Fentanyl Crisis Spurs Need for Help With Multiple-Drug Overdoses (1)

The record number of Americans dying from a mix of drugs laced with fentanyl is driving research into medications that can eliminate multiple substances from the body.

The National Institute on Drug Abuse is prioritizing research to counteract overdoses from more than one drug. One promising medication could start initial safety testing as soon as June or July.

“Many people, if not most people, in some areas are dying with multiple substances in their body,” said Sarah E. Wakeman, medical director for the Massachusetts General Hospital Substance Use Disorder Initiative.

Fentanyl, a synthetic opioid that’s anywhere between 50 to 100 times stronger than morphine, is fueling the latest wave of the opioid crisis, particularly when mixed with other drugs such as methamphetamine or cocaine. Those drug combinations make the drug overdose response “much harder and much more complex,” NIDA Director Nora D. Volkow said.

Expanded Treatment Options

Volkow’s agency, which is part of the National Institutes of Health, has made expanding the range of treatment options for substance use disorders a key focus area. That work includes research into fentanyl vaccines and monoclonal antibodies that can can bind to methamphetamine and trap it before the drug enters the brain, heart tissue, and other organs.

NIDA also is funding Clear Scientific’s pursuit of a treatment that can remove methamphetamine and fentanyl the same way existing products can remove toxins from the bloodstream.

“It’s almost like Pac-Man,” Clear Scientific CEO Shekar Shetty said. “Once it gets into your blood, it’s able to latch on to the target molecule, and it binds it and it removes it from the body to the urine.”

Clear Scientific is developing an intravenous version of its drug and also looking into an intramuscular version. Shetty said the Cambridge, Mass., biopharma company plans to submit its investigational new drug application to the Food and Drug Administration next month, with first-in-human safety studies potentially beginning this summer. More advanced clinical trials to determine dosing and to study how the drug interacts with the body could happen in the first quarter of next year.

‘Quite Lethal’ Combinations

State and federal officials, including at the FDA, have worked for years to make the opioid reversal medication naloxone more readily available, and FDA advisers recently voted to make naloxone available without a prescription. But while naloxone is safe and highly effective on opioids, it may not fully address all the products contributing to the current state of the drug overdose crisis.

Naloxone works very quickly to counteract an opioid overdose. But the effect doesn’t always last, particularly if there’s a lot of fentanyl in the body, Xinhua Li, Clear Scientific’s executive vice president of drug development, said.

Too much opioid in the body will slow or stop breathing to potentially fatal levels. Meanwhile, stimulants such as cocaine and meth constrict blood vessels and increase the risk of an arrhythmia.

“You can see why this combination could be actually quite lethal, and there naloxone may not be sufficient,” Volkow said.

Naloxone will improve oxygenation of the blood, “but it will not per se alleviate the vasoconstriction or the arrhythmogenic effects of methamphetamine and cocaine,” Volkow said.

Li and Shetty see their product as complementary to naloxone.

“By the time the patient comes to the hospital, naloxone is reviving the breathing and our drug is beginning to remove it from the body so that it does not have the long-term effects,” Shetty said. “We see our drug being used in the continuum of care.”

Record Number of Overdose Fatalities

Detection of multiple drugs in the body has escalated as drug overdose deaths have more than doubled in just a few years. A report published Feb. 21 by Millennium Health found positive drug tests for fentanyl jumped 146% between 2019 and 2022. Out of those positive tests, more than 83% of them also contained additional drugs, including heroin, prescription opioids, methamphetamine, or cocaine.

There are overdose-reversal medications for sedatives like benzodiazepines, but they carry the risk of seizures. Holly Geyer, an addiction medicine physician and a hospital medicine physician at the Mayo Clinic in Phoenix, said if someone is chronically dependent on sedatives, providers will support those patients through the withdrawal process as opposed to reversing the over-sedation process because of the toxicities.

“We can actually induce more problems than we fix outside of use of naloxone,” Geyer said.

Having safe options for non-opioid overdose reversal such as benzodiazepines or the sedative xylazine is important, Wakeman said. “If we had similar medications that didn’t have side effects and have risks like seizure and could be given in the field, I think they would be used and would be really helpful.”

However, some doctors and harm-reduction specialists question whether new drugs are the right path to pursue, or whether it’s better to focus efforts on getting existing overdose reversal medications like naloxone into the hands of people who can use them to save lives.

“The scientists have done their part. What we need are social service programs and medical clinics to serve people who use drugs to get the overdose reversal medication into the hands of people who could use it,” along with low-cost options, Mary Sylla, director of overdose prevention policy and strategy for the Harm Reduction Coalition, said.

Timothy W. Westlake, an emergency room physician in Oconomowoc, Wis., about 35 miles from Milwaukee, said there is not “a lot of utility” for non-opioid reversal agents, as they usually treat those patients with supportive care.

“It’s OK to just wait for it to where it wears itself out in the body to metabolize it and break it down. There’s not a threat to having the drugs still circulating in the body like there is with opiates as far as causing respiratory suppression,” Westlake said. “I don’t know that there’s a need for reversal agents in the same way.”

But Shetty recalled how staff at a San Diego hospital told him four emergency nurses had been physically assaulted by a patient who had taken methamphetamine. “They would love to have something like this, to remove the methamphetamine from the body, so that they can do what they need to give care to that patient,” Shetty said.

Variety of Solutions Needed

NIDA is also funding research into devices that could restore breathing or a user-friendly device to counteract cardiac arrhythmias from drug overdoses.

They’re also working on a device that could deliver naloxone automatically, similar to an insulin pump for diabetes. But Volkow said that raises the question of whether someone with an opioid use disorder who’s seeking out illicit fentanyl will wear a device that will monitor them continuously.

“No matter what technology or medication or intervention that we are developing, we have to be aware that it is possible that they will not be useful for everyone,” Volkow said. “Then it becomes important to have various alternatives.”