People with opioid use disorder (OUD) experience aversive opioid withdrawal symptoms (OWS) including nausea, diarrhea, vomiting, and anxiety, which emerge when blood opioid levels wane. These symptoms perpetuate unprescribed opioid use and accompanying morbidity and mortality, costing society nearly $80 billion per year. Withdrawal symptoms also emerge upon initiation of OUD pharmacotherapy with µ opioid receptor antagonists (buprenorphine: partial; naltrexone: full), complicating, and sometimes resulting in patient refusal of, treatment initiation or continuation. Better management of OWS is considered a gateway to opioid dependence treatment. The a2-adrenergic receptor agonists clonidine and lofexidine attenuate opioid withdrawal symptoms by inhibiting noradrenergic signaling. However, these agents have shortcomings: they dont fully suppress withdrawal symptoms or subjective discomfort, they induce problematic side effects (hypotension, sedation, discontinuation syndrome), their dosing must be adjusted for renal or hepatic impairment patients, and, as oral medications, they are slow acting. Thus, there is an urgent unmet need for better and faster-acting treatments. One strategy to reduce OWS severity is to lower opioid-induced inflammation and oxidative stress, which upregulate noradrenergic tone, sympathetic nervous system (SNS) activity, and OWS severity. Inhaled xenon (Xe) gas inhibits inflammation and SNS activity and is hypothesized to attenuate OWS severity. Xe is used at low concentration (28%) as an imaging agent and rarely induces hypotension or dizziness, even in critical care populations. Xe rapidly (within minutes) equilibrates in brain and other tissues and inhibits SNS activity, suggesting that it may be superior to a2-adrenergic agonists for attenuating OWS. Moreover, Xe has no demonstrable abuse liability, making it superior to opioid agonist substitution treatment for relieving OWS. In this Phase I STTR program, we propose to conduct preclinical proof of concept studies in morphine-dependent mice to determine whether 30% Xe, which is non-sedating when given by inhalation, rapidly reduces OWS severity. If Xe is effective, we will file an IND for a human STTR Phase II study to evaluate whether Xe decreases OWS during medically-managed opioid tapering required before buprenorphine initiation. Nobilis Therapeutics developed a proprietary portable hand-held Xe inhalation device and the drug/device combination has been cleared by the US Food and Drug Administration for testing in humans with Posttraumatic-Stress Disorder. This device also could be used in OUD studies, supporting capital efficiency with exit potential. Nobilis holds a patent covering Xes anti-inflammatory effects and licenses a patent from McLean Hospital covering Xes antianxiety effects. Accordingly, elements are in place to develop and market Xe therapy, if effective, to several potential clients including care providers and companies that sell buprenorphine, naltrexone, and Xe. Thus, commercial viability is high. Public Health Relevance Statement Narrative We propose to develop a portable hand-held xenon inhalation device to rapidly attenuate opioid withdrawal symptoms (OWS), on demand, which emerge spontaneously or upon initiation of and/or maintenance with buprenorphine or naltrexone treatment in people with opioid use disorder (OUD). Reducing OWS is an unmet clinical need worth solving because the morbidity and mortality associated with OUD, driven largely by unprescribed opioid use to alleviate OWS, is substantial and costs society an estimated $80 billion/year. If effective against OWS, xenon inhalation likely would be superior to existing treatments because of its rapid effects and favorable safety and side-effect profiles, and xenon therapy can be disseminated by our experienced team in a capital efficient manner with exit potential.
Project Terms: Adrenergic Agonists ; Adrenergic Receptor Agonist ; Adrenomimetics ; Anesthesia procedures ; Anesthesia ; Anxiety ; Blood ; Blood Reticuloendothelial System ; Brain ; Brain Nervous System ; Encephalon ; Buprenorphine ; Capital ; Client ; Clonidine ; Klofenil ; Critical Care ; Diarrhea ; Dizziness ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Elements ; Gases ; Goals ; Hand ; Hospitals ; Human ; Modern Man ; Hypotension ; Low Blood Pressure ; Vascular Hypotensive Disorder ; Inflammation ; Inhalation Device ; Inhalators ; Inhaler ; Kidney ; Kidney Urinary System ; renal ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Maintenance ; Morbidity - disease rate ; Morbidity ; Morphine ; Infumorph ; Kadian ; MS Contin ; MSir ; Morphia ; Oramorph ; Oramorph SR ; Roxanol ; Statex SR ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; Naltrexone ; Nalorex ; Nemexin ; ReVia ; Vivitrol ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Nausea ; opioid withdrawal ; opiate withdrawal ; opioid detox ; opioid detoxification ; Panic Disorder ; panic anxiety syndrome ; Legal patent ; Patents ; Patients ; Adrenergic Receptor ; Adrenoceptors ; Epinephrine Receptors ; adenoreceptor ; Relapse ; Rewards ; Safety ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Societies ; Post-Traumatic Stress Disorders ; PTSD ; Post-Traumatic Neuroses ; Posttraumatic Neuroses ; Posttraumatic Stress Disorders ; post-trauma stress disorder ; posttrauma stress disorder ; traumatic neurosis ; Supervision ; Sympathetic Nervous System ; Syndrome ; Testing ; Time ; Tissues ; Body Tissues ; Treatment Refusal ; Patient Refusal of Treatment ; United States Food and Drug Administration ; Food and Drug Administration ; USFDA ; Vomiting ; Emesis ; Xenon ; Xe element ; lofexidine ; mu opioid receptors ; μ opioid receptors ; μ-OR ; μOR ; Schedule ; Withdrawal Symptom ; Procedures ; Hepatic ; Clinical ; Phase ; Medical ; Individual ; Withdrawal ; Licensing ; Opioid ; Opiates ; Oxidative Stress ; non-opioid analgesic ; non-narcotic analgesic ; non-opiate analgesic ; non-opioid ; non-opioid therapeutics ; nonnarcotic analgesics ; nonopiate analgesic ; nonopioid ; nonopioid analgesics ; Therapeutic ; Attenuated ; sedation ; Sedation procedure ; programs ; Hour ; Severities ; Complex ; Oral ; Opiate Dependence ; opioid addiction ; opioid dependence ; opioid dependent ; Opiate Addiction ; experience ; noradrenergic ; drug seeking behavior ; Devices ; Modeling ; handheld device ; handheld equipment ; portability ; Dose ; Symptoms ; Data ; Antiinflammatory Effect ; anti-inflammatory effect ; Small Business Technology Transfer Research ; STTR ; Development ; developmental ; pre-clinical ; preclinical ; cost ; Outcome ; Population ; Impairment ; phase 2 study ; phase II study ; prescription opioid ; licit opioid ; opiate medication ; opioid medication ; prescribed opiate ; prescribed opioid ; prescription opiate ; head-to-head comparison ; head-to-head analysis ; imaging agent ; opioid use disorder ; opiate use disorder ; opioid use ; opiate consumption ; opiate drug use ; opiate intake ; opiate use ; opioid consumption ; opioid drug use ; opioid intake ; Opioid Antagonist ; Opiate Antagonist ; Opiate receptor antagonist ; Opioid receptor antagonist ; opioid therapy ; opiate therapy ; care providers ; primary care provider ; Inhalation ; Inhaling ; Opioid agonist ; Opiate agonist ; Opiate receptor agonist ; Opioid receptor agonist ; buprenorphine treatment ; side effect ; off-label use ; off-label application ; off-label prescribing ; opioid tapering ; patients who use opioids ; opioid patient ; Hyperactivity ; Helping to End Addiction Long-term ; HEAL Initiative ; Helping End Addiction Long-term ; Helping End Addiction Longterm ; Helping to End Addiction Longterm ;
