Sublingual dexmedetomidine (BXCL501) reduces opioid withdrawal symptoms: findings from a multi-site, phase 1b/2, randomized, double-blind, placebo-controlled trial.

Background: Like other alpha-2-adrenergic receptor agonists, dexmedetomidine may reduce the severity of opioid withdrawal but with fewer adverse cardiovascular effects.Objective: This study assessed the safety of sublingual dexmedetomidine (BXCL501) and its preliminary efficacy in treating opioid withdrawal (ClinicalTrials.gov: NCT04470050).Methods: Withdrawal was induced among individuals with physiological dependence on opioids via discontinuation of oral morphine (Days 1-5). Participants were randomized to receive placebo or active BXCL501: 30, 60, 90, 120, 180, and 240 µg twice daily (Days 6-12). Treatment-emergent adverse events (TEAEs) were the primary outcome measure. Secondary outcomes included the Clinical and Subjective Opiate Withdrawal Scales (COWS and SOWS-Gossop, respectively), and the Agitation and Calmness Evaluation Scale (ACES).Results: Of 225 participants enrolled, 90 discontinued during morphine stabilization. Post-BXCL501 randomization (Day 6) data were available from 135 participants (73% male), with 33% completing thru Day 12. In total, 36 subjects reported 1 or more TEAE. Higher doses of BXCL501 (i.e. 180 and 240 µg, twice daily) increased the frequency of: hypotension, orthostatic hypotension, and somnolence. TEAEs related to BXCL501 were mild or moderate in severity, except for one participant in the 120 µg condition whose orthostatic hypotension and bradycardia were classified as severe. Higher BXCL501 dose conditions (120, 180, and 240 µg) resulted in statistically significant reductions in COWS & SOWS scores. Mean ratings on the ACES were between 3 (mild), 4 (normal), and 5 (mild calmness), with few significant differences as a function of dose.Conclusions: These findings support the continued development of BXCL501 for the management of opioid withdrawal.

Sublingual Dexmedetomidine for Agitation Associated with Schizophrenia or Bipolar Disorder: A Post Hoc Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to be Helped or Harmed.

INTRODUCTION: The objective was to use the evidence-based medicine metrics of number needed to treat, number needed to harm, and likelihood to be helped or harmed to appraise the clinical efficacy and tolerability of sublingual dexmedetomidine in adults with agitation associated with schizophrenia or bipolar disorder. METHODS: Sublingual dexmedetomidine data for this post hoc analysis were obtained from two similarly designed, double-blind, randomized, placebo-controlled studies of adults with schizophrenia or bipolar disorder. Response to treatment was defined as a ≥ 40% reduction from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC). Tolerability was assessed by evaluating rates of adverse events. RESULTS: The number needed to treat (95% confidence interval) estimate versus placebo for PEC response at 2 h post-dose was 3 (2, 3) for the sublingual dexmedetomidine 180-µg group (n = 125) and 3 (3, 4) for the 120-µg group (n = 129) in the study of patients with schizophrenia and 3 (2, 3) for the sublingual dexmedetomidine 180-µg group (n = 126) and 4 (3, 6) for the 120-µg group (n = 126) in the study of patients with bipolar disorder. Number needed to harm values versus placebo were greater than 10 for all adverse events except somnolence, where the number needed to harm (95% confidence interval) was 7 (5, 10) for all doses pooled from both studies. In all instances, likelihood to be helped or harmed values were greater than 1 for efficacy versus applicable tolerability outcomes. CONCLUSIONS: The number needed to treat, number needed to harm, and likelihood to be helped or harmed of sublingual dexmedetomidine support a favorable benefit-risk profile in adults with acute agitation associated with schizophrenia or bipolar disorder. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT04268303 , NCT04268303. CLINICALTRIALS: gov, https://clinicaltrials.gov/ct2/show/NCT04276883 , NCT04276883.

Sublingual Dexmedetomidine for the Treatment of Acute Agitation in Adults With Schizophrenia or Schizoaffective Disorder: A Randomized Placebo-Controlled Trial.

Objective: Determine if sublingual dexmedetomidine, a selective α2 adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or schizoaffective disorder.Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults diagnosed with schizophrenia or schizoaffective disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The study was conducted at 15 US sites between January 23, 2020, and May 8, 2020. Participants were randomized to sublingual dexmedetomidine 180 µg, 120 µg, or matching placebo. The primary efficacy endpoint was mean change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC) total score at 2 hours postdose.Results: Altogether, 380 participants (mean age 45.6 years, 63.4% identifying as male, 77.9% identifying as Black or African American) were randomized; 380 (100%) self-administered study medication, and 372 (97.9%) completed the study. The mean PEC total score at baseline (17.6) indicated mild to moderate agitation. At 2 hours postdose, the least squares mean changes (SE) from baseline were -10.3 (0.4) for sublingual dexmedetomidine 180 µg, -8.5 (0.4) for 120 µg, and -4.8 (0.4) for placebo. Least squares mean differences (97.5% confidence intervals) in the sublingual dexmedetomidine groups were -5.5 (-6.7 to -4.3) for 180 µg and -3.7 (-4.9 to -2.5) for 120 µg (both P < .001 vs placebo). The most commonly encountered adverse events with dexmedetomidine (incidence ≥ 5% and ≥ 2× rate observed with placebo) were somnolence, dry mouth, and hypotension for the 120 µg dose, and somnolence, dizziness, orthostatic hypotension, and oral hypoesthesia for the 180 µg dose.Conclusions: Treatment with sublingual dexmedetomidine 180 µg or 120 µg was more efficacious than placebo in reducing acute agitation associated with schizophrenia as measured by PEC scores at 2 hours postdose.Trial Registration: ClinicalTrials.gov identifier: NCT04268303.