An update on migraine: Current and new treatment options.

ABSTRACT: Migraine headache is a common and potentially debilitating disorder often treated by physician associates/assistants (PAs) and other providers. With the recent advances in new drugs and device technology for the treatment of migraine, the American Headache Society has released a consensus statement on both preventive and acute strategies for clinical practice. The US FDA has recently approved various types of medications and devices for the treatment and prevention of migraine attacks including several calcitonin gene-related peptide (CGRP) receptor inhibitors, a selective serotonin receptor agonist (SSRA), noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e-TNS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS), among other pharmacologic and nonpharmacologic options. This article provides a review of migraine prevention and acute treatment protocol, highlighting new approaches to both.

Serotonin regulation of mitochondria in kidney diseases.

Serotonin, while conventionally recognized as a neurotransmitter in the CNS, has recently gained attention for its role in the kidney. Specifically, serotonin is not only synthesized in the kidney, but it also regulates glomerular function, vascular resistance, and mitochondrial homeostasis. Because of serotonin's importance to mitochondrial health, this review is focused on the role of serotonin and its receptors in mitochondrial function in the context of acute kidney injury, chronic kidney disease, and diabetic kidney disease, all of which are characterized by mitochondrial dysfunction and none of which has approved pharmacological treatments. Evidence indicates that activation of certain serotonin receptors can stimulate mitochondrial biogenesis (MB) and restore mitochondrial homeostasis, resulting in improved renal function. Serotonin receptor agonists that induce MB are therefore of interest as potential therapeutic strategies for renal injury and disease. SIGNIFICANCE STATEMENT: Mitochondrial dysfunction is associated with many human renal diseases such as acute kidney injury, chronic kidney disease, and diabetic kidney disease, which are associated with increased morbidity and mortality. Unfortunately, none of these pathologies has an FDA-approved pharmacological intervention, underscoring the urgency of identifying new therapeutics for such disorders. Studies show that induction of mitochondrial biogenesis via serotonin (5-hydroxytryptamine, 5-HT) receptors reduces kidney injury markers, restores mitochondrial and renal function after kidney injury, and decreases mortality, suggesting that targeting 5-HT receptors may be a promising therapeutic avenue for mitochondrial dysfunction in kidney diseases. While numerous reviews describe the importance of mitochondria and mitochondrial quality control mechanisms in kidney disease, the relevance of 5-HT receptor-mediated mitochondrial metabolic modulation in the kidney has yet to be thoroughly explored.

Exploration of Lasmiditan 200 mg Versus 100 mg for the Treatment of Migraine: A Meta-analysis Based on Aggregate Data.

OBJECTIVES: Lasmiditan holds important potential in treating migraine, but its ideal dose remains elusive. This meta-analysis is conducted based on aggregate data and aims to compare the efficacy of lasmiditan 200 mg versus 100 mg for acute treatment of migraine attack. METHODS: PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases were systematically searched, and we included the randomized controlled trials comparing the efficacy of lasmiditan 200 mg versus 100 mg for migraine patients. This meta-analysis was conducted using the random-effect model or fixed-effect model based on the heterogeneity. The primary outcome was pain free at 2 hours. Secondary outcomes included pain relief at 2 hours, pain free at 24 hours, most bothersome symptom free at 2 hours, and adverse events. RESULTS: Seven randomized controlled trials and 6515 patients were included in this meta-analysis. Compared with lasmiditan 100 mg for migraine patients, lasmiditan 200 mg was able to significantly improve pain free at 2 hours (odd ratio [OR], 1.28; 95% confidence interval [CI], 1.14-1.44; P < 0.0001) and pain free at 24 hours (OR, 1.35; 95% CI, 1.14-1.60; P = 0.0005), but showed no effect on pain relief at 2 hours (OR, 1.00; 95% CI, 0.90-1.12; P = 0.98) or most bothersome symptom free at 2 hours (OR, 0.93; 95% CI, 0.83-1.03; P = 0.17). Lasmiditan 200 mg was associated with the increase in adverse events compared with lasmiditan 100 mg (OR, 1.28; 95% CI, 1.15-1.43; P < 0.0001). CONCLUSIONS: Lasmiditan 200 mg is more effective to improve pain free at 2 hours and 24 hours than lasmiditan 100 mg for the acute treatment of migraine patients.

Long-term treatment with lasmiditan in patients with migraine: post hoc analysis of treatment patterns and outcomes from the open-label extension of the CENTURION randomized trial.

BACKGROUND: The objective of this analysis was to gain new insights into the patient characteristics and other factors associated with lasmiditan usage and clinical outcomes under conditions resembling the real-world setting. METHODS: This was a post hoc analysis of data from the 12-month, open-label extension (OLE) of the phase 3, double-blind, randomized, controlled CENTURION trial, which examined the efficacy and safety of lasmiditan as acute treatment across four migraine attacks. Patients completing the main study who treated ≥ 3 attacks could continue in the OLE. The initial lasmiditan dose was 100 mg, with dose adjustments to 50 mg or 200 mg allowed at the investigator's discretion. Patient and clinical characteristics were summarized by dosing pattern and completion status. Safety was assessed based on adverse event (AE) frequency by number of doses. RESULTS: In total, 445 patients treated ≥ 1 migraine attacks with lasmiditan during the OLE, 321 of whom (72.1%) completed the study. Forty-seven percent of patients remained on the 100-mg initial dose during the OLE whereas 20.2% used both 100 mg and 50 mg, 30.6% used both 100 mg and 200 mg, and 6 (1.3%) used multiple dose levels. All dosing patterns were associated with clinical and patient-reported improvement; however, the 100-mg group had the highest proportion of patients reporting improvement in the Patient Global Impression of Change - Migraine Headache Condition (56.5% vs 33.4%-52.2%). In comparison, all three groups that made dose adjustments had higher rates of completion compared to the 100-mg group (72.1%-83.3% vs 68.9%). The frequency of AEs decreased with continued use of lasmiditan. Concomitant triptans and lasmiditan use did not increase AE frequency. CONCLUSIONS: Based on high persistence and patient satisfaction rates, the 100-mg dose appears optimal for most patients. For those who adjusted dose levels, dose adjustments appeared beneficial to improve efficacy or tolerability, retaining patients on treatment. Collectively, the data suggest that patients who experienced efficacy continued to use lasmiditan regardless of the occurrence or frequency of AEs, and continued use appeared associated with fewer AEs. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT): 2018-001661-17; ClinicalTrials.gov: NCT03670810; registration date: September 12, 2018.

Serotonergic agonism and pharmacologically-induced adolescent stress cause operant-based learning deficits in mice.

BACKGROUND: The interplay between environmental stress and genetic factors is thought to play an important role in the pathogenesis and maintenance of obsessive-compulsive disorder (OCD). However, the relative contribution of these causative antecedents in the manifestation of cognitive inflexibility-a phenotype often seen in obsessive-compulsive (OC)- spectrum disorders-is not fully understood. METHOD: In this study, we treated mice with 50 mg/L corticosterone (CORT, a glucocorticoid stress hormone) in their drinking water during adolescence. In adulthood, we assessed anxiety-like behaviour and locomotor activity; along with operant-based discrimination and reversal learning. RU-24969, a selective serotonin receptor 5-HT1A/1B receptor agonist, was used as an acute pharmacological model of OC-like behaviour. RU-24969 (5 mg/kg) was administered prior to each reversal learning testing session. RESULTS: We found that acute treatment with 5 mg/kg RU-24969 induced stereotyped hyperlocomotion in vehicle- and CORT-treated mice. Furthermore, pre-treatment with CORT in adolescence produced subtle anxiety-like behaviour in adult mice, and also resulted in an impairment to late-stage discrimination learning and alterations to reversal learning. Finally, acute treatment with 5 mg/kg RU-24969 caused an impairment to early-stage reversal learning. CONCLUSION: Whilst we revealed dissociable detrimental effects of adolescent CORT treatment and acute 5-HT1A/1B receptor agonism on discrimination and reversal learning, respectively, we did not find evidence of additive deleterious effects of these two treatments. We therefore suggest that while disrupted serotonergic signalling is likely to be involved in the cognitive phenotype of OC-spectrum disorders, distinct neuropathological pathways may be at play in mediating the role of stress as an antecedent in OCD and related illnesses.

Comparison of Lasmiditan 200 mg Versus 100 mg for Migraine Patients: A Meta-analysis of Randomized Controlled Studies.

INTRODUCTION: The ideal dose of lasmiditan for migraine is not clear. This meta-analysis aims to compare the efficacy of lasmiditan 200 mg versus 100 mg for migraine patients. METHODS: We have searched several databases including PubMed, Embase, Web of Science, EBSCO, and Cochrane Library Databases and selected the randomized controlled trials comparing the efficacy of lasmiditan 200 mg versus 100 mg for migraine patients. This meta-analysis was conducted using the random-effect model. RESULTS: Five randomized controlled trials were included in this meta-analysis. Compared with lasmiditan 100-mg group in migraine patients, lasmiditan 200-mg group was associated with substantially increased pain free at 2 hours (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.12-1.44; P = 0.0002) and pain free at 24 hours (OR, 1.31; 95% CI, 1.08-1.60; P = 0.007) but demonstrated no obvious impact on pain relief at 2 hours (OR, 1.02; 95% CI, 0.91-1.16; P = 0.72) or MBS free at 2 hours (OR, 0.94; 95% CI, 0.77-1.14; P = 0.52). In addition, the incidence of adverse events was higher in lasmiditan 200-mg group than that in lasmiditan 100-mg group (OR, 1.29; 95% CI, 1.15-1.45; P < 0.0001). CONCLUSIONS: Lasmiditan 200 mg is better for the treatment of migraine patients than lasmiditan 100 mg.

Design, Synthesis, Molecular Docking, and Biological Evaluation of Novel Pimavanserin-Based Analogues as Potential Serotonin 5-HT2A Receptor Inverse Agonists.

There is concern for important adverse effects with use of second-generation antipsychotics in Parkinson's disease psychosis (PDP) and dementia-related psychosis. Pimavanserin is the only antipsychotic drug authorized for PDP and represents an inverse agonist of 5-HT2A receptors (5-HT2AR) lacking affinity for dopamine receptors. Therefore, the development of serotonin 5-HT2AR inverse agonists without dopaminergic activity represents a challenge for different neuropsychiatric disorders. Using ligand-based drug design, we discovered a novel structure of pimavanserin analogues (2, 3, and 4). In vitro competition receptor binding and functional G protein coupling assays demonstrated that compounds 2, 3, and 4 showed higher potency than pimavanserin as 5-HT2AR inverse agonists in the human brain cortex and recombinant cells. To assess the effect of molecular substituents for selectivity and inverse agonism at 5-HT2ARs, molecular docking and in silico predicted physicochemical parameters were performed. Docking studies were in agreement with in vitro screenings and the results resembled pimavanserin.

Eltoprazine modulated gamma oscillations on ameliorating L-dopa-induced dyskinesia in rats.

AIM: Parkinson's disease (PD) is a pervasive neurodegenerative disease, and levodopa (L-dopa) is its preferred treatment. The pathophysiological mechanism of levodopa-induced dyskinesia (LID), the most common complication of long-term L-dopa administration, remains obscure. Accumulated evidence suggests that the dopaminergic as well as non-dopaminergic systems contribute to LID development. As a 5-hydroxytryptamine 1A/1B receptor agonist, eltoprazine ameliorates dyskinesia, although little is known about its electrophysiological mechanism. The aim of this study was to investigate the cumulative effects of chronic L-dopa administration and the potential mechanism of eltoprazine's amelioration of dyskinesia at the electrophysiological level in rats. METHODS: Neural electrophysiological analysis techniques were conducted on the acquired local field potential (LFP) data from primary motor cortex (M1) and dorsolateral striatum (DLS) during different pathological states to obtain the information of power spectrum density, theta-gamma phase-amplitude coupling (PAC), and functional connectivity. Behavior tests and AIMs scoring were performed to verify PD model establishment and evaluate LID severity. RESULTS: We detected exaggerated gamma activities in the dyskinetic state, with different features and impacts in distinct regions. Gamma oscillations in M1 were narrowband manner, whereas that in DLS had a broadband appearance. Striatal exaggerated theta-gamma PAC in the LID state contributed to broadband gamma oscillation, and aperiodic-corrected cortical beta power correlated robustly with aperiodic-corrected gamma power in M1. M1-DLS coherence and phase-locking values (PLVs) in the gamma band were enhanced following L-dopa administration. Eltoprazine intervention reduced gamma oscillations, theta-gamma PAC in the DLS, and coherence and PLVs in the gamma band to alleviate dyskinesia. CONCLUSION: Excessive cortical gamma oscillation is a compelling clinical indicator of dyskinesia. The detection of enhanced PAC and functional connectivity of gamma-band oscillation can be used to guide and optimize deep brain stimulation parameters. Eltoprazine has potential clinical application for dyskinesia.

Reverse Engineering Drugs: Lorcaserin as an Example.

Novel central nervous system (CNS)-based therapies have been difficult to produce due to the complexity of the brain, limited knowledge of CNS-based disease development and associated pathways, difficulty in penetrating the blood brain barrier, and a lack of reliable biomarkers of disease. Reverse engineering in drug development allows the utilization of new knowledge of disease pathways and the use of innovative technology to develop medications with enhanced efficacy and reduced toxicities. Lorcaserin was developed as a specific 5HT2C serotonin receptor agonist for the treatment of obesity with limited off-target effects at the 5HT2A and 5HT2B receptors. This receptor specificity limited the hallucinogenic and cardiovascular side effects noted with other serotonin receptor agonists. Reverse engineering approaches to drug development reduce the cost of producing new medications, identify specific populations of patients that will derive the most benefit from therapy, and produce novel therapies with greater efficacy and limited toxicity.

Current and emerging pharmacotherapy for menstrual migraine: a narrative review.

INTRODUCTION: In this article, we discuss menstrual migraine (MM), which can be categorized as menstrually related migraine (MRM) or pure menstrual migraine (PMM). MM attacks are often longer, more severe, and harder to treat than other migraine attacks. Appropriate treatment strategies include acute treatment, short term preventive treatment, and daily preventive treatment, depending on the patient's pattern of migraine and occurrence of migraine outside the menstrual period. AREAS COVERED: A PubMed, Cochrane Library, Medline, and Ovid search from inception to October 2022 provided articles relating to MM pathophysiology and treatment. EXPERT OPINION: In patients for whom standard acute therapy is inadequate, short term or daily preventive treatment should be considered. Patients with PMM may be adequately managed with short term preventive treatment started 2 days prior to the onset of migraine and continued for 5-6 days. Frovatriptan is the mainstay of short-term prevention. Patients who experience additional attacks outside the menstrual period may benefit from daily preventive treatment. Estrogen-containing contraceptive treatment may be effective in appropriately selected patients. Emerging research on the pathophysiology of MM indicates that oxytocin agonists and CGRP antagonists may prove to be effective treatment options.

Augmentation therapy with tandospirone citrate in vascular depression patients with mild cognitive impairment: A prospective randomized clinical trial.

Cognitive impairment is a prominent clinical manifestation of vascular depression (VaDep). The current study aimed to assess the efficacy of tandospirone citrate in VaDep cases with mild cognitive impairment (VaDep-MCI) as well as the role of plasma monoamine neurotransmitters during the treatment. In this single-blind, randomized controlled study, 116 participants were randomly assigned to the tandospirone (tandospirone citrate-escitalopram) and control (escitalopram) groups. The primary endpoints were changes in cognitive test scores from baseline to Week 8, including the Rey Auditory Verbal Learning Test (RAVLT), Semantic Verbal Fluency (SVF) test, Trail Making Test (TMT), Digital Span Test (DST) and Clock Drawing Test (CDT) scores. Generalized estimating equation models were used to examine repeated measures. The results showed that compared with the changes in the control group from baseline to Week 8, the tandospirone group showed more significant changes in SVF score at Weeks 4 (p < 0.05) and 8 (p < 0.001), and TMT (B-A) score at Week 8 (p < 0.05). RAVLT, DST and DCT scores were relatively stable in both groups during the study period. Moreover, mediation analysis showed that these results were not mediated by the alleviation of depression symptoms. Partial Spearman correlation analysis showed that only plasma 5-hydroxytryptamine (5-HT) was positively correlated with Hamilton Depression Rating Scale score after Bonferroni correction (r = 0.347, p < 0.001). Augmentation therapy with tandospirone citrate improved the executive and language functions of VaDep-MCI patients. Additionally, plasma 5-HT levels may serve as a potential biomarker of VaDep severity. These findings may provide clinical insights into the treatment of vascular depression.

Efficacy of Lasmiditan Across Patient and Migraine Characteristics in Japanese Patients with Migraine: A Secondary Analysis of the MONONOFU Trial.

INTRODUCTION: This MONONOFU trial subgroup analysis evaluates the efficacy of lasmiditan across patient and migraine characteristics in Japanese patients with migraine. METHODS: MONONOFU trial was a multicenter, randomized, double-blind, placebo-controlled study. The patients were randomly assigned in a 3:7:6:7 ratio to receive lasmiditan 50 mg, 100 mg, 200 mg, or placebo for a single migraine attack within 4 h of pain onset. Efficacy of lasmiditan vs placebo was evaluated at 2 h post dose for proportion of patients with headache pain freedom. Efficacy was assessed across patient characteristics (age, sex, body weight, cardiovascular risk factors (CVRF), and comorbidity of tension-type headache), migraine disease characteristics (history of migraine with aura, migraine prevention therapy, triptan response, and triptan use or nonuse), and migraine attack characteristics (headache severity, aggressive headache, attack during perimenstrual period, time to dosing, time of dosing, experienced treatment-emergent adverse event (TEAE) of dizziness, and experienced TEAE of somnolence). Logistic regression was used; all subgroup analyses were not analyzed with multiplicity-adjusted statistical tests. RESULTS: Treatment-by-subgroup interactions (by each arm) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups and lasmiditan doses, except for CVRF (100 mg and 200 mg), migraine with aura (50 mg), triptan response (50 mg), and time to dosing (200 mg). Treatment-by-subgroup interactions (by overall) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups, except for CVRFs. Higher proportions of patients were pain free at 2 h post dose when treated with lasmiditan (50 mg, 100 mg, and 200 mg) versus placebo, irrespective of most patient characteristics, migraine disease characteristics, and migraine attack characteristics. CONCLUSION: Although few interactions were observed, lasmiditan could be a promising acute treatment option in a wide range of Japanese patients with migraine, as efficacy is not generally influenced by patient and migraine characteristics.

Rimegepant, Ubrogepant, and Lasmiditan in the Acute Treatment of Migraine Examining the Benefit-Risk Profile Using Number Needed to Treat/Harm.

OBJECTIVES: To develop and compare benefit-risk profiles for rimegepant, ubrogepant, and lasmiditan based on a network meta-analysis (NMA) of published clinical trials. METHODS: A fixed-effects Bayesian NMA of randomized controlled trials of lasmiditan, rimegepant, and ubrogepant for the acute treatment of adults with migraine were used to determine risk differences for efficacy and safety outcomes of the 3 treatments compared with pooled placebo. Risk differences were used to calculate number needed to treat (NNT) for pain relief and pain freedom at 2 and 2 to 24 hours and freedom from most bothersome symptoms at 2 hours; and number needed to harm (NNH) for dizziness and nausea, relative to placebo. RESULTS: Results were based on 5 randomized controlled trials (NCT03461757, NCT02828020, NCT02867709, NCT02439320, and NCT02605174). NNT to achieve sustained pain relief at 2 to 24 hours was lowest for rimegepant 75 mg (5; 95% credible interval [Crl]: 4, 7) and ubrogepant 100 mg (5; 95% Crl: 4, 8) and highest for ubrogepant 25 mg (8; 95% Crl: 5, 16). Rimegepant had the lowest NNT to achieve sustained pain freedom at 2 to 24 hours and lasmiditan 50 mg had the highest (7; 95% Crl: 5, 12 vs. 26; 95% Crl: 13, 95). NNH for dizziness and nausea was highest for ubrogepant 25 mg (28; 95% Crl: 15, 62 and 99; 95% Crl: -2580, 2378, respectively). Lasmiditan 200 mg had the lowest NNH for dizziness and rimegepant 75 mg had the lowest NNH for nausea. CONCLUSIONS: The benefit-risk profiles of lasmiditan, rimegepant, and ubrogepant may improve clinical decision-making.

Ditans: a new prospective for the therapy of migraine attack?

INTRODUCTION: Migraine attack is characterized by disabling pain and associated symptoms. Triptans represent the "gold standard" therapy, but cardiac subjects have significant limitations for this approach. New drug families are under consideration to expand therapeutic offerings, especially in the presence of contraindications or for non-responsive patients. This review aimed to analyze studies related to the category of "ditans," with a focus on lasmiditan, which is available for human use. MATERIALS AND METHODS: We consulted PubMed/MEDLINE, Web of Science, and www. CLINICALTRIALS: gov to find both original and review articles on the mechanism of action of 5-HT1F agonists in migraine, and for randomized, double-blind, placebo-controlled trials (RCTs) on the family of drugs called "ditans," with a focus on "lasmiditan," published in the time frame of 01-Jan-2010 to 31-Mar-2022. Only studies conducted in human subjects and published in English were included in this review. RESULTS: We retrieved four RCTs (named SAMURAI, SPARTAN, GLADIATOR, and CENTURION) and several studies that analyzed the efficacy and safety of lasmiditan. Lasmiditan at increasing doses showed significant improvement in pain and most other troublesome symptoms at 2 h. Adverse events were mild and mainly represented by dizziness, vertigo, drowsiness, and fatigue. No vasoconstrictive effects were described, suggesting the use of ditans as a safe option in chronic cardio- and cerebro-vascular disease. DISCUSSION: Lasmiditan could be a viable alternative to triptans, although further RCT studies and real-world evidence are needed to better understand its potential and possible adverse events in a larger population.

Tegaserod: What's Old Is New Again.

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are common gastrointestinal disorders imposing considerable impact on the quality of life and well-being of affected individuals. A paucity of evidence-based treatment options exist for CIC and IBS-C sufferers. Tegaserod, a 5-HT4 agonist, has a substantial body of preclinical and clinical study evidence to support its beneficial role in modulating sensorimotor function of the luminal gastrointestinal tract. Tegaserod was first approved for use by the U.S. Food and Drug Administration for the management of IBS-C and CIC in 2002 and 2004, respectively. Tegaserod enjoyed a successful uptake in the management of these disorders during its first several years of availability in the United States, but was later withdrawn from the market in 2007 over concerns related to adverse cardiovascular events. Since then, additional safety data has been generated, and following a resubmission and review by the Food and Drug Administration, in April 2019, tegaserod was once again approved for use in IBS-C under a more restricted labeling, confining use to women under 65 years of age without heart disease or additional cardiovascular risk factors. This review summarizes the regulatory journey of tegaserod and details the existing pharmacokinetic, physiologic, clinical, and safety data of tegaserod generated over the last 2 decades. The discussion also examines the future of tegaserod in the treatment of these constipation disorders, as well as its potential role in other related disorders of brain-gut interaction.

Pre-treatment with Tandospirone attenuates fentanyl-induced respiratory depression without affecting the analgesic effects of fentanyl in rodents.

Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the "TS + fentanyl" and "saline + fentanyl" group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.

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

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

The 5-HT1A receptor agonist, 8-OH-DPAT, attenuates long-lasting pain in imiquimod-induced psoriasis in mice.

Psoriasis pain is a common symptom underestimated and rarely evaluated in psoriasis clinical trials. This work aimed to investigate whether the development of secondary chronic allodynia and hyperalgesia in the imiquimod (IMQ)-induced psoriasis mice model could be modulated by anti-inflammatory agents and compound 48/80 (C48/80) and to determine whether the activation of 5-HT1A receptor modulates these nociceptive behaviours. C57BL/6 male mice were treated with 5% IMQ for 7 days. The paw withdrawal responses to von Frey filaments (10 and 250 mN) were used to assess the allodynia and hyperalgesia. Nociceptive behaviours were also evaluated using ketorolac 15 mg/kg s.c., adalimumab 10 mg/kg s.c. and C48/80 10 mg/kg i.p. Then, the serum serotonin and the impact of 8-OH-DPAT (1 mg/kg s.c), a 5-HT1A receptor agonist, on long-lasting pain were examined. Mice receiving IMQ showed enhanced nociception, which decreased with all tested compounds. The serum serotonin in the IMQ group showed a significant decrease (947.042 ng/ml) regarding the control group (1143.68 ng/ml). The pretreatment with 8-OH-DPAT alleviated pain-related behaviours. These results suggest that the long-lasting pain resulting from psoriasis inflammation is also associated with the serotonergic system. The 5-HT1A receptor should be further explored as a potential therapeutic target for psoriasis pain modulation.

Buspirone in the management of refractory irritable bowel syndrome: A case report.

RATIONALE: Irritable bowel syndrome (IBS) is a chronic and debilitating functional disorder of the gastrointestinal tract manifested by abdominal pain and bowel habit dysregulation. The pathophysiology is complex and management targets symptom resolution. Therapeutic interventions range from dietary modification, psychological interventions, exercise, to the use of antispasmodics, antibiotics, and antidepressants. Anecdotal reports have suggested that buspirone may be beneficial in the treatment of functional dyspepsia and IBS and its physiological effect of reducing gastric tone provides a rational for its benefit. PATIENT CONCERNS: A 28-year-old man with unremarkable past medical and psychiatric history presented with worsening abdominal pain, bloating, and bowel movement dysregulation of over 6-year duration. DIAGNOSES: Physical examination revealed mild distension and discomfort on deep palpation. Thorough blood investigations, stool analysis and culture, and imaging were unremarkable except for the detection of mucus with stool. The patient was diagnosed with irritable bowel syndrome with mixed habits. INTERVENTIONS: Dietary adjustment and a range of medications (mebeverine, simethicone, loperamide, rifaximin, sertraline and amitriptyline) yielded unsatisfactory response of were not tolerated. Buspirone was eventually introduced. OUTCOMES: Buspirone was associated with a significant and sustained improvement in IBS symptoms and quality of life. LESSONS: This case suggests that buspirone was effective in treating refractory IBS. Further research is needed to assess the role of buspirone in IBS management.