As the U.S.'s opioid crisis barrels on, the healthcare system has scrambled to both treat the addicted population and wean the market off of years of prescribing highly addictive medicines for cases from dental surgery to chronic back pain.
Meanwhile, another challenge is emerging: synthetic, illicit opioids such as fentanyl now account for nearly half of overdose deaths, eclipsing prescribed medicines.
For Opiant Pharmaceuticals Inc., the originators of overdose antidote Narcan Nasal Spray, treating addicted patients "has become an arms race," CEO Roger Crystal said, adding that there are more than 2 million people addicted to opioids in the U.S.
"I don't see that significantly changing immediately until we get more medication out there," he said. In the meantime, opioid antidotes such as Narcan, which is now sold by ADAPT Pharma Inc., need better reimbursement and access pathways according to Crystal.
Opioid overdoses are marked by slowed and eventually stopped breathing, which Narcan, also known by its generic name naloxone, temporarily reverses. Earlier this year, U.S. Surgeon General Jerome Adams said it was "critical" that naloxone be more widely available and carried even by friend and family of opioid users.
That approach worries others.
"People are using Narcan as a party favor," said John Hsu, CEO of the early-stage opioid developer Quivive Pharmaceuticals.
"We have to use opioids because there's nothing better — so we treat the side effects," he said in an interview, describing the company's preclinical product, an opioid with an added respiratory stimulant designed to prevent overdoses.
The generic respiratory stimulant that Quivive is using also has abuse-deterrent factors, according to Hsu. Patients that take too many will experience anxiety and dysphoria, which the company believes will remove the main draw of taking multiple pills.
"Everyone is avoiding the opioid market because no one can figure out a way to make money," Hsu said. "If everyone is running away from the situation, I've got to run toward it."
The other opioid crisis
Yet safer prescription opioids are just one piece of the puzzle. A "crisis within a crisis" is the building use of illegal opioids such as fentanyl and its fast-emerging, potent relative carfentanil, said Opiant's Crystal. These synthetic versions were involved in more than 45% of U.S. opioid overdose deaths in 2016, according to the latest data from the National Institutes of Health.
The elephant tranquilizer carfentanil is 100 times more potent than fentanyl, which itself is more than 50 times stronger than heroin. Canadian authorities recently seized a single kilogram of carfentanil in the town of Calgary; Crystal said that amount could kill 35 million people.
Opiant is developing its own more potent overdose antidote, an early-stage therapy called nalmefene that is also supposed to last longer. The drug, which is also used to treat alcohol dependence, cleared phase 1 trials for overdose use earlier this year.
"Before it became a disease of soccer moms, it was dismissed," Crystal said. "Now it's sort of the crisis next door."
Growing support for cannabis
Back in the world of prescription drugs, physicians and policymakers searching for a nonopioid option are increasingly landing on medical marijuana.
Lowering restrictions on the plant, which the federal government has deemed a Schedule 1 drug with no medical use and high abuse potential, could help "reverse the opioid epidemic," former U.S. House Speaker John Boehner recently tweeted.
Boehner's thinking on marijuana has evolved, he said while announcing he joined the board of a New York-based, multistate cannabis company, Acreage Holdings.
Marijuana decriminalization is increasingly showing up on state referendums and passing, while a bill that would leave its legalization entirely up to the states was recently introduced in the U.S. Senate. During comments on the sidelines of the recent G-7 Summit, President Donald Trump said he "probably will end up supporting" that legislation.
The market is saturated with cannabis companies looking to get into pain management, said CURE Pharmaceutical Holding Corp. Chief Operations Officer Jessica Rousset.
CURE, which makes small gum grafts and dissolving oral patches to deliver medicines, is also exploring the potential of certain cannabis compounds, called cannabinoids, though not in pain.
Yet the California company's work on cannabis use for sleep apnea and possible cancer treatments has been gradual in the U.S., where the Drug Enforcement Agency is "not particularly collaborative" about setting up manufacturing licenses for cannabis-based products, she said.
There are a host of potential options that have not been explored, among them the hallucinogenic Amazon vine Ayahuasca and the psychoactive west African tree root Ibogaine, Rousset added. Early-stage research suggests that both could be used to treat addiction, but no human trials have been conducted.
"We're still exploring in that realm of taboo compounds that really should be studied because they might have some interesting therapeutic opportunities," Rousset said.