Xenon gas inhalation as a novel treatment for opioid withdrawal syndrome

ABSTRACT Opioid withdrawal symptoms (OWS) are highly aversive and occur in people with opioid use disorder (OUD) when their blood opioid levels wane, thereby increasing sympathetic nervous system (SNS) activity, a driver of OWS. OWS drive people to seek out and take opioids, including unprescribed opioids contaminated with fentanyl, leading to overdoses and tens of thousands of deaths per year. Managing OWS is considered a “gateway to opioid dependence treatment” and the “safest and most practical approach” for treating OUD. Xenon gas (Xe), which is used in humans at high concentration as an inhaled anesthetic and at lower concentrations as an inhaled imaging agent, inhibits SNS activity. Xe has no appreciable addiction liability and at subsedative doses induces few side effects in humans. Therefore, Xe has good potential for development as a novel treatment for OWS. McLean Hospital researchers recently reported in morphine-dependent mice that brief (10-min) exposure to inhaled 20% Xe inhibits naltrexone-precipitated OWS. General Biophysics, LLC is developing inhaled Xe treatment to inhibit inflammation leading to dementia. In this new Phase 1 STTR program, we seek to partner with McLean Hospital, which holds intellectual property covering the use of Xe to treat OUD (US 9,737,562 B2; EU 2931291 B1), and with Brigham Women’s Hospital, with who we have been collaborating on our dementia program, to develop inhaled Xe for blunting OWS. In addition to administrative activities, including holding a pre-IND meeting with FDA and designing the future clinical trial, we will propose target engagement studies to demonstrate attenuation of OWS according to the following specific aims: Aim 1: Using banked frozen brain tissues harvested from morphine-dependent mice in our prior study of Xe effects on naltrexone-precipitated opioid withdrawal symptoms, analyze effects of in vivo Xe inhalation on GSK3b protein expression and on MCP-1, IL-6, and IL-10 mRNA expression. Aim 2: Investigate effect of in vivo Xe inhalation on of GSK3b signaling in blood monocytes from healthy adults. Aim 3: In blood samples from patients with OUD experiencing OWS during medical opioid tapering, determine whether in vitro Xe exposures suppress inflammatory monocytes. This information will be used in designing the clinical trial to be submitted for Phase II STTR grant application. If Xe is effective, it could help reduce morbidity and mortality among the many people with OUD who do not benefit from existing treatments that target OWS. We look forward to submitting our application and we thank you very much for designing this Funding Opportunity.