Abstract
BackgroundRespiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT) releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV) morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO2), a measure of respiratory-depression, were evaluated and these data are reported here.MethodsSingle-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO2 was measured by noninvasive capnography.ResultsSignificant differences in EtCO2 least-squares means across all treatments for maximal effect (Emax) and area under the effect curve (AUE0-2, AUE0-8, AUE0-24) were detected (all p ≤ 0.0011). EtCO2 Emax values for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p < 0.0001) and were not significantly different vs placebo (41.9 mm Hg). Median time to reach maximal effect (TEmax) was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h).ConclusionsResults provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO2 when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation.
Highlights
Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone
Since 1999, poisoning deaths in the United States involving opioid analgesics have more than tripled [1,2]; deaths from opioid analgesics have surpassed those from heroin and cocaine [3,4]
With the increase in opioid-related drug overdose deaths in the United States comes a need for harm reduction strategies to address the issues of misuse, abuse, and diversion at their sources, and to consider what might occur in the community setting
Summary
Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphineinduced euphoric effects vs intravenous (IV) morphine alone. As tolerance to opioid psychoactive effects increases with use over time, the user often progresses from the oral route to the intranasal or intravenous (IV) route to attain greater opioid effects and more rapid onset of action [5,7,8,9,10]. Respiratory depression involves inadequate response to hypercapnia or hypoxia, resulting in a decrease in respiratory rate and/or decrease in minute ventilation below normal [15,16]. Opioid-induced respiratory depression can occur within minutes of IV injection and typically can result in death in < 1 to 3 hours following opioid exposure [7,19,20]
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