Fentanyl overdose: naloxone reversibility and reduced cross tolerance
Overdose deaths in North America involving fentanyls (fentanyl and structurally opioids) has risen dramatically over the last decade. In 2017 fentanyls were involved in more overdose deaths than heroin or prescription opioids in the USA, with nearly 30,000 fatalities recorded (1). Respiratory depression is the primary cause of death following consumption of fentanyls or other opioids.
In addition to the known danger of fentanyls being far more potent than morphine, there is also a growing body of evidence that naloxone, the opioid antagonist administered to rescue respiration during overdose, is less effective against the respiratory depression induced by the fentanyls when compared to morphine (2). These observations suggest that higher doses of naloxone or repeated doses of naloxone are required to rescue an overdose where fentanyls are suspected to be involved. Fentanyls are also known to induce muscle rigidity, colloquially known as “wooden chest” that may contribute to the suppression of respiration in overdose. Opioid users often consume fentanyls accidentally when they are cut with more common opioids such as heroin. In these cases, the degree of cross tolerance that prolonged heroin use will provide against fentanyls, and the relative safety against overdose that tolerance provides, is unknown.
We utilised whole body plethysmography to measure mouse respiration and osmotic mini-pumps to deliver prolonged (6 day) opioid administration. Our findings demonstrate that fentanyl has a faster rate of onset of respiratory depression than heroin. In addition to reducing respiratory rate fentanyls also depressed tidal volume, potentially by inducing muscle stiffness. We also observed that at least a 10-fold greater dose of naloxone was required to reverse fentanyl respiratory depression when compared to that required to reverse an equi-effective dose of morphine. Furthermore, prolonged morphine treatment was less effective at inducing tolerance to acute, on top fentanyl compared to acute, on top morphine.
These data further illustrate that fentanyl, and likely most fentanyls, are extremely dangerous due to a combination of high potency, induction of muscle rigidity, relative resistance to naloxone and less cross tolerance to other opioids.