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. 2019 Feb 1:10:2042098618821274.
doi: 10.1177/2042098618821274. eCollection 2019.

Effects of intravenous oxycodone alone or in combination with naltrexone on measures of respiratory depression: a randomized placebo-controlled study

Almasa Bass  1 , Lynn R Webster  2 , Kyle T Matschke  3 , Bimal K Malhotra  4 , Gernot Wolfram  1
Affiliations

Effects of intravenous oxycodone alone or in combination with naltrexone on measures of respiratory depression: a randomized placebo-controlled study

Almasa Bass et al. Ther Adv Drug Saf. .

Abstract

Background: Abuse of prescription opioids, particularly by intravenous (IV) administration, can cause respiratory depression and death. ALO-02, an abuse-deterrent opioid formulation, is designed to release sequestered naltrexone upon manipulation by crushing, thereby antagonizing the pharmacologic effects of oxycodone. This exploratory post-hoc analysis examined the effects of IV administration of simulated crushed ALO-02 on end-tidal carbon dioxide (EtCO2), a surrogate marker of respiratory depression.

Methods: Data were obtained from a randomized, double-blind, placebo-controlled, three-way crossover study in nondependent recreational opioid users that evaluated the abuse potential of IV administered oxycodone 20 mg + naltrexone 2.4 mg (simulating crushed ALO-02) versus oxycodone 20 mg or placebo. EtCO2 was measured as a secondary endpoint using noninvasive capnography at baseline and postdose intervals, up to 24 h.

Results: Baseline EtCO2 (mean ± standard error of the mean (SEM)) values (n = 33) were similar across treatments: 33.5 ± 0.9, 33.5 ± 0.8, and 34.0 ± 0.7 mmHg for oxycodone 20 mg + naltrexone 2.4 mg, oxycodone 20 mg, and placebo, respectively. After dosing, mean ± SEM of the maximum effect (Emax) on EtCO2 was 37.5 ± 0.6, 40.5 ± 0.8, and 36.9 ± 0.6 mmHg for oxycodone 20 mg + naltrexone 2.4 mg, oxycodone 20 mg, and placebo, respectively. Emax values were significantly lower for oxycodone 20 mg + naltrexone 2.4 mg versus oxycodone 20 mg (p = 0.0005), and not different from placebo (p > 0.05).

Conclusions: This abuse-potential study suggests that naltrexone released from ALO-02 tampering by crushing attenuates oxycodone-induced increase of EtCO2 in nondependent recreational opioid users.

Keywords: intravenous; opioid overdose; opioids; oxycodone; prescription opioid abuse; respiratory depression.

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Conflict of interest statement

Conflict of interest statement: KTM and BKM are full-time employees of Pfizer and hold stock and/or stock options. AB and GW were full-time employees of Pfizer during the conduct of this study and held stock and/or stock options. LKW is a full-time employee of PRA Health Sciences (formerly CRI Lifetree), where the study was conducted. In the past 12 months, LKW received honoraria/travel expenses for consultation and advisory board participation for the following companies: AstraZeneca, Cara Therapeutics, Charleston Laboratories, Depomed, Egalet, Insys Therapeutics, Jazz Pharamaceuticals, Kaleo, Marathon Pharmaceuticals, Merck, Pfizer, Proove Biosciences, Teva Pharmaceutical Industries, Trevena, Shionogi, and Zogenix.

Figures

Figure 1.
Figure 1.
Mean (SEM) levels of EtCO2 (mmHg) at baseline and time points postdose (a), and mean (SEM) Emax EtCO2 (mmHg) compared with predose (b). The doses of oxycodone and naltrexone refer to oxycodone hydrochloride (20 mg) and naltrexone hydrochloride (2.4 mg). (a) Mean EtCO2 levels for placebo, oxycodone, and simulated ALO-02 at 5 min were 32.4, 33.2, and 31.9 mmHg, respectively, and 33.2, 37.2, and 33.1 mmHg, respectively, at 15 min. #p = 0.0001 oxycodone 20 mg versus placebo. †p = 0.0005 oxycodone 20 mg versus oxycodone 20 mg + naltrexone 2.4 mg. Emax, maximum effect; EtCO2, end-tidal carbon dioxide; SEM, standard error of the mean.
Figure 2.
Figure 2.
Mean (SEM) pulse oximetry (%) at baseline and time points postdose. The doses of oxycodone and naltrexone refer to oxycodone hydrochloride (20 mg) and naltrexone hydrochloride (2.4 mg). SEM, standard error of the mean; SpO2, peripheral capillary oxygen saturation.
Figure 3.
Figure 3.
Mean (SEM) respiratory rate (respirations/min) at baseline and time points postdose. The doses of oxycodone and naltrexone refer to oxycodone hydrochloride (20 mg) and naltrexone hydrochloride (2.4 mg). SEM, standard error of the mean.
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