0571 OPIOIDS AND SLEEP APNEA: ANTAGONISM OF REMIFENTANIL-INDUCED RESPIRATORY DEPRESSION BY CX1739 IN TWO CLINICAL MODELS OF OPIOID INDUCED RESPIRATORY DEPRESSION

Abstract

Introduction: Annually, U.S. pharmacies dispense nearly 250 million prescriptions for opioid pain relievers. While opioids are useful and effective analgesics, they produce unwanted side effects, including opioid induced respiratory depression (OIRD), which resulted in over 30,000 deaths in 2014. The OIRD produced by opioids is most sensitively detected during sleep and is manifested as apnea/hypopnea, or central sleep apnea (CSA). Approximately 2% of the 51 million U.S. surgery patients and 40 ‐ 50% of patients on chronic opioid therapy for pain management have CSA, which is the major risk factor for opioid overdose and lethality. An unmet medical need exists for an agent that can antagonize OIRD without compromising the analgesic effects of opioids. We herein describe the results of a phase IIa clinical trial that evaluated the ability of CX1739 to overcome OIRD. Methods: Randomized, Blinded, Placebo‐controlled, Cross‐Over with Acute Dose Escalation of CX1739; 4 Weekly visits; 2 protocols for remifentanil: a. REMI‐Bolus evaluated respiratory parameters in an opioid overdose model, using a bolus of remifentanil (1 mcg/kg) to achieve significant respiratory depression; b. REMI‐Infusion evaluated respiratory, pain, and pupilometry measures using an infusion of remifentanil to achieve a steady state blood concentration of approximately 2 ng/ml with 50% respiratory rate depression as a model of OIRD produced oral opioid treatment for chronic pain. Results: The results of the REMI‐Infusion analysis demonstrate that, compared to placebo, CX1739 (300 mg or 900 mg) significantly reduces OIRD under steady‐state opioid concentrations. The remifentanil effects on analgesia, pupillography and BIS were not altered. The results of the REMI‐Bolus analysis demonstrate that CX1739 does not prevent rapid respiratory depression after intravenous, bolus injection of remifentanil. Administration of CX1739 at an acute dose up to 900 mg was safe and the adverse event profile is comparable to placebo. Conclusion: This proof‐of‐concept trial provides evidence to explore the use of the ampakine CX1739 in the prevention of opioid induced respiratory depression, particularly in patients receiving sub‐acute, post‐surgical intravenous opioid treatment as well as in oral opioid treatment for chronic pain, where OIRD often presents as central sleep apnea.