Healthcare resource utilization and associated costs among patients with migraine in Finland: A retrospective register-based study.

Migraine is a common chronic brain disorder, characterized by recurring and often disabling attacks of severe headache, with additional symptoms such as photophobia, phonophobia and nausea. Migraine affects especially the working age population. The objective of this retrospective observational register-based study was to analyze the use of healthcare services and associated costs in Finnish migraine patients. Study was based on aggregate data from January 1st, 2020, to December 31st, 2021, from the Finnish Institute for Health and Welfare's national registries. Patients were grouped into nine patient groups according to medication prescriptions and diagnoses. Healthcare resource utilization in specialty, primary, and occupational healthcare was assessed and analyzed separately for all-cause and migraine related healthcare contacts from a one-year period. The total number of patients was 175 711, and most (45%) of the patients belonged to a group that had used only one triptan. Migraine related total healthcare resource utilization was greater for patients that had used two or more triptans compared to those that had used only one. The patients with three or more preventive medications had the highest total migraine related healthcare resource utilization of the studied patient cohorts. Of the total annual healthcare costs 11.5% (50.6 million €) was associated to be migraine related costs. Total per patient per year healthcare costs were highest with patients that had used three or more preventive medications (5 626 €) and lowest in those with only one triptan (2 257 €). Our findings are in line with the recent European Headache Federation consensus statement regarding the unmet need in patients who have had inadequate response to two or more triptans. When assessing the patient access and cost-effectiveness of novel treatments for the treatment of migraine within different healthcare systems, a holistic analysis of the current disease burden along with potential gains for patients and healthcare service providers are essential information in guiding decision-making.

Risk of Stroke and Myocardial Infarction Among Initiators of Triptans.

Importance: Triptans are contraindicated in patients with ischemic heart disease or previous myocardial infarction, and caution is advised when prescribing these drugs to patients with vascular risk factors. However, controlled observational studies have either shown no association or an apparent lower risk, possibly owing to a channeling of triptans to individuals at low risk of cardiovascular outcomes, and it remains unclear whether avoiding triptan treatment for these patients is meaningful. Objective: To establish whether an association between triptans and ischemic events could be demonstrated using a self-controlled design because this type of design is robust to the previously mentioned type of confounding. Design, Setting, and Participants: All people in nationwide Danish registries who were initiating triptans and all the ischemic events that they experienced were identified. A case-crossover design was used to estimate odds ratios (OR) for associations between first-ever triptan use and ischemic outcomes, comparing triptan exposure in the 2-week period up to the event with four 2-week reference periods. Data were obtained for the period January 1995 to August 2022. Included from the population of Denmark were individuals redeeming a prescription for any triptan and experiencing at least 1 of 3 predefined ischemic outcomes. No one was excluded. Exposure: Initiation of any triptan. Main Outcomes and Measures: Acute myocardial infarction, ischemic stroke, or nonspecified stroke. Results: Identified were a total of 429 612 individuals (median [IQR] age, 38 [28-48] years; 325 687 female [75.8%]) who redeemed a first prescription for a triptan in the study period. Of these patients, 11 (0.003%) had a myocardial infarction with the first triptan prescription in either a focal or referent window (odds ratio [OR], 3.3; 95% CI, 1.0-10.9), 18 (0.004%) had ischemic stroke (OR, 3.2; 95% CI, 1.3-8.1), and 35 (0.008%) had ischemic/nonspecified stroke (OR, 3.0; 95% CI, 1.5-5.9). Case patients had a median age of approximately 60 years and had a high-risk cardiovascular profile. Conclusions and Relevance: Results of this case-crossover study suggest that triptan initiation was associated with higher risk of ischemic stroke and myocardial infarction. For the individual patient with low background cardiovascular risk, the risk of an ischemic event after triptan initiation was very low.

The 5-HT1B and 5-HT1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans.

The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT1B and 5-HT1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal suppositories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects.

5-HT1F agonists.

5-Hydroxytryptamine (HT)/serotonin receptor agonism has been a long-recognized property of triptan medications, and more recently, the study and development of medications with selective binding to the 1F receptor subtype have been explored. While the exact mechanism contributing to decreased symptoms of an acute migraine attack remains unclear, selective 5-HT1F agonists have demonstrated clinical efficacy with lasmiditan as the only approved medication from this class to date. Lasmiditan lacks vasoconstrictive properties, giving it utility in specific patient populations in whom triptans should be avoided. Availability, central nervous system (CNS) side effects, and 8-hour driving restriction may affect its clinical use.

Serotonergic and Adrenergic Neuroreceptor Manipulation Ameliorates Core Symptoms of ADHD through Modulating Dopaminergic Receptors in Spontaneously Hypertensive Rats.

The core symptoms of attention deficit hyperactivity disorder (ADHD) are due to the hypofunction of the brain's adrenergic (NE) and dopamine (DA) systems. Drugs that enhance DA and NE neurotransmission in the brain by blocking their transporters or receptors are the current therapeutic strategies. Of late, the emerging results point out the serotonergic (5-HT) system, which indirectly modulates the DA activity in reducing the core symptoms of ADHD. On this basis, second-generation antipsychotics, which utilize 5-HT receptors, were prescribed to children with ADHD. However, it is not clear how serotonergic receptors modulate the DA activity to minimize the symptoms of ADHD. The present study investigates the efficacy of serotonergic and alpha-2 adrenergic receptor manipulation in tackling the core symptoms of ADHD and how it affects the DA neuroreceptors in the brain regions involved in ADHD. Fifteen-day-old male spontaneously hypertensive rats (SHRs) received 5-HT1A agonist (ipsapirone) or 5-HT2A antagonist (MDL 100907) (i.p.) or alpha-2 agonist (GFC) from postnatal days 15 to 42 along with age-matched Wistar Kyoto rats (WKY) (n = 8 in each group). ADHD-like behaviors were assessed using a battery of behavioral tests during postnatal days 44 to 65. After the behavioral tests, rat brains were processed to estimate the density of 5-HT1A, 5-HT2A, DA-D1, and DA-D2 neuroreceptors in the prefrontal cortex, the striatum, and the substantia nigra. All three neuroreceptor manipulations were able to minimize the core symptoms of ADHD in SHRs. The positive effect was mainly associated with the upregulation of 5-HT2A receptors in all three areas investigated, while 5-HT1A was in the prefrontal cortex and the substantia nigra. Further, the DA-D1 receptor expression was downregulated by all three neuroreceptor manipulations except for alpha-2 adrenergic receptor agonists in the striatum and 5-HT2A antagonists in the substantia nigra. The DA-D2 expression was upregulated in the striatum while downregulated in the prefrontal cortex and the substantia nigra. In this animal model study, the 5-HT1A agonist or 5-HT2A antagonist monotherapies were able to curtail the ADHD symptoms by differential expression of DA receptors in different regions of the brain.

Patterns of anti-CGRP mAbs use and variation of triptan consumption following treatment initiation: A descriptive drug utilization study in the Tuscany region, Italy.

OBJECTIVE: To describe the pattern of anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) utilization in the Tuscany region, Italy, and the variation of triptan consumption after treatment initiation. BACKGROUND: Given the recent commercialization of anti-CGRP mAbs as migraine preventive medications, real-world evidence on their patterns of utilization and their impact on migraine abortive medication use is still limited. METHODS: A retrospective, descriptive, cohort study on the real-world utilization of anti-CGRP mAbs was performed using the population-based regional administrative database of Tuscany. Patients with ≥1 anti-CGRP mAb dispensing (namely erenumab, galcanezumab, fremanezumab) between April 1, 2019, and September 30, 2021, were identified. The first dispensing was the cohort entry (CE). New users (NUs) were patients with no anti-CGRP mAb dispensing before CE. Kaplan-Meier (KM) curves were plotted to describe the cumulative probability of remaining with the initial anti-CGRP mAb during a 15-month follow-up period as a measure of treatment persistence. Among NUs with ≥2 triptan dispensings during the 6 months before CE (i.e., baseline), the mean monthly number of triptan dosage units dispensed was measured in five consecutive follow-up time windows (months 1-3, 4-6, 7-9, 10-12, 13-15) and the difference from the baseline was calculated. RESULTS: A total of 624 NUs (erenumab = 295, galcanezumab = 223, fremanezumab = 106) were identified, of whom 188 (78%) were women. Mean age was 49.2 years (standard deviation [SD] = 12.6). The survival to discontinuation at 6, 12, and 15 months was about 69%, 48%, and 6%, respectively. The survival to switch was about 6% at 15 months. The observed variation of triptan consumption at 3/6/9/12/15 months and the corresponding SD was -4.4 [8.2]/-5.2 [9.0]/-5.5 [9.2]/-5.4 [9.2]/-4.5 [10.0], respectively. CONCLUSION: Patient demographics reflect the place of these medications in therapy. Overall, findings seem to indicate a favorable tolerability and effectiveness profile. Further studies are warranted to better establish the long-term comparative effectiveness, safety, and cost effectiveness of anti-CGRP mAbs compared to other preventive medications.

Triptan non-response in specialized headache care: cross-sectional data from the DMKG Headache Registry.

BACKGROUND: Triptans are effective for many migraine patients, but some do not experience adequate efficacy and tolerability. The European Headache Federation (EHF) has proposed that patients with lack of efficacy and/or tolerability of ≥ 2 triptans ('triptan resistance') could be considered eligible for treatment with the novel medications from the ditan and gepant groups. There is little data on the frequency of 'triptan resistance'. METHODS: We used patient self-report data from the German Migraine and Headache Society (DMKG) Headache Registry to assess triptan response and triptan efficacy and/or tolerability failure. RESULTS: A total of 2284 adult migraine patients (females: 85.4%, age: 39.4 ± 12.8 years) were included. 42.5% (n = 970) had failed ≥ 1 triptan, 13.1% (n = 300) had failed ≥ 2 triptans (meeting the EHF definition of 'triptan resistance'), and 3.9% (n = 88) had failed ≥ 3 triptans. Compared to triptan responders (current use, no failure, n = 597), triptan non-responders had significantly more severe migraine (higher frequency (p < 0.001), intensity (p < 0.05), and disability (p < 0.001)), that further increased with the level of triptan failure. Responders rates were highest for nasal and oral zolmitriptan, oral eletriptan and subcutaneous sumatriptan. CONCLUSION: In the present setting (specialized headache care in Germany), 13.1% of the patients had failed ≥ 2 triptans. Triptan failure was associated with increased migraine severity and disability, emphasizing the importance of establishing an effective and tolerable acute migraine medication. Acute treatment optimization might include switching to one of the triptans with the highest responder rates and/or to a different acute medication class. TRIAL REGISTRATION: The DMKG Headache Registry is registered with the German Clinical Trials Register (DRKS 00021081).

The Serotonin 1A (5-HT1A) Receptor as a Pharmacological Target in Depression.

Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin 1A (5-HT1A) receptor in the pathophysiology of depression. Stimulation of the 5-HT1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT1A receptor, the evidence implicating it in depression and in the effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT1A 'biased agonism', using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effects of 5-HT1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT1A biased agonists.

5-HT1A agonists for levodopa-induced dyskinesia in Parkinson's disease.

Levodopa is the most effective agent for treating the symptoms of Parkinson's disease (PD). However, levodopa-induced dyskinesia remains a significant complication that manifests after few years of treatment, for which therapeutic options remain limited. Several agonists of the serotonin type 1A (5-HT1A) receptor with varying levels of efficacy and interaction at other sites, have been tested in the clinic. Clinical trials testing 5-HT1A agonists have yielded inconsistent results in alleviating dyskinesia, especially that the antidyskinetic benefit observed was often accompanied by an adverse effect on motor function. In this article, we summarize and analyze the various clinical trials performed with 5-HT1A agonists in PD patients with dyskinesia and offer perspectives on the future of this class of agents in PD.

After prolonged treatment with levodopa, patients with Parkinson's disease might start to experience abnormal involuntary movements, called 'dyskinesias'. These abnormal movements may be difficult to cope with since they can occur for several hours during the day and can hamper the quality of life. A potential approach to reduce the severity of dyskinesia, which has been the focus of extensive research, consists of stimulating a target inside the brain called the 5-HT_1A receptor. Several drugs harbouring this mechanism of action have been tested in clinical studies. Here, we provide an overview of these clinical studies and discuss their results.

[Anxiolytics: Appropriate Use of Benzodiazepine Receptor Agonists].

Anxiolytics are a class of drugs that include benzodiazepine receptor agonists and serotonin 1A receptor partial agonists. Although benzodiazepine receptor agonists have anxiolytic, sedative-hypnotic, muscle relaxant, and anticonvulsant effects, their use should be carefully monitored due to their potential for paradoxical reactions, withdrawal symptoms, and dependence. On the other hand, serotonin 1A receptor partial agonists have a slower onset, and their use also presents challenges. In clinical practice, having a thorough understanding of the various types of anxiolytics and their unique features is crucial.

Defining migraine days, based on longitudinal E-diary data.

BACKGROUND: There is a need for standardization of the definition of a migraine day for clinical and research purposes. METHODS: We prospectively compared different definitions of a migraine day with E-diary data of n = 1494 patients with migraine. We used a baseline definition based on migraine characteristics with a duration of ≥4 hours OR triptan intake (independently from its effect) OR (visual) aura lasting 5-60 minutes. RESULTS: Of all migraine days defined by triptan intake only, 66.2% had a duration <4 hours. Adjusting the headache duration criterion to ≥30 minutes led to a decrease in days defined by triptan intake only and resulted in a 5.4% increase in total migraine days (equals 0.45 migraine day increase in monthly migraine days). These additional migraine days had a median duration of 2.5 hours. CONCLUSION: We propose to define a migraine day as follows: 1) (a) headache duration ≥30 minutes; (b) matching ≥2 of four characteristics: unilateral, pulsating, moderate to severe pain, aggravation by or causing avoidance of routine physical activity; and (c) during headache ≥1 of the following: nausea and/or vomiting, photophobia and phonophobia or 2) (visual) aura duration 5-60 minutes or 3) a day with headache for which acute migraine-specific medication is used irrespective of its effect.

Efficacy of a long-term acting triptan for Headache attributed to aeroplane travel: a case report.

Headache attributed to aeroplane travel (AH) is a well-defined nosological entity whose diagnostic criteria have been published in the third provisional International Classification of Headache Disorders (ICHD) and confirmed in the definitive version. Despite the severe intensity of pain, less than half of the AH cases described used medications for preventing the attack. The most frequent prophylactic therapy spontaneously used by sufferers are simple analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), and nasal decongestants, achieving a complete or partial benefit in about 50% of patients. A complete response of AH to fast-acting triptans has been reported. We describe the case of a 37-year-old migrainous woman suffers from AH in about 75% of her flights who preempted the attacks by using a long-acting triptan (frovatriptan). Giving triptans' mechanism of action, an involvement of the trigemino-vascular system in the pathogenesis of AH could be advanced.

Effect of 5-HT1A Receptor Partial Agonists of the Azapirone Class as an Add-On Therapy on Psychopathology and Cognition in Schizophrenia: A Systematic Review and Meta-Analysis.

BACKGROUND: There are ongoing efforts to examine the effect of 5-HT1A receptor partial agonists as an add-on therapy for several symptoms of schizophrenia. By conducting a systematic review and meta-analysis, we evaluated whether augmentation with 5-hydroxtrypatamine (5-HT)1A partial agonists of the azapirone class improves psychotic symptoms and attention/processing speed, a key domain of cognition, in patients with schizophrenia. METHODS: A literature search was performed from 1987 to February 25, 2022, to identify randomized controlled trials. The standardized mean difference (SMD) with 95% confidence intervals (CI) was calculated when there were 2 or more studies. Seven studies, involving 435 patients, met the inclusion criteria. RESULTS: Random-effects model meta-analyses revealed that add-on therapy with buspirone or tandospirone had a significant beneficial effect on overall psychotic symptoms (SMD = -1.13, 95% CI = -1.98 to -0.27) and positive symptoms (SMD = -0.72, 95% CI =-1.31 to -0.12), while the effect on negative symptoms did not reach statistical significance (SMD = -0.93, 95% CI = -1.90 to 0.04). A significant positive effect was also observed on attention/processing speed (SMD = 0.37, 95% CI = 0.12 to 0.61). CONCLUSIONS: These findings support the idea that some compounds that stimulate 5-HT1A receptors provide an effective pharmacologic enhancer in the treatment of schizophrenia. Further clinical trials are warranted to determine the benefits of the adjunctive use of 5-HT1A partial agonists in ameliorating symptoms and improving functional outcomes in patients with schizophrenia or other psychiatric disorders.

Efficacy of rimegepant for the acute treatment of migraine based on triptan treatment experience: Pooled results from three phase 3 randomized clinical trials.

BACKGROUND: This post-hoc analysis from three phase 3 treatment trials of rimegepant 75 mg - an oral small molecule calcitonin gene-related peptide receptor antagonist for acute and preventive treatment of migraine - assessed efficacy in adults with migraine based on triptan treatment experience. METHODS: Participants were assigned to one of four groups based on triptan treatment experience: insufficient response (e.g. lack of efficacy and/or poor tolerability) to 1 triptan, insufficient response to ≥2 triptans, current triptan users, and triptan-naïve participants. The co-primary efficacy endpoints were pain freedom and most bothersome symptom freedom at two hours postdose. RESULTS: In the three trials (N = 3507; rimegepant n = 1749, placebo n = 1758), 1235 (35.2%) participants had a history of insufficient response to 1 triptan (n = 910 [25.9%]) or ≥2 triptans (n = 325 [9.3%]), and 2272 (64.8%) had no history of insufficient response to triptans (current use = 595 [17.0%], naïve = 1677 [47.8%]). Rimegepant was effective on the co-primary endpoints in all subgroups (p ≤ 0.013), except for freedom from the most bothersome symptom in the triptan-naïve group (p = 0.06). No differences on co-primary endpoints were found in pairwise comparisons of rimegepant-treated participants. CONCLUSIONS: Rimegepant was effective for the acute treatment of migraine in adults with a history of insufficient response to 1 or ≥2 triptans and in current triptan users. Efficacy on co-primary endpoints did not differ based on the number of insufficient triptan responses.Trial registration: Clinicaltrials.gov: NCT03235479, NCT03237845, NCT03461757.

Ulotaront: a TAAR1/5-HT1A agonist in clinical development for the treatment of schizophrenia.

INTRODUCTION: Current antipsychotics are postsynaptic dopamine-2(D2) receptor blockers, which often, but not always, effectively improve acute psychotic symptoms and prevent relapse in schizophrenia and other severe mental disorders, but are associated with various side effects, including parkinsonism, akathisia, sedation/somnolence, and cardiometabolic alterations. Furthermore, the efficacy of current antipsychotics for negative and cognitive symptoms in schizophrenia is limited. Ulotaront is a novel trace-amine-associated receptor-1(TAAR1) agonist with serotonin-1A receptor agonist activity, and without postsynaptic D2-receptor antagonism. Phase 2 clinical data for ulotaront in patients with acutely exacerbated schizophrenia are promising regarding the potential improvement in positive, negative, and depressive symptoms. AREAS COVERED: An overview of the pharmacokinetic and pharmacodynamic properties of ulotaront is given. Summary of clinical efficacy and safety/tolerability from Phase 1/2-trials, and of ongoing Phase 3-trials, is also given. EXPERT OPINION: Ulotaront is a promising agent for the treatment of schizophrenia with an apparent benign safety profile, which might provide a much-needed new and different treatment option for various domains of schizophrenia. Data from larger Phase 3-trials, including for relapse prevention, schizophrenia subdomains, and in adolescents, are awaited. If ongoing Phase 3-trials in adults are successful, further research on combination regimens with existing antipsychotics, and in treatment-resistant schizophrenia as well as in mood disorders would be desirable.

European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure.

BACKGROUND: Triptans are migraine-specific acute treatments. A well-accepted definition of triptan failure is needed in clinical practice and for research. The primary aim of the present Consensus was to provide a definition of triptan failure. To develop this definition, we deemed necessary to develop as first a consensus definition of effective treatment of an acute migraine attack and of triptan-responder. MAIN BODY: The Consensus process included a preliminary literature review, a Delphi round and a subsequent open discussion. According to the Consensus Panel, effective treatment of a migraine attack is to be defined on patient well-being featured by a) improvement of headache, b) relief of non-pain symptoms and c) absence of adverse events. An attack is considered effectively treated if patient's well-being, as defined above, is restored within 2 hours and for at least 24 hours. An individual with migraine is considered as triptan-responder when the given triptan leads to effective acute attack treatment in at least three out of four migraine attacks. On the other hand, an individual with migraine is considered triptan non-responder in the presence of failure of a single triptan (not matching the definition of triptan-responder). The Consensus Panel defined an individual with migraine as triptan-resistant in the presence of failure of at least 2 triptans; triptan refractory, in the presence of failure to at least 3 triptans, including subcutaneous formulation; triptan ineligibile in the presence of an acknowledged contraindication to triptan use, as specified in the summary of product characteristics. CONCLUSIONS: The novel definitions can be useful in clinical practice for the assessment of acute attack treatments patients with migraine. They may be helpful in identifying people not responding to triptans and in need for novel acute migraine treatments. The definitions will also be of help in standardizing research on migraine acute care.

Synergistic effect of serotonin 1A and serotonin 1B/D receptor agonists in the treatment of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats.

BACKGROUND: The gold standard for symptomatic relief of Parkinson's disease (PD) is L-DOPA. However, long-term treatment often leads to motor complications such as L-DOPA-induced dyskinesia (LID). While amantadine (Gocovri™) is the only approved therapy for dyskinesia in PD patients on the American market, it is associated with neurological side effects and limited efficacy. Thus, there remains a high unmet need for addressing LID in PD patients worldwide. OBJECTIVE: The objective of this study was to evaluate the efficacy, safety and performance compared to approved treatments of the serotonin receptor 1A (5-HT1A) and 5-HT1B/D agonists buspirone and zolmitriptan in the 6-hydroxydopamine unilaterally lesioned rat model for PD. METHODS: The hemiparkinsonian 6-OHDA-lesioned rats underwent chronic treatment with L-DOPA to induce dyskinesia and were subsequently used for efficacy testing of buspirone, zolmitriptan and comparison with amantadine, measured as abnormal involuntary movement (AIM) scores after L-DOPA challenge. Safety testing was performed in model and naïve animals using forelimb adjusting, rotarod and open field tests. RESULTS: 5-HT1A and 5-HT1B/D agonism effectively reduced AIM scores in a synergistic manner. The drug combination of buspirone and zolmitriptan was safe and did not lead to tolerance development following sub-chronic administration. Head-to-head comparison with amantadine showed superior performance of buspirone and zolmitriptan in the model. CONCLUSIONS: The strong anti-dyskinetic effect found with combined 5-HT1A and 5-HT1B/D agonism renders buspirone and zolmitriptan together a meaningful treatment for LID in PD.

Potential Channeling Bias in the Evaluation of Cardiovascular Risk: The Importance of Comparator Selection in Observational Research.

BACKGROUND: Comparator selection is an important consideration in the design of observational research studies that evaluate potential associations between drug therapies and adverse event risks. It can affect the validity of observational study results, and potentially impact data interpretation, regulatory decision making, and patient medication access. OBJECTIVE: The aim of this study was to assess the impact of comparator selection bias using two real-world case studies evaluating an increased rate of acute myocardial infarction (AMI). METHODS: Data from the Truven Health Analytics MarketScan® electronic medical claims database were used to conduct two retrospective observational cohort studies, utilizing a cohort new-user design, comparing AMI risk between testosterone replacement therapy (TRT) and phosphodiesterase-5 inhibitors (PDE5is) in men treated for hypogonadism, and triptans versus other prescribed acute treatments for migraine in adults. All patients were enrolled continuously in a health plan (no enrollment gap > 31 consecutive days) for ≥ 1 year before index. Baseline period was defined as 365 days prior to index. Exposure was defined by prescription and outcome of interest was defined as occurrence of AMI. Using Cox proportional hazard models, primary analysis for the TRT cohort compared AMI risk between propensity score (PS)-matched TRT-treated and untreated patients; secondary analysis evaluated risk between PS-matched TRT-treated and PDE5i-treated patients. For the triptan cohort, primary analysis compared AMI/ischemic stroke risk between PS-matched triptan-treated and opiate-treated patients; secondary analysis evaluated risk between PS-matched triptan-treated and nonsteroidal anti-inflammatory drug (NSAID)-treated patients and PS-matched non-prescription-treated migraine patients and general patients. RESULTS: No significant association between TRT and AMI was observed among TRT-treated (N = 198,528, mean age 52.4 ± 11.4 years) versus PDE5i-treated men (N = 198,528, mean age 52.3 ± 11.5 years) overall (adjusted hazard ratio [aHR] 1.01; 95% CI 0.95-1.07; p = 0.80). Among patients with prior cardiovascular disease (CVD), risk of AMI was significantly increased for TRT-treated versus PDE5i-treated patients (aHR 1.13; 95% CI 1.03-1.25). The triptan study included three comparisons (triptans [N = 436,642] vs prescription NSAIDs [N = 334,152], opiates [N = 55,234], and untreated migraine [N = 1,168,212]), and a positive control (untreated vs general non-migraine patients [N = 11,735,009]). Analyses of MI risk in migraine patients prescribed triptans versus NSAIDs/opiates had mixed results: the point estimate ranged from 0.33 to 0.84 depending on chosen study window. CONCLUSIONS: Cardiovascular outcomes were not worse in hypogonadism patients with TRT versus PDE5i; however, a potential association with AMI was found in patients with prior CVD receiving TRT versus PDE5i. Findings pointed to a pseudo-protective effect of triptans versus untreated migraine patients or those potentially older and less healthy patients exposed to prescription NSAIDs or opiates. Triptan users should not be compared with those using other anti-migraine prescriptions when evaluating cardiovascular outcomes in migraine patients. Presence of high cardiovascular risks may contribute to channeling bias-healthier subjects being selected to receive treatment-highlighting the importance of choosing comparators wisely in observational studies.

Triptan medication use among patients with migraine with contraindications in the US.

OBJECTIVE: We sought to investigate the prevalence of triptan use among patients with migraine who have contraindications to triptan usage, and to explore specifics of the medication prescribed, dosage, and route of administration. BACKGROUND: Triptan medications are a mainstay of acute migraine therapy, but little is known about prevalence and patterns of triptan prescribing among patients with contraindications in the United States. METHODS: In this retrospective cohort study, we used data from the IBM Marketscan database to identify patients aged ≥ 18 years with migraine from January 1, 2016, to December 31, 2017, using International Classification of Diseases, Clinical Modification 10 codes. Contraindications to triptan medications were identified by review of package labels as listed on the US Food and Drug Administration website. Triptan medications were identified from the IBM Micromedex Redbook linked to prescription claims along with route of administration and dosage. RESULTS: Of 1,038,472 individuals diagnosed with migraine, 400,112 (38.5%) were prescribed triptan medication, and of those who were prescribed a triptan, 55,707 (13.9%) had at least one contraindication, with the most common contraindication being cardiac arrhythmia (33,696/400,112 individuals, 8.4%) followed by cerebrovascular disease (14,787/400,112, 3.7%) and coronary artery disease (10,236/400,112, 2.6%). Sumatriptan was the most prescribed triptan (261,736/1,038,472, 25.2%), and the subcutaneous and intranasal routes were more commonly prescribed among those with contraindications compared with those without contraindications. DISCUSSION: A substantial proportion of patients with migraine with contraindications were prescribed triptan medications. These findings call for further research on the outcomes of patients with medical contraindications who are prescribed triptan medications, and for greater clarity in prescribing guidelines about the optimal approach for acute therapy among patients with migraine.

Low adherence to the guideline for the acute treatment of migraine.

The real-world use of triptans in the treatment of migraine is disappointing. Only 12% of the Danish migraine population purchased a triptan between 2014 and 2019, and only 43% repurchased a triptan after first prescription. The aim of the present study was to assess whether physicians and patients adhere to the therapeutic guideline on acute migraine treatment. We interviewed 299 triptan experienced participants with migraine and 101 triptan naïve participants with migraine from the Danish Migraine Population Cohort, using a semi-structured questionnaire. Descriptive statistical analyses were used to study the association with triptan use and the assessed factors. Among triptan naïve participants with migraine, 64% had consulted their general practitioner about their migraine, of whom only 23% received information about the possibility of triptan treatment. Among triptan experienced participants, 77% had only tried one type of triptan. Only 12% could recall they had been informed by their general practitioner to try each triptan three times before giving up. Twenty percent were informed to try three different triptans in total, if the first did not work. In disagreement with the guideline, participants who reported a low pain reduction by a triptan had only tried one type of triptan. Our study shows a low adherence to therapeutic guideline for the attack treatment of migraine. There is a need for better education of general practitioners regarding treatment of migraine. Future campaigns should aim to inform both the public and the general practitioner about antimigraine treatments.