol, which inhibits PDE-3, in a randomized, double-blind, placebo-controlled, two-way crossover study involving persons with PPTH attributed to mild traumatic brain injury. The randomized participants were allocated to receive oral administration of either 200-mg cilostazol or placebo (calcium tablet) on two separate experiment days. The primary end point was the incidence of migraine-like headache during a 12-hour observation window post-ingestion. The secondary endpoint was the area under the curve (AUC) for reported headache intensity scores during the same observation window. RESULTS: Twenty-one persons underwent randomization and completed both experiment days. The mean participants' age was 41.4 years, and most (n = 17) were females. During the 12-hour observation window, 14 (67%) of 21 participants developed migraine-like headache post-cilostazol, in contrast to three (14%) participants after placebo (P =.003). The headache intensity scores were higher post-cilostazol than after placebo (P <.001). CONCLUSIONS: Our results provide novel evidence showing that PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. Given that PDE-3 inhibition increases intracellular cAMP levels, our findings allude to the potential therapeutic value of targeting cAMP-dependent signaling pathways in the management of PPTH. Further investigations are imperative to substantiate these insights and delineate the importance of cAMP-dependent signaling pathways in the neurobiologic mechanisms underlying PPTH. GOV IDENTIFIER: NCT05595993.

Hypersensitivity to opening of ATP-sensitive potassium channels in post-traumatic headache.

OBJECTIVE: To investigate whether levcromakalim (a KATP channel opener) induces migraine-like headache in people with persistent post-traumatic headache who had no known history of migraine. METHODS: In a randomized, double-blind, placebo-controlled, 2-way crossover trial, participants were randomly assigned to receive a 20-minute continuous intravenous infusion of levcromakalim (50 µg/mL) or placebo (isotonic saline) on two separate experimental days with a 1-week wash-out period in between. The primary endpoint was the difference in incidence of migraine-like headache between levcromakalim and placebo during a 12-hour observational period after infusion start. The secondary endpoint was the difference in area under the curve for baseline-corrected median headache intensity scores between levcromakalim and placebo during the 12-hour observational period. RESULTS: A total of 21 participants with persistent post-traumatic headache were randomized and completed the trial. During the 12-hour observational period, 12 (57%) of 21 participants reported experiencing migraine-like headache following the levcromakalim infusion, compared with three after placebo (P = 0.013). Moreover, the baseline-corrected median headache intensity scores were higher following the levcromakalim infusion than after placebo (P = 0.003). CONCLUSION: Our findings suggest that KATP channels play an important role in the pathogenesis of migraine-like headache in people with persistent post-traumatic headache. This implies that KATP channel blockers might represent a promising avenue for drug development. Further research is warranted to explore the potential therapeutic benefits of KATP channel blockers in managing post-traumatic headache.Trial Registration: ClinicalTrials.gov Identifier: NCT05243953.

Menstrual migraine is caused by estrogen withdrawal: revisiting the evidence.

OBJECTIVE: To explore and critically appraise the evidence supporting the role of estrogen withdrawal in menstrual migraine. MAIN BODY: Menstrual migraine, impacting about 6% of reproductive-age women, manifests as migraine attacks closely related to the menstrual cycle. The estrogen withdrawal hypothesis posits that the premenstrual drop in estrogen levels serves as a trigger of migraine attacks. Despite its wide acceptance, the current body of evidence supporting this hypothesis remains limited, warranting further validation. Estrogen is believed to exert a modulatory effect on pain, particularly within the trigeminovascular system - the anatomic and physiologic substrate of migraine pathogenesis. Nevertheless, existing studies are limited by methodologic inconsistencies, small sample sizes, and variable case definitions, precluding definitive conclusions. To improve our understanding of menstrual migraine, future research should concentrate on untangling the intricate interplay between estrogen, the trigeminovascular system, and migraine itself. This necessitates the use of robust methods, larger sample sizes, and standardized case definitions to surmount the limitations encountered in previous investigations. CONCLUSION: Further research is thus needed to ascertain the involvement of estrogen withdrawal in menstrual migraine and advance the development of effective management strategies to address unmet treatment needs.

PACAP38- and VIP-induced cluster headache attacks are not associated with changes of plasma CGRP or markers of mast cell activation.

BACKGROUND: Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide can provoke cluster headache attacks in up to half of cluster headache patients in their active phase. At present, it is unknown whether provoked attacks are mediated via calcitonin gene-related peptide or mast cell activation. METHODS: All enrolled patients with cluster headache were randomly allocated to receive a continuous infusion of either PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We collected clinical data and measured plasma levels of calcitonin gene-related peptide and markers of mast cell activation (tryptase and histamine) at fixed time points: at baseline (T0), at the end of the infusion (T20), 10 min after the infusion (T30), and 70 min after the infusion (T90). RESULTS: Blood was collected from episodic cluster headache patients in active phase (n = 14), episodic cluster headache patients in remission (n = 15), and chronic cluster headache patients (n = 15). At baseline, plasma levels of calcitonin gene-related peptide, tryptase, and histamine were not different among the three study groups. Plasma levels of calcitonin gene-related peptide (p = 0.7074), tryptase (p = 0.6673), or histamine (p = 0.4792) remained unchanged during provoked attacks compared to attack-free patients. CONCLUSION: Cluster headache attacks provoked by either PACAP38 or vasoactive intestinal polypeptide were not accompanied by alterations of plasma calcitonin gene-related peptide, tryptase or histamine. The provoked attacks may not be mediated by calcitonin gene-related peptide or mast cell activation.Trial Registration: The study is registered at ClinicalTrials.gov (NCT03814226).

Cluster headache - The worst possible pain on YouTube.

In clinical practice, patients with cluster headache often ask questions or mention information that they have seen or heard on the Internet. Because YouTube (www.youtube.com) is the second most visited Web site worldwide and offers a plethora of video content, we found it timely to ascertain the quality of information on cluster headache that is freely available on YouTube. We conducted an inquiry on YouTube on January 24, 2022, with the search term "cluster headache." Eligible YouTube videos included those with ≥10,000 views and content related to cluster headache. We assessed the quality and reliability of the videos with the Global Quality Scale and DISCERN, respectively. The search strategy identified 644 videos of which 134 were eligible for inclusion. The sources of the included videos were categorized as "healthcare professional/institution" (n = 45), "personal experience" (n = 52), and "other" (n = 37). According to the Global Quality Scale, 70 (52%) were low quality, 34 (25%) were of moderate quality, and 30 (22%) were of high quality. According to DISCERN, 104 (78%) were of low reliability, 28 (21%) were of moderate reliability, and 2 (1%) were of high reliability. The quality and reliability of cluster headache-related information on YouTube has room for improvement, even the content provided by healthcare providers. These findings should incentivize stakeholders, for example, government services, professional societies, healthcare providers, to provide accessible and better information on cluster headache.

CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: To ascertain whether intravenous infusion of calcitonin gene-related peptide (CGRP) can induce migraine-like headache in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) and no pre-existing migraine. METHODS: A non-randomized, single-arm, open-label study at a single site in Denmark. Eligible participants were aged 18 to 65 years and had a known history of persistent post-traumatic headache attributed to mild TBI for ≥ 12 months. All participants received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min. A headache diary was used to collect outcome data until 12 h after the start of CGRP infusion. The primary end point was the incidence of migraine-like headache during 12-hour observational period. RESULTS: A total of 60 participants completed the study protocol and provided data for the analysis of the primary end point. The median age was 32.5 (IQR, 25.5-43.0) years; 43 participants (72%) were female. Following CGRP infusion, 43 (72%) of 60 participants developed migraine-like headache during the 12-hour observational period. The median time to peak headache intensity was 40 min (IQR, 20-60), and the median peak headache intensity was 6 (IQR, 5-8) on the 11-point numeric rating scale. CONCLUSION: Intravenous infusion of CGRP is a potent inducer of migraine-like headache in people with persistent post-traumatic headache attributed to mild TBI. This observation underscores the importance of CGRP in the genesis of migraine-like headache that is often experienced by individuals who are afflicted by persistent post-traumatic headache. Further research is warranted to ascertain whether other signaling molecules also contribute to the disease mechanisms underlying post-traumatic headache.

The effect of pituitary adenylate cyclase-activating peptide-38 and vasoactive intestinal peptide in cluster headache.

BACKGROUND: Previously reported increases in serum levels of vasodilating neuropeptides pituitary adenylate cyclase-activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) during attacks of cluster headache could indicate their involvement in cluster headache attack initiation. We investigated the attack-inducing effects of PACAP38 and vasoactive intestinal peptide in cluster headache, hypothesising that PACAP38, but not vasoactive intestinal peptide, would induce cluster-like attacks in episodic active phase and chronic cluster headache patients. METHODS: In a double-blind crossover study, 14 episodic cluster headache patients in active phase, 15 episodic cluster headache patients in remission phase and 15 chronic cluster headache patients were randomly allocated to receive intravenous infusion of PACAP38 (10 pmol/kg/min) or vasoactive intestinal peptide (8 pmol/kg/min) over 20 min on two study days separated by at least 7 days. We recorded headache intensity, incidence of cluster-like attacks, cranial autonomic symptoms and vital signs using a questionnaire (0-90 min). RESULTS: In episodic cluster headache active phase, PACAP38 induced cluster-like attacks in 6/14 patients and vasoactive intestinal peptide induced cluster-like attacks in 5/14 patients (p = 1.000). In chronic cluster headache, PACAP38 and vasoactive intestinal peptide both induced cluster-like attacks in 7/15 patients (p = 0.765). In episodic cluster headache remission phase, neither PACAP38 nor vasoactive intestinal peptide induced cluster-like attacks. CONCLUSIONS: Contrary to our hypothesis, attack induction was lower than expected and roughly equal by PACAP38 and vasoactive intestinal peptide in episodic active phase and chronic cluster headache patients, which contradicts the PAC1-receptor as being solely responsible for attack induction.Trial registration: clinicaltrials.gov (identifier NCT03814226).

Two-hour infusion of vasoactive intestinal polypeptide induces delayed headache and extracranial vasodilation in healthy volunteers.

BACKGROUND: In recent years, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) have gained special interest in headache science. VIP and PACAPs (two isoforms, PACAP27 and PACAP38) are related in structure and function, as are their receptors, but they show differences in vasodilating- and headache-inducing properties. Intravenous infusion of PACAP27 or PACAP38, but not VIP, induces a long-lasting dilation of cranial arteries and delayed headache. The relationship between the long-lasting cranial vasodilation and headache development is not fully clarified. METHODS: In a double-blinded, placebo-controlled, crossover study in 12 healthy volunteers, diameter changes of cranial arteries, occurrence of headache and the parasympathetic system were examined before, during and after a 2-hour continuous intravenous infusion of VIP and placebo. Primary endpoints were the differences in area under the curve for the superficial temporal artery diameter and headache intensity scores, as well as in headache incidence, between VIP and placebo. RESULTS: The superficial temporal artery diameter was significantly larger on the VIP day compared to placebo (p < 0.001) and the dilation lasted for more than 2 h. The incidence of headache was higher (p = 0.003) on the VIP day compared to the placebo day. The difference in headache intensity scores was more evident in the post-infusion period (120-200 min, p = 0.034) and in the post-hospital phase (4-12 h, p = 0.025). Cranial parasympathetic activity, measured through the production of tears, was higher during VIP compared to placebo (p = 0.033). CONCLUSION: Continuous intravenous infusion of VIP over 2 h induced a long-lasting cranial vasodilation, activation of the cranial parasympathetic system, and delayed mild headaches in healthy volunteers.Trial Registration: The study is registered at ClinicalTrials.gov (NCT03989817).

Dizziness and vertigo during the prodromal phase and headache phase of migraine: A systematic review and meta-analysis.

OBJECTIVE: To assess the proportion of individuals who report dizziness and/or vertigo during the prodromal phase or headache phase of migraine. METHODS: The databases of MEDLINE and EMBASE were searched for studies on dizziness and/or vertigo during the prodromal phase or headache phase of migraine. Pooled relative frequencies were estimated using a random-effects meta-analysis. RESULTS: We identified nine articles eligible for inclusion. Of these, one study reported results for the prodromal phase, seven studies for the headache phase and one study for both the prodromal and headache phase. In the prodromal phase, 9.0% of individuals with migraine reported dizziness, while 3.3% reported vertigo. During the headache phase, relative frequency of dizziness ranged from 6.7% to 59.6%, while vertigo ranged from 6.4% to 44.7%. The meta-analysis showed a relative frequency of 35.7% for dizziness (95% CI = 13.7-61.5%, I2 = 99%) and 33.9% for vertigo (95% CI = 26.7-41.5%, I2 = 87%). Study quality was rated 5/9 or below for seven studies and 6/9 or above for two studies. CONCLUSION: We found that there is a scarcity of literature on dizziness and vertigo as prodromal- and headache-associated symptoms in individuals with migraine. Methodological variations confound comparisons of epidemiological patterns, although it appears that dizziness and vertigo are more frequent during the headache phase of migraine, compared with the prodromal phase. Future studies should ensure use of standardized definitions and rigorous methodology to enable accurate measurements of dizziness and vertigo in migraine.

Risk Factors for the Development of Post-Traumatic Headache Attributed to Traumatic Brain Injury: A Systematic Review.

OBJECTIVE: To systematically identify risk factors for the development of post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) as defined in the International Classification of Headache Disorders (ICHD). BACKGROUND: PTH is a common sequela of TBI and a leading cause of injury-related disability worldwide. However, little is known about risk factors for the development of PTH attributed to TBI. METHODS: We searched PubMed and Embase for literature on risk factors for the development of acute and/or persistent PTH attributed to TBI in accordance with any version of the ICHD. Original studies published in English and of prospective, cross-sectional or retrospective design were considered for the review. Data extraction was performed independently by 2 investigators. RESULTS: Of 1993 potentially relevant articles identified, 3 articles met the inclusion criteria. The following risk factors were assessed for the development of acute PTH: age, sex, type of injury, loss of consciousness, previous TBIs, history of primary headache disorders, history of chronic pain condition other than headache, current treatment for depression/anxiety, attention or learning disorders, body mass index, and other diseases (not further specified). None of the included studies assessed risk factors for the development of persistent PTH. CONCLUSIONS: We found that there is little evidence for any risk factors involved in the development of acute PTH, whereas no study had assessed risk factors for the development of persistent PTH. Further studies are warranted and should be powered to examine possible risk factors for the development of PTH. Rigorous methodology and standardized monitoring should be prioritized to support high-quality research and validate potential findings.

Efficacy, tolerability, and safety of erenumab for the preventive treatment of persistent post-traumatic headache attributed to mild traumatic brain injury: an open-label study.

BACKGROUND: Calcitonin gene-related peptide (CGRP) has recently been implicated in the pathogenesis of post-traumatic headache (PTH), which raises the prospect for therapeutic use of monoclonal antibodies targeting CGRP or its receptor. Therefore, we decided to assess the efficacy, tolerability, and safety of erenumab for prevention of persistent PTH attributed to mild traumatic brain injury. METHODS: A single-center, non-randomized, single-arm, open-label study of erenumab for adults aged 18-65 years with persistent PTH. Patients were assigned to receive 140-mg erenumab monthly by two subcutaneous 1-mL injections, given every 4 weeks for 12 weeks. The primary outcome measure was the mean change in number of monthly headache days of moderate to severe intensity from baseline (4-week pretreatment period) to week 9 through 12. Tolerability and safety endpoints were adverse events (i.e. number and type). RESULTS: Eighty-nine of 100 patients completed the open-label trial. At baseline, the mean monthly number of headache days of moderate to severe intensity was 15.7. By week 9 through 12, the number was reduced by 2.8 days. The most common adverse events were constipation (n = 30) and injection-site reactions (n = 15). Of 100 patients who received at least one dose of erenumab, two patients discontinued the treatment regimen due to adverse events. CONCLUSIONS: Among patients with persistent PTH, erenumab resulted in a lower frequency of moderate to severe headache days in this 12-week open-label trial. In addition, erenumab was well-tolerated as discontinuations due to adverse events were low. Placebo-controlled randomized clinical trials are needed to adequately evaluate the efficacy and safety of erenumab in patients with persistent PTH. TRIAL REGISTRATION: ClinicalTrials.Gov, NCT03974360. Registered on April 17, 2019 - Retrospectively registered.

The Impact of Biosimilar Use on Total Cost of Care and Provider Financial Performance in the Medicare Oncology Care Model: A Population-Based Simulation Study.

INTRODUCTION: Payment for oncology care is increasingly moving from fee-for-service to value-based payment (VBP). VBPs are agreements in which providers are held accountable for total cost of care (TCOC) through risk-sharing arrangements with payers that tie reimbursement levels to TCOC benchmarks. Oncology biosimilars may play an important role in managing financial risk in the VBPs like Medicare's Oncology Care Model (OCM), but there has been limited research in this area. The objective of this study is to estimate the impact of biosimilar adoption on TCOC and oncology provider financial performance under the terms of the Medicare OCM. METHODS: We conducted a population-based simulation study using the Medicare Limited Data Set (LDS) and the methodology of Medicare's OCM. The primary outcome was the simulated average change in TCOC per 6-month episode of care attributable to use of biosimilars as an alternative to reference products. The study population consisted of episodes of care in 2020 and using the reference product or corresponding biosimilar for bevacizumab, rituximab, trastuzumab, epoetin alfa, filgrastim, or pegfilgrastim. TCOC was calculated for each episode of care with use of reference products only and compared with TCOC with corresponding biosimilars. The simulation calculated TCOC outcomes in cohorts of 100 episodes sampled from the Medicare LDS study population using a Monte Carlo simulation with 10,000 iterations. RESULTS: Among the total of 8281 6-month oncology care episodes identified in the study period (initiating January 2020 to July 2020) in Medicare claims, 1586 (19.2%) episodes met OCM and study criteria and were included. Applying the simulation methods to these observed episodes, biosimilar substitution reduced mean TCOC per episode by $1193 (95% CI $583-1840). The cost reduction from biosimilars represented 2.4% of the average TCOC benchmark and led to a 15% reduction in the risk of providers needing to pay recoupments to Medicare for exceeding TCOC benchmarks. CONCLUSIONS: On the basis of our simulation study using observed Medicare claims and OCM criteria, we found that biosimilar substitution for reference products can significantly lower episode TCOC and improve provider financial performance under the terms of the largest value-based payment model implemented to date.

Induction of cluster headache after opening of adenosine triphosphate-sensitive potassium channels: a randomized clinical trial.

ABSTRACT: Activation of adenosine triphosphate-sensitive potassium (K ATP ) channels has been implicated in triggering migraine attacks. However, whether the opening of these channels provoke cluster headache attacks remains undetermined. The hallmark of cluster headache is a distinct cyclical pattern of recurrent, severe headache episodes, succeeded by intervals of remission where no symptoms are present. In our study, we enrolled 41 participants: 10 with episodic cluster headaches during a bout, 15 in the attack-free remission period, and 17 diagnosed with chronic cluster headaches. Over 2 distinct experimental days, participants underwent a continuous 20-minute infusion of levcromakalim, a K ATP channel opener, or a placebo (isotonic saline), followed by a 90-minute observational period. The primary outcome was comparing the incidence of cluster headache attacks within the postinfusion observation period between the levcromakalim and placebo groups. Six of 10 participants (60%) with episodic cluster headaches in bout experienced attacks after levcromakalim infusion, vs just 1 of 10 (10%) with placebo ( P = 0.037). Among those in the remission phase, 1 of 15 participants (7%) reported attacks after levcromakalim, whereas none did postplacebo ( P = 0.50). In addition, 5 of 17 participants (29%) with chronic cluster headache had attacks after levcromakalim, in contrast to none after placebo ( P = 0.037). These findings demonstrate that K ATP channel activation can induce cluster headache attacks in participants with episodic cluster headaches in bout and chronic cluster headache, but not in those in the remission period. Our results underscore the potential utility of K ATP channel inhibitors as therapeutic agents for cluster headaches.

Moving forward in GME reform: a 4 + 1 model of resident ambulatory training.

BACKGROUND: Traditional ambulatory training models have limitations in important domains, including opportunities for residents to learn, fragmentation of care delivery experience, and satisfaction with ambulatory experiences. New models of ambulatory training are needed. AIM: To compare the impact of a traditional ambulatory training model with a templated 4 + 1 model. SETTING: A large university-based internal medicine residency using three different training sites: a patient-centered medical home, a hospital-based ambulatory clinic, and community private practices. PARTICIPANTS: Residents, faculty, and administrative staff. PROGRAM DESCRIPTION: Development of a templated 4 + 1 model of residency where trainees do not attend to inpatient and outpatient responsibilities simultaneously. PROGRAM EVALUATION: A mixed-methods analysis of survey and nominal group data measuring three primary outcomes: 1) Perception of learning opportunities and quality of faculty teaching; 2) Reported fragmentation of care delivery experience; 3) Satisfaction with ambulatory experiences. Self-reported empanelment was a secondary outcome. Residents' learning opportunities increased (p = 0.007) but quality of faculty teaching was unchanged. Participants reported less fragmentation in the care residents provide patients in the inpatient and outpatient setting (p < 0.0001). Satisfaction with ambulatory training improved (p < 0.0001). Self-reported empanelment also increased (p < 0.0001). Results held true for residents, faculty, and staff at all three ambulatory training sites (p < 0.0001). DISCUSSION: A 4 + 1 model increased resident time in ambulatory continuity clinic, enhanced learning opportunities, reduced fragmentation of care residents provide, and improved satisfaction with ambulatory experiences. More studies of similar models are needed to evaluate effects on additional trainee and patient outcomes.

Real-world efficacy and tolerability of fremanezumab in adults with chronic migraine: a 3-month, single-center, prospective, observational study.

Background: Following the promising pre-marketing placebo-controlled randomized clinical trials of fremanezumab, post-marketing studies are necessary to verify efficacy and tolerability in various real-world settings. The present study assessed real-world efficacy and safety of fremanezumab. Methods: A 3-month, single-center, prospective, observation study of adults with chronic migraine who were treated with monthly subcutaneous injections of 225 mg fremanezumab in Denmark. The primary outcome was defined as proportion of patients who achieved ≥30% reduction in monthly migraine days (MMDs) from baseline to weeks 9-12. Among secondary outcomes were ≥50 and ≥75% responder rates and the proportion of patients reporting adverse events. Results: A total of 91 patients with chronic migraine were enrolled and received at least one dose of fremanezumab of whom 89 patients (98%) completed the 3-months treatment period. At baseline, the mean (SD) number of monthly headache days was 24.3 ± 5.8 and mean number of MMDs was 18.5 ± 7.4. The number of patients who achieved ≥30% reduction in MMDs from baseline to weeks 9-12 was 58 (65%), while 45 (51%) and 21 (24%) had ≥50 and 75% reduction in MMD, respectively. Twenty-one patients (23%) reported adverse event, in which the most common were constipation (4.4%), fatigue (4.4%) and dizziness (3.3%). No serious adverse events were reported. Conclusion: In adult chronic migraine patients with previous failure of conventional oral migraine preventives, fremanezumab was found to be effective and well-tolerated.