Naloxone dosage for opioid reversal: current evidence and clinical implications

Abstract

Current contextOpioid overdoses have quadrupled in the past 15 years, and in 2015 there were over 33,000 opioidrelated deaths in the United States. 1 Opioid overdose induces respiratory depression that can lead to hypoxia, hypercarbia and death. In an attempt to expedite treatment and improve outcomes following overdose, naloxone is increasingly being utilized in a pre-hospital setting by both emergency personnel and prescribed to laypersons for out-of-hospital administration. 2 Efficacy of reversal following naloxone administration by laypersons is high, having been reported at 75-100%, 3 and in general take-home naloxone programs are considered effective for reducing opioid-overdose mortality. 4 Naloxone overall is a safe medication, and is not known to cause harm when administered in typical doses to opioid-naïve patients. [5][6][7][8] There is concern about the precipitation of opioid-withdrawal syndrome following its administration in the setting of prior opioid exposure. Despite the long-standing use of naloxone to reverse the symptoms of opioid overdose or toxicity, appropriate dosing remains controversial, with varying doses recommended over time and by medical specialty. 9 In a hospital setting, this medication is typically administered initially in a low dose, which is then titrated to optimize reversal of opioid-induced respiratory depression while attempting to minimize the risk of withdrawal. 10 In a non-medical setting, the ideal of gradually titrating naloxone to effect is not practical, thus a single standardized initial dose for out-of-hospital naloxone rescue has been sought. This review will evaluate the literature to address the question of optimal naloxone dosing to reverse opioidinduced respiratory depression while minimizing patient risk. HistoryNaloxone was developed in the early 1960s as a novel opioid antagonist with fewer side effects than its predecessors. 11 Naloxone hydrochloride is a competitive mu-opioid receptor antagonist historically used only by trained clinical professionals for the reversal of opioid overdose in an emergency or inpatient setting. It is approved for administration by a variety of routes, including intravenous (IV), intramuscular (IM), subcutaneous (SQ) and intranasal (IN), but is also administered via inhalation following nebulization or endotracheal tube in intubated patients. [12][13][14] Formulations for many other routes of administration are currently under development, including sublingual and buccal. 15 Naloxone is not typically administered orally due Naloxone dosage for opioid reversal: current evidence and clinical implications Rachael Rzasa Lynn and JL Galinkin Abstract: Opioid-related mortality is a growing problem in the United States, and in 2015 there were over 33,000 opioid-related deaths. To combat this mortality trend, naloxone is increasingly being utilized in a pre-hospital setting by emergency personnel and prescribed to laypersons for out-of-hospital administration. With increased utilization of naloxone there has been a subsequent reduc...

Fentanyl depression of respiration: Comparison with heroin and morphine

“…Our finding that naloxone less readily reversed respiratory depression by fentanyl compared with morphine confirms reports from studies in humans that more naloxone may be required to reverse a fentanyl overdose compared to a heroin overdose (Fairbairn et al, 2017;Lynn & Galinkin, 2018;Peterson et al, 2016;Schumann et al, 2008;Somerville et al, 2017). In our study, we allowed the depression of respiration by each agonist to reach maximum before naloxone was administered to mimic how the drugs would be administered in an overdose situation.…”

“…Fentanyls induce muscle stiffness (Benthuysen, Smith, Sanford, Head, & Dec-Silver, 1986;Streisand et al, 1993) including in intercostal and diaphragm muscles, often referred to as "wooden chest," and this is likely to make it harder to breathe. There have been several reports suggesting that depression of respiration by fentanyls shows reduced sensitivity to reversal by naloxone (Fairbairn et al, 2017;Lynn & Galinkin, 2018;Peterson et al, 2016;Schumann, Erickson, Thompson, Zautcke, & Denton, 2008). In one report, several cases were recorded in which multiple doses of naloxone were required before recovery of respiration following a fentanyl overdose (Somerville et al, 2017).…”

Naloxone-Induced Non-Cardiogenic Pulmonary Edema: A Case Report

“…In Schwartz and Koenigsberg, the administration of furosemide and nitroglycerine morphine sulfate resulted in the resolution of naloxone-induced non-cardiogenic edema [12]. Furthermore, Lynn and Galinkin suggest that the pulmonary edema resulting from naloxone resolves quickly in response to a diuretic or even, in some cases, additional opioid [9]. …”

“…Although it is unclear if the occurrence of adverse symptoms such as pulmonary edema is dose dependent, newer guidelines from the American Heart Association recommend using the lowest effective dose of naloxone necessary to elicit the desired response [9]. …”

The six Rs of managing high-risk opioid prescribing

“…35 Naloxone, a mu-opioid receptor antagonist, reverses the effects of opioid overdose. 36 In Australia it is available as a vial, prefilled syringe or nasal spray. Naloxone, and accompanying training on its administration, should be offered to all patients who are at risk of opioid overdose, including those on high-risk opioid medications.…”