Synthetic drugs worrying doctors

Study: Multiple doses of naloxone needed to reverse overdoses

Doctors are warning of several novel and potent synthetic opioids that could require more than one dose of the overdose reversal drug naloxone to counteract.

A report published at the end of August in the American Medical Association's JAMA Network Open Journal focuses on brorphine and several synthetic opioids in the nitazene drug class: isotonitazene, metonitazene and N-piperidinyl etonitazene. It was co-authored by Dr. Alexandra Amaducci, emergency medicine physician and medical toxicologist with Lehigh Valley Health Network.

LVHN is one of 10 hospital sites participating in the Fentalog Study, a five-year project to investigate the growing epidemic of fentanyl analogs conducted by the American College of Medical Toxicology's Toxicology Investigators Consortium and the Icahn School of Medicine at Mount Sinai. The new report covers patients who presented to emergency departments at 1 of 10 participating sites with an opioid overdose from Sept. 21, 2020, to Sept. 27, 2022.

None of the patients included in the study was in the Lehigh Valley. Amaducci said while more research is necessary, a few things are clear: These drugs are potent and people may take them when they believe they are taking a different drug, like heroin or fentanyl.

"Patients may not know that these are chemicals that they are potentially ingesting. It's my understanding that patients are not intending to use these particular novel potent opioids or nitazenes. They just happen to be in the drug supply," Amaducci said. "This is an opportunity to educate the public that these chemicals exist. They are in the drug supply across the country, meaning they could be anywhere."

But she said for clinicians, emergency medical technicians and other health care providers, the biggest takeaway is that there are patients experiencing opioid overdoses who may need more than one dose of naloxone to reverse their symptoms.

"These drugs are in existence, so if one dose of naloxone doesn't work, it doesn't necessarily mean that (clinicians) are wrong in their diagnosis of this as an overdose; it might mean that they just need to give a repeated dose or a higher dose to overcome the effects of the potent opioid," Amaducci said.

While brorphine and nitazenes are not chemically related to fentanyl, like fentanyl, the drugs are synthetic opioids and are highly potent. Brorphine is significantly stronger than morphine, and some nitazenes have been found to be up to 1,000 times as potent as morphine and 10 times stronger than fentanyl.

Brorphine and 10 types of nitazenes are listed as Schedule I by the U.S. Drug Enforcement Administration, meaning they have no approved medical use in the U.S. and are characterized as having a high potential for abuse.

The study identified 11 patients who overdosed and only tested for fentanyl, and nine patients who overdosed and tested positive for fentanyl and brorphine or fentanyl and a nitazene.

For those who tested positive for a nitazene and fentanyl:

Both who took isotonitazene had depressed levels of consciousness and required two doses of naloxone to reverse symptoms

Both who took metonitazene experienced cardiac arrest. One died despite receiving three doses of naloxone. The other lived after receiving three doses but an overall larger quantity of naloxone.

The three who tested positive for N-piperidinyl etonitazene had varying symptoms and required various amounts of naloxone. One had low oxygen saturation and a depressed level of consciousness and needed three doses of naloxone to reverse symptoms. Another had respiratory depression and a depressed level of consciousness and required a single large dose. The third had respiratory depression and a depressed level of consciousness and received five small doses and an infusion before symptoms were reversed.

The two patients who tested positive for fentanyl and brorphine only required a single dose of naloxone, however they reported they believed they had used a more common opioid like heroin or fentanyl.

Overall, the brorphine and nitazene patients received a significantly higher number of naloxone doses in-hospital compared with the fentanyl-only group. Amaducci said this speaks to the potency of these drugs.

"The biggest problem with an opioid overdose is that it causes people to stop breathing. So you could give them a small dose and they resumed breathing again. However, these drugs can last longer in your system than naloxone does. Then naloxone wears off and these drugs are still persistent and you may require another dose of naloxone or a third dose or a fourth dose or even an infusion until the drug effect wears off," Amaducci said.

While nitazenes and brorphine have started to show up in certain areas of the U.S., they are still relatively rare overall.

Patrick Trainor, acting assistant special agent in charge and spokesperson for the DEA's Philadelphia division, said while there have been instances where these drugs were detected in Philadelphia, it's only been a handful of cases. Most of the time, nitazenes and brorphine are being cut into other drugs and there isn't much of a demand for them on their own, though that may change as time goes on.

But, he added, the rise in synthetic opioids follows a trend.

"Unfortunately, the illicit drug trade over the past few years has made a … very seismic shift from semi-synthetic drugs, like heroin, to purely synthetic drugs," Trainor said.

Trainor said this is because, unlike semi-synthetic drugs like cocaine or heroin, there is no crop growing involved -- illicit drug manufacturers just need the precursor chemicals to make the synthetic drugs. He added that it is easier to tweak chemical formulas and create analogs that can temporarily skirt narcotics laws.

"We have seen in the past with synthetic drugs that as they get scheduled, different analogs are made because in order for a drug to be scheduled or made illegal, it has to be defined structurally and chemically," Trainor said. "Certainly, when you alter a chemical structure of a drug, you're certainly doing so in part to stay ahead of any federal or state scheduling issues, but you're also creating an illicit drug in a relatively controlled environment with a very clearly defined set of precursor chemicals."

Craig Scheetz, chief deputy district attorney for Lehigh County, said the office has not prosecuted any cases involving nitazenes or brorphine. He added he reached out to the Pennsylvania State Police Forensic Services and was told while nitazenes have been detected in Pennsylvania, state police labs haven't received samples from the Lehigh Valley.

If and when they show up in the Lehigh Valley, he said, nitazenes and brorphine will be treated the same as any other Schedule I drug.

"If they do show up they will be they will be prosecuted for them, just like any other drug -- heroin, fentanyl -- they will be prosecuted for it," Scheetz said.