Chronic and neuropathic pain remain significant clinical challenges owing to limited efficacy and safety concerns associated with conventional analgesics, including opioids and NSAIDs. Voltage-gated sodium channels, particularly Nav1.7 and Nav1.8, have emerged as promising non-opioid targets for pain modulation, given their selective expression in peripheral nociceptors and critical roles in pain signal transmission. Recent advances in structural biology and pharmacology have enabled the development of highly selective inhibitors targeting these channels. This review explores sodium channel inhibitors currently in clinical development, with a focus on suzetrigine (VX-548), the first US Food and Drug Administration (FDA)-approved Nav1.8 inhibitor for acute pain, as well as other investigational agents such as ralfinamide, OLP-1002, LTGO-33 and HBW-004285. Despite setbacks in early candidates owing to selectivity and tolerability issues, ongoing trials demonstrate renewed optimism for a new class of analgesics that may overcome the limitations of traditional pain therapies. We discuss key pharmacological challenges observed in earlier trials including functional redundancy, species differences, and on-target side effects, and outline how emerging strategies, such as structural biology-guided design, combination therapies, and precision medicine, are paving the way for safer, more effective, nonaddictive pain treatments.
Eating disorders (EDs) are complex psychiatric conditions characterized by disruptions in eating behaviors, body image concerns, and profound medical and psychosocial consequences. Despite their significant global prevalence, coupled with high morbidity and mortality rates, pharmacological treatment options remain limited. This review synthesizes evidence from clinical drug trials conducted between 1 January 2010 and 1 January 2025, supplemented with relevant literature, to evaluate the current and emerging pharmacological landscape for EDs. A systematic search of the U.S. Clinical Trials Registry (ClinicalTrials.gov) identified 43 eligible phase I-IV clinical trials for the treatment of anorexia nervosa (n = 12), binge eating disorder (n = 27), bulimia nervosa (n = 2), and rumination disorder (n = 2). Among 24 distinct compounds studied, only 1 agent, lisdexamfetamine dimesylate, received approval from the U.S. Food and Drug Administration (FDA) for an ED during this period. Notably, few agents have demonstrated positive results in late-stage trials and remain in development for EDs as of 2025. While some emerging agents show promise, such as solriamfetol and psilocybin, there remains a significant lack of evidence-based pharmacological interventions for anorexia nervosa and a dearth of progress in pharmacotherapy for bulimia nervosa. Overall, the past 15 years have witnessed limited advancements in pharmacotherapy for EDs. There remains an urgent need for rigorous clinical trials in this area in addition to increased prioritization of ED research at the public health level to overcome longstanding barriers in the treatment of EDs.
Background and aims: Evidence directly comparing ocrelizumab (OCR) and ofatumumab (OFA) after sphingosine-1-phosphate receptor modulators (S1PRMs) withdrawal is limited, even though this transition period carries an increased risk of disease reactivation and the two anti-CD20 agents differ in molecular properties that may influence post-S1PRM outcomes. We compared effectiveness, safety, and tolerability of OFA versus OCR in relapsing-remitting multiple sclerosis (RRMS) after S1PRM therapy.
Methods: We retrospectively analyzed adult (> 18 years) patients with RRMS from 23 Italian centers who switched from S1PRMs to OCR or OFA (October 2016 to July 2024). Clinical outcomes included annualized relapse rate (ARR), cumulative relapse incidence, confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), and variation in the expanded disability status scale score (ΔEDSS) from baseline to last follow-up. Magnetic resonance imaging (MRI) outcomes included time to overall MRI activity, new/enlarging T2 lesions, and new T1 Gd-enhancing lesions. Persistence on anti-CD20 and safety were also assessed. We applied inverse probability of treatment weighting (IPTW) to balance baseline covariates, and used Cox, Andersen-Gill, and regression models, further adjusted for variables with residual imbalance, to compare outcomes.
Results: We included 225 subjects (mean age 43.3 ± 10.6 years; OCR = 131, OFA = 94), with a median follow-up of 33 months. After IPTW, groups were well balanced. Compared with OCR, OFA was associated with lower ARR (adjusted relative risk [aRR] 0.22, 95% CI 0.06-0.86, p = 0.030) and relapse hazard (adjusted hazard ratio [aHR] 0.21, 95% CI 0.05-0.83, p = 0.026). When restricting washout to ≤ 10 weeks and applying spline-based Andersen-Gill models, results remained consistent, with OFA showing a lower relapse risk than OCR across short-to-intermediate washout intervals. CDP hazard was lower (aHR 0.38, 95% CI 0.15-0.94, p = 0.038), while PIRA and CDI did not differ. ΔEDSS favored OFA (adjusted mean difference [aMD] - 0.26, 95% CI - 0.51 to - 0.02, p = 0.046). OFA showed a lower hazard of overall MRI activity (aHR 0.41, 95% CI 0.19-0.92, p = 0.030), with similar risk for new T1 Gd+ lesions. A sensitivity analysis restricted to patients who switched to OFA or OCR during the same availability window yielded results consistent with the primary analysis. Treatment persistence was shorter on OFA, but absolute discontinuation rates were low in both groups. Severe AEs were rare and did not differ.
Conclusions: In S1PRM-exposed RRMS, OFA was associated with reduced relapse risk, disability accumulation, EDSS worsening, and MRI activity compared with OCR, with overall good tolerability and safety.
Treatment resistance in bipolar disorder (BD) is common, and innovative treatments are needed. The opioid system is under investigation as a new target treatment of depression and BD, notably the treatment of depressive symptoms. This narrative review aims to synthesize the evidence related to opioid-receptor-modulating drugs in treating BD. The protocol was preregistered at Open Science Framework. A search of the literature databases Embase, PubMed, and PsycINFO was conducted in March 2024 for studies involving the treatment of manic or depressive symptoms of BD with an opioid-receptor-modulating drug. The studies revealed a preliminary antimanic but transient effect of intravenous naloxone and potential antimanic effects of pentazocine. Methadone showed an effect on regulating manic symptoms. The existing evidence on the effects of opioid-receptor-modulating drugs in BD is scarce, and most studies are older and based on small samples. Clinically, opioid-receptor-modulating drugs cannot be recommended or integrated into the treatment of BD. Still, well-designed, randomized controlled trials are needed to draw any firm conclusions.
Background and objectives: Anti-calcitonin gene-related peptide (CGRP) therapies have significantly improved migraine prevention, but the long-term impact of discontinuation remains unclear. This systematic review and meta-analysis aimed to evaluate clinical outcomes following the cessation of anti-CGRP therapy.
Methods: PubMed, Embase, and Cochrane databases were searched up to September 2024 for randomized or observational studies reporting post-discontinuation effects in patients with episodic or chronic migraine who had been preventively treated with anti-CGRP monoclonal antibodies or gepants. The primary outcome was the mean change in monthly migraine days from baseline to post-discontinuation. Secondary outcomes included acute headache medication use, the mean change in migraine frequency from active therapy to treatment cessation, and ≥ 50% responder rates. Heterogeneity was assessed with prediction intervals (PIs) for binary outcomes and I2 statistics for continuous data. Random-effects models pooled mean differences (MDs) and risk ratios (RRs), with subgroup analyses based on follow-up duration, study design, and individuals with chronic migraine.
Results: Eight studies (n = 1012) evaluating anti-CGRP monoclonal antibodies interruption were included. No studies on gepant cessation were found. Monthly migraine days decreased significantly post-discontinuation compared with baseline (MD -3.78; 95% CI -4.89, -2.67; I2 = 57%; p < 0.05), with reductions of - 5.70 days at 1 month and - 3.62 days at 3 months. Patients with chronic migraine showed sustained reductions (MD - 6.54; 95% CI - 8.64, - 4.43; I2 = 68%; p < 0.05) in the days per month with migraine between cessation and pre-treatment periods. Monthly acute headache medication days declined from baseline (MD - 1.74; 95% CI - 2.84, - 0.64; I2 = 0%; p < 0.05). Monthly migraine days increased at 3 months after discontinuation compared with just before discontinuation (MD 4.43; 95% CI 2.61, 6.25; I2 = 86%; p < 0.05), with monthly acute headache drug usage rising by 3.22 days. Responder rates of ≥ 50% declined (RR 0.42; 95% CI 0.33, 0.53; PI 0.17, 1.03; p < 0.05).
Conclusions: Migraine burden worsened after discontinuation of anti-CGRP targeting therapies but remained lower than pretreatment levels. Further research is needed to explore disease-modifying potential and optimal discontinuation strategies. PROSPERO registration number CRD42024595771.
Background and objectives: Excessive daytime sleepiness (EDS) is a prominent symptom of obstructive sleep apnea (OSA), negatively affecting patients' quality of life. The objective of this study was to assess the efficacy and safety of solriamfetol in patients with OSA with EDS from China.
Methods: This multicenter, randomized, double-blind, placebo-controlled phase 3 trial compared solriamfetol (75/150 mg once daily) with placebo for 12 weeks. Adults diagnosed with OSA, mean Maintenance of Wakefulness Test (MWT) sleep latency < 30 min, and Epworth Sleepiness Scale (ESS) score ≥ 10 were included. Patients with disorders causing EDS other than OSA were excluded. Co-primary endpoints were change from baseline to week 12 in MWT mean sleep latency and ESS score; a key secondary endpoint was improvement on Patient Global Impression of Change (PGI-C), assessed on a seven-point scale. MWT was performed at baseline and at weeks 2, 5, and 12, whereas the ESS and PGI-C were evaluated at weeks 2, 5, 8, and 12. Safety and tolerability were assessed on the basis of treatment-emergent adverse events (TEAEs), laboratory tests, vital signs, 24-h ambulatory blood pressure monitoring, 12-lead electrocardiogram, and physical examination. Statistical analyses of co-primary endpoints were performed on the full analysis set (FAS) using a mixed model for repeated measures (MMRM). Safety analyses were performed on the safety population. A hierarchical testing sequence was used to control multiplicity.
Results: Of the 204 patients randomized (1:1) into placebo and solriamfetol groups, 192 completed the study (96 in each group). Co-primary endpoints were met, with significantly increased mean MWT sleep latency (P < 0.0001) and decreased ESS score (P = 0.0017) in the solriamfetol group (MWT, n = 95; ESS, n = 97) versus placebo (MWT, n = 95; ESS, n = 96) at week 12. Higher proportion of participants receiving solriamfetol (n = 90; 89.1%) reported improvement in PGI-C versus placebo (n = 77; 77.0%; P = 0.0221). At least one TEAE was reported in solriamfetol (n = 84; 82.4%) and placebo (n = 67; 65.7%) groups. The occurrence of serious TEAEs was low, with one incidence in both groups. Most frequently reported TEAEs in solriamfetol group included upper respiratory tract infection, dizziness, hyperuricemia, hypertension, hyperlipidemia, hypertriglyceridemia, and increased blood creatine phosphokinase. Most TEAEs were of mild/moderate severity and did not lead to study treatment discontinuation.
Conclusions: Solriamfetol demonstrated substantial efficacy and acceptable safety in Chinese patients with OSA with EDS, reinforcing its role as a viable treatment option.
Trial registration: ClinicalTrials.gov: NCT06103825.
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