Pharmacological Profiling of Antifentanyl Monoclonal Antibodies in Combination with Naloxone in Pre- and Postexposure Models of Fentanyl Toxicity

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 reduction in mortality following an opioid overdose. Reversal of opioid toxicity may precipitate an opioid-withdrawal syndrome. At the same time, there is a risk of inadequate response or re-narcotization after the administration of a single dose of naloxone in patients who have taken large doses or long-acting opioid formulations, as the duration of effect of naloxone is shorter than that of many opioid agonists. As out-of-hospital use of this medication is growing, so too is concern about effective but safe dosing.

Fentanyl and its analogs have been mainstays for the treatment of severe to moderate pain for many years. In this review, we outline the structural and corresponding synthetic strategies that have been used to understand the structure-biological activity relationship in fentanyl-related compounds and derivatives and their biological activity profiles. We discuss how changes in the scaffold structure can change biological and pharmacological activities. Finally, recent efforts to design and synthesize novel multivalent ligands that act as mu and delta opioid receptors and NK-1 receptors are discussed.

Fentanyl overdose deaths have reached “epidemic” levels in North America. Death in opioid overdose invariably results from respiratory depression. In the present work, we have characterized how fentanyl depresses respiration, and by comparing fentanyl with heroin and morphine, the active breakdown product of heroin, we have sought to determine the factors, in addition to high potency, that contribute to the lethality of fentanyl. Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole body plethysmography. Intravenously administered fentanyl produced more rapid depression of respiration than equipotent doses of heroin or morphine. Fentanyl depressed both respiratory rate and tidal volume. Fentanyl did not depress respiration in μ‐opioid receptor knockout mice. Naloxone, the opioid antagonist widely used to treat opioid overdose, reversed the depression of respiration by morphine more readily than that by fentanyl, whereas diprenorphine, a more lipophilic antagonist, was equipotent in reversing fentanyl and morphine depression of respiration. Prolonged treatment with morphine induced tolerance to respiratory depression, but the degree of cross tolerance to fentanyl was less than the tolerance to morphine itself. We propose that several factors (potency, rate of onset, lowered sensitivity to naloxone, and lowered cross tolerance to heroin) combine to make fentanyl more likely to cause opioid overdose deaths than other commonly abused opioids. Lipophilic antagonists such as diprenorphine may be better antidotes than naloxone to treat fentanyl overdose.