Repurposing FDA-approved oxytocin to treat opioid-induced respiratory depression

George Washington University, Washington DC

Investigators

Abstract

Opioid addiction and misuse is a serious national crisis that affects public health, as well as social and economic welfare. The opioid crisis has been greatly exacerbated by the increased availability of synthetic opioids, such as fentanyl, and by the increased prescribing of opioid pain relievers. Opioid overdose kills 130 people in the United States every day. The primary cause of death associated with opioids is opioid-induced respiratory depression (OIRD). Naloxone, a competitive antagonist of mu-opioid receptors (MORs), has a rapid onset and helps reverse OIRD but is short acting and re-dosing is often necessary. A recently approved MOR antagonist, nalmefene, is long-acting, however both naloxone and nalmefene reverse opioid mediated analgesia and induce acute withdrawal leading to low adherence that limit their use for OIRD prevention particularly in highly vulnerable populations such as patients chronically receiving high doses of opioids for pain. In addition, naloxone does not reverse opioid induced muscle rigidity, upper airway obstruction in patients with underlying obstructive sleep apnea, and may cause pulmonary edema. Alternative, non-opioid receptor antagonist-based approaches for both OIRD treatment and prevention are needed. Our approach targets Oxytocin (OXT), as our work has shown OXT is effective for treatment of sleep disordered breathing by increasing respiratory rate and decreasing the duration of the apneic/hypopneic events and severity of hypoxemia in patients with obstructive sleep apnea. OXT is FDA approved for other uses. Our overarching hypothesis, based on our exciting Preliminary Data, is that OXT prevents fentanyl associated mortality, and reduces fentanyl evoked respiratory depression and increased incidence of apneas. In response to PAR-22-200, we propose to conduct studies that will evaluate the potency, efficacy, and duration of action of OXT in reversing OIRD and reducing opioid lethality. In Specific Aim 1: we will identify, validate and optimize OXT dose, routes of administration (intranasal (IN), subcutaneous (sub- Q), and intravenous (IV)), and need for redosing, to reverse acute OIRD induced by fentanyl. In Specific Aim 2: we will use an animal model of chronic pain and daily ED50 administration of fentanyl to test if OXT provides additional analgesia and helps prevent the risk of overdose lethality and OIRD that occurs with chronic opioid use and opioid tolerance. In Specific Aim 3: we will test the hypothesis that selective chemogenetic activation of OXT neurons in the paraventricular nucleus of the hypothalamus will prevent and treat OIRD. In Specific Aim 4: we will obtain the approvals required for two clinical trials. In Specific Aim 5: we will quantify, in a double blinded, placebo-controlled phase 2 clinical trial, the therapeutic efficacy of OXT in decreasing apneas, respiratory depression and oxygen desaturations in patients given opioids upon in-hospital recovery from laparoscopic bariatric surgery. In Specific Aim 6: we will test in a double blinded, placebo-controlled phase 2 clinical trial, the therapeutic efficacy of OXT in decreasing A) the severity of sleep disordered breathing; B) pain perception, C) opioid dose and D) drug liking in patients on chronic opioid therapy for chronic pain.