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

Opioid use in the United States and abroad is an endemic part of society
with yearly increases in overdose rates and deaths. As rates of overdose
incidence increase, the use of the safe and effective reversal agent,
naloxone, in the form of a nasal rescue spray is being fielded and used by
emergency medical technicians (EMTs) at a greater and greater rate.
Despite advances in the deployment of these rescue products, deaths are
continuing to increase. There is evidence that repeated dosing of a
naloxone nasal spray (such as Narcan) is becoming more common due to the
amount and type of opiate being administered. Despite the benefits of
naloxone related to opioid reversals, we lack repeated dosing guidelines
as a function of opiates and the amount the patient has taken.
Goal-directed rescue dosing, where respiratory markers such as oxygen
saturation or end-tidal carbon dioxide, are being used as an indication of
the patient's recovery. These rescue methods require time, training,
and understanding by the EMT to administer with most patients receiving
naloxone doses with no follow-up or additional monitoring. 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 demonstrate 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. By
designing the model to include circulation and respiration we investigate
physiological markers that may be used in goal-directed therapy rescue
treatments.