320 Effects of Intravenous Oxycodone Alone or in Combination With Naltrexone on End-Tidal Carbon Dioxide: A Randomized, Controlled Study

Harmful effects associated with prescription opioid abuse and misuse, particularly when administered intravenously (IV), can lead to respiratory depression and death. Opioid-induced respiratory depression can be reversed by timely administration of an opioid antagonist. ALO-02 is an abuse-deterrent opioid formulation comprising pellets of extended-release oxycodone HCl surrounding sequestered antagonist naltrexone HCl (12% ratio); upon tampering, the naltrexone is released, thereby reducing the pharmacologic effects of oxycodone, including those associated with abuse. This was confirmed in a human abuse potential study wherein IV administration of oxycodone 20 mg and naltrexone 2.4 mg in solution (simulating crushed and dissolved ALO-02 20 mg/2.4 mg capsule strength) significantly reduced “drug liking” and “high” compared with oxycodone 20 mg alone. In the same study, the effects on end-tidal CO2 (EtCO2), a surrogate marker of respiratory depression (Miner et al. Acad Emerg Med 2002, 9:275-80), were evaluated and these results are reported here. A single-center, randomized, double-blind, placebo-controlled, three-way crossover study (NCT01825447) in nondependent recreational opioid users evaluated the abuse potential of oxycodone 20 mg + naltrexone 2.4 mg (to simulate crushed and dissolved ALO-02 capsule) compared with oxycodone 20 mg or placebo (0.9% NaCl) administered IV over 4 min ± 15 sec. As a secondary endpoint, EtCO2 (mmHg) was measured using noninvasive capnography at baseline and postdose intervals, up to 24 h. Respiratory rate and pulse oximetry were also measured (data to be provided in poster). The safety population (n=33, received at least one treatment) had a mean ± SD age of 26.2 ± 6.0 years and consisted mostly of white (88%), male (88%) participants. Mean ± SEM EtCO2 measurements at baseline were similar across treatments (33.5 ± 0.9, 33.5 ± 0.8, 34.0 ± 0.7 mmHg for oxycodone 20 mg + naltrexone 2.4 mg, oxycodone 20 mg, placebo, respectively). Following study treatments, mean EtCO2 for placebo or oxycodone 20 mg + naltrexone 2.4 mg remained approximately at baseline level throughout the 24-h assessment period, whereas administration of oxycodone 20 mg resulted in a slight increase in EtCO2 mostly during the first hour postdose. Mean maximum value (Emax) of EtCO2 during the 24-h assessment period was significantly greater for oxycodone 20 mg versus placebo (p=0.0001), whereas Emax for oxycodone 20 mg + naltrexone 2.4 mg was significantly less than oxycodone 20 mg (P = .0005) and did not differ from placebo (P = .5175) (mean ± SEM: 37.5 ± 0.6, 40.5 ± 0.8, and 36.9 ± 0.6 mmHg, respectively). Similarly, mean change in EtCO2 from baseline to Emax was significantly less for oxycodone 20 mg + naltrexone 2.4 mg than oxycodone 20 mg (P = .0035), and did not differ from placebo (P = .1782) (Emax for oxycodone 20 mg was significantly greater than placebo, P = .0001). Results suggest that should ALO-02 be abused by crushing, dissolving and injecting, the naltrexone may attenuate oxycodone-induced elevations of EtCO2 in nondependent recreational opioid users. Further studies using direct measures of respiratory function are needed to determine if the risk of respiratory depression is reduced when oxycodone is co-administered with naltrexone in the same fixed ratio.