Naloxone
Loren Bonner
Federal agencies like FDA and CDC have cited the need for higher doses of naloxone to reverse opioid overdoses, especially as fentanyl and other synthetic opioids have crept into illegal drugs, causing overdose deaths to skyrocket.
In 2021, FDA authorized two new high-dose formulations of naloxone: Kloxxado (Hikma Pharmaceuticals, PLC), an 8 mg intranasal naloxone product, and Zimhi (Adamis Pharmaceuticals Corporation), a high-dose injectable form of naloxone that delivers 5 mg of naloxone, an increase of more than 12 times the standard 0.4 mg intramuscular injection. Narcan (Emergent BioSolutions), a 4 mg intranasal naloxone product, has been available since 2015. A 2 mg version of Narcan was also approved by FDA but has never been marketed.
“Fentanyl is more potent, so the thought process is that we need to give more naloxone,” said Jeffrey Bratberg, PharmD, FAPhA, clinical professor at the University of Rhode Island College of Pharmacy. “The thought is that ‘the dose makes the poison,’ or that the concentration or potency relates directly to outcome.”
While Bratberg and other experts in the harm reduction space acknowledge these high-dose forms of naloxone may have been developed with good intentions, they worry about them causing more harm than good.
“I don’t think these more powerful forms or increasingly potent antidotes are necessary, and I worry about their consequences,” said Lucas Hill, PharmD, BCACP, clinical associate professor at the University of Texas at Austin College of Pharmacy.
He said the reason current low-dose forms of naloxone are preferred is because experiencing severe protracted opioid withdrawal—while not life-threatening—is what many people who use opioids try to avoid.
“Opioid withdrawal is a particularly agonizing withdrawal syndrome,” Hill said.
Many argue, however, that even if withdrawal is more painful with the dose is amped up, isn’t it better to be alive?
“That may be true in the moment,” said Hill. “But we could create a situation where those at the highest risk are not willing to carry naloxone—that high-dose form—or they are reluctant to call for help because responders carry that higher dose form.”
Hill said they have seen from preliminary studies that most people with substance use disorders are still willing to accept the relatively high 4 mg dose naloxone nasal spray, but they worry that may not be the case if the dose increases further.
“To this day, it’s true that harm reduction experts who have worked directly with people who use illegal drugs for decades prefer to distribute the 0.4 mg vials for intramuscular injection, and they find that one to two doses is enough,” said Hill, who is also the director of the Pharmacy Addictions Research & Medicine Program at the University of Texas at Austin College of Pharmacy.
Are higher doses necessary?
Not only can higher doses present unintended consequences, but the question remains as to whether they are even necessary.
“Our current opioid overdose treatment hasn’t failed us,” said Bratberg.
A small study from July 2021 published in Clinical Toxicology found that “the dose of naloxone administered for overdose reversal was not associated with the measured fentanyl concentration in blood specimens,” when 19 out of 20 individuals were tested for fentanyl in an emergency department.
Instead of bringing new naloxone products to market, Bratberg and others believe regulators and policy makers should prioritize certain strategies for making naloxone more widely available.
This includes making naloxone available OTC, increasing funding for community harm reduction programs,permanently eliminating insurance copayments and prior-authorization requirements, and mandating coprescribing and codispensing naloxone with all higher risk opioid prescriptions and medications for opioid use disorder. New naloxone formulations that permit dose titration would be advantageous as well, noted Bratberg.
More than opioids
The answer to whether amped up antagonists are needed gets even more complicated because most overdose deaths currently involve more than one drug—and many of these drugs are synthetic and more powerful.
Hill even noted increasing reports of novel synthetic benzodiazepines in the illegal drug supply.
But only opioids respond to naloxone.
“Heroin is really a thing of the past,” Hill said. “Novel synthetic illegal drugs are here to stay, and as the heroin supply continues to shift to other potent synthetic opioids, we will likely see a continued rise in death rates.” ■