Whole body physiology model to simulate respiratory depression of fentanyl and associated naloxone reversal

Background Opioid use in the United States and abroad is an endemic part of society with yearly increases in overdose rates and deaths. In response, the use of the safe and effective reversal agent, naloxone, is being fielded and used by emergency medical technicians at a greater rate. There is evidence that repeated dosing of a naloxone nasal spray is becoming more common. Despite this we lack repeated dosing guidelines as a function of the amount of opiate the patient has taken.Methods To measure repeat dosing guidelines, we construct a whole-body model of the pharmacokinetics and dynamics of an opiate, fentanyl on respiratory depression. We then construct a model of nasal deposition and administration of naloxone to investigate repeat dosing requirements for large overdose scenarios. We run a single patient through multiple goal directed resuscitation protocols and measure total naloxone administered.Results Here we show that naloxone is highly effective at reversing the respiratory symptoms of the patient and recommend dosing requirements as a function of the fentanyl amount administered. We show that for increasing doses of fentanyl, naloxone requirements also increase. The rescue dose displays a nonlinear response to the initial opioid dose. This nonlinear response is largely logistic with three distinct phases: onset, rapid acceleration, and a plateau period for doses above 1.2 mg.Conclusions This paper investigates the total naloxone dose needed to properly reverse respiratory depression associated with fentanyl overdose. We show that the current guidelines for a rescue dose may be much lower than required. Opioids such as fentanyl are a type of drug that reduce pain. However, the overdose of opioids causes severe breathing issues that can lead to death. Overdose of opioids is an increasing problem across the globe, particularly among people with opioid use disorder. To prevent death, first responders can administer a drug called naloxone that rapidly reverses the effects of opioids. However, the optimum amount of naloxone to administer is unclear. We use a mathematical model to investigate the effect of administering different amounts of naloxone during fentanyl overdose. Our findings suggest that the amount of naloxone to administer that is currently usually administered may be insufficient. Further research should enable naloxone usage guidelines to be optimized, which could improve survival following opioid overdose. Baird et al model opioid overdose and naloxone administration in a whole-body physiology model. The derived total naloxone rescue doses obtained are much higher than the current suggested guidelines.