Posted with permission from STAT

ATLANTA - Dr. Nora Volkow has heard a frightening scenario play out around the country. People are administering naloxone to synthetic opioid drug users who have overdosed. But the antidote doesn't work well. So they give another dose. And it's only after multiple doses - four, five, even six times - that drug users finally come to their senses.

Naloxone is the only widely available drug to reverse opioid overdoses. But anecdotal reports of its limitations against synthetic opioids are on the rise. Spurred by that public health threat - as well as a booming commercial market for the antidote - drug companies, researchers, and health officials are eagerly eyeing the development of new treatments to augment the use of naloxone or, in some cases, potentially replace it.

"The strategies we've done in the past for reversing overdoses may not be sufficient," Volkow, director of the National Institute for Drug Abuse, said in a recent speech at the 2018 National Rx Drug Abuse and Heroin Summit. "We need to develop alternatives solutions to reversing overdoses."

Those alternatives are taking a variety of forms. One biotech company is studying a drug with similar mode of action as naloxone - an opioid antagonist - but one that lasts roughly four times longer. Some addiction medicine specialists are hopeful that a different drug, buprenorphine, presently used to treat opioid addiction, could also be tweaked to reverse an overdose. Meanwhile, the National Institutes of Health hopes to pursue research into drugs that wouldn't counteract the opioids directly but rather keep the patient breathing - the thing that causes so many overdoses to be fatal.

The new reversal agents are sorely needed, according to people like Dr. Jay Kuchera, a Florida-based addiction medicine specialist for Resolute Pain Solutions, who believes that "naloxone is being outgunned" by more potent drugs like fentanyl and carfentanil.

"Naloxone seemed to be great for the older opioids," Kuchera said. "But now that we're encountering these nonmedical, ungodly [opioids] like carfentanil ... we need to get with the times."

Naloxone sales are growing, and as of 2016, one industry-funded report estimated the antidote's market was worth more than $1 billon. But prices for the drug have been rising - a single dose, which once cost as little as a few dollars a dose, now runs anywhere from $20 to more than $2,000 for a dose - and the fact that synthetic opioids may require multiple doses of the antidote could exacerbate the pricing debate.

But other experts point out that federal research dollars spent on naloxone alternatives come at the cost of efforts to improve naloxone itself - or to fund interventions that keep people from becoming addicted in the first place. Above all, they want better evidence of naloxone's limitations against synthetic opioids.

"It's a story here, a case series there, a newspaper report from a paramedic," said Dr. Dan Ciccarone, professor of family and community medicine at the University of California, San Francisco. "But show me the data."

The next naloxone

Back in 1995, the Food and Drug Administration approved Revex, an injectable formulation of the opioid antagonist nalmefene, to combat opioid overdoses. But Baxter, Revex's manufacturer, discontinued the drug for business reasons in 2008.

Opiant Pharmaceuticals, the California company that developed a nasal spray version of naloxone called Narcan, has recently picked up where Baxter leff off. The company is now in the process of studying a nasal spray of nalmefene as a potential reversal agent to revive synthetic opioid overdose victims. Two months ago, Opiant presented positive results from a Phase 1 clinical study to a FDA panel, and hopes to submit the drug for FDA approval by 2020.

"Compounds like fentanyl, carfentanil, and other synthetic opioids act for longer periods of time," said Dr. Roger Crystal, CEO of Opiant. "The concern is that naloxone's half-life doesn't provide sufficient cover to prevailing amounts of fentanyl in the blood."

That discrepancy can mean that fentanyl levels in the blood can outlast naloxone levels, and the drug user can slip back into an overdose after the treatment wears off.

Another approach would be to repurpose an existing drug, buprenorphine - one of the most popular forms of medication-assisted treatment for opioid users. Some addiction experts are intrigued by the idea of buprenorphine as overdose reversal agent, as the drug could easily be used to segue drug users into long-term treatment. However, no human trials have yet begun.

Buprenorphine not only has a strong affinity for the same receptors as fentanyl, it has a longer half-life than naloxone. Iranian researchers have tested buprenorphine on rats experiencing overdose and found that it worked alongside naloxone to reverse overdose without sparking symptoms of withdrawal. And a case study published in the Annals of Emergency Medicine last year reported that buprenorphine helped reverse a 20-year-old man's respiratory depression caused by opioids.

Still, according to Dr. Andrea Barthwell, once the deputy drug czar for President George W. Bush, that application of buprenorphine is hindered by the fact that it isn't as fast-acting as naloxone. Naloxone typically reverses overdoses within minutes.

"Pharmacokinetically, buprenorphine might not work, but I won't bury the idea of it as a reversal agent," Ciccarone said. "Maybe there's a way to modify buprenorphine - or another partial agonist. That would be interesting to pursue."

Finally, a third approach, being pursued by federal agencies, is whether certain drugs could help keep overdose victims breathing, without directly counteracting the opioids' effects.

For that purpose, Volkow wants to further study ampakines, drugs that interact with the brain's AMPA receptors, and which have previously been considered for the treatment of Alzheimer's disease and schizophrenia. Several studies have suggested that ampakines may counter respiratory depression. One study, published in Anesthesiology in 2009, found that one kind of ampakine protected rats from respiratory depression caused by fentanyl.

In a recent New England Journal of Medicine report, NIH Director Francis Collins and Volkow touted two other kinds of therapies currently used to treat respiratory depression that might someday be adapted to help respond to overdoses. Those include drugs that target serotonin receptors and a device that electrically stimulates the phrenic nerve to force diaphragm movement and maintain breathing. Volkow thinks these therapies, with the right corporate and research partners, could be available in as soon as three years.

"There are so many people dying that we have to recognize the urgency," Volkow told STAT. "We obviously value basic science, but at the same time we have to recognize because of the current situation, the development of medication the can help address the crisis has become our top priority."

Funding priorities

Still, some health experts believe research should first focus on improving naloxone rather than replacing it.

For all the anecdotes, Ciccarone isn't convinced that intranasal naloxone is ineffective against fentanyl. The main reason: insufficient data. Without more evidence, he finds it hard to tell if naloxone isn't working, or if the laypeople administering naloxone aren't doing so in a timely enough fashion. He feels there are many open questions: "Do peers, families, or lovers have it? Is it in their briefcase or pocket? Then, in the moment of need, are they willing and able to use it correctly?"

"I'm not opposed to looking at longer-acting blockers," Ciccarone continued. "But I see gaps in the treatment portfolio. It'll be cheaper and easier to fill those gaps rather than spend millions of dollars for developing new drugs."

Dr. Natalie Kirilichin, assistant professor of emergency medicine at George Washington University, worries that newer drugs to reverse synthetic opioid overdoses might be more expensive - and ultimately less accessible to the people who most need an antidote.

Ultimately, Dr. Andrew Kolodny, co-director of opioid policy research at Brandeis University, believes that investing in longer-acting opioid reversal drugs may be worthwhile. But in the midst of an opioid epidemic, where there's only so much funding to go around, he said officials should devote more money toward "upstream interventions" - ones that prevent drug use or help treat opioid addiction - in an effort to save more lives.

"I would prioritize addiction treatment," Kolodny said. "I think it's worthwhile to invest in opioid overdose antidotes - but it should be a lower priority to research."

For all the different alternatives, health officials, researchers, and doctors don't expect naloxone to go away. Crystal, the CEO of Opiant, believes rising opioid deaths will drive up demand for both naloxone and newer reversal agents like nalmefene. Volkow, for her part, agrees. 

"Naloxone is not going to disappear," Volkow said. "Naloxone will always be an incredibly valuable drug. Maybe we'll combine [the use of] naloxone with another drug. I don't think it'll go away."