UVA Poison Expert Warns of Emerging Synthetic Opioids That Fentanyl Tests May Miss

An emerging class of synthetic opioids is causing concern among poison experts because the drugs can trigger potentially deadly overdoses while escaping fentanyl test strips and many hospital drug screens.

Dr. Christopher P. Holstege, director of UVA Health’s Blue Ridge Poison Center and chief of the University of Virginia’s Division of Medical Toxicology, is warning about substances known informally as “orphines,” potent synthetic opioids that began appearing in the United States in 2019.

No orphine cases have been confirmed by UVA Health locally, Holstege said, but reports from colleagues and laboratories elsewhere in the country have him concerned that the drugs could become another threat in an increasingly unpredictable illicit drug supply.

“I worry someone is going to get one of these substances, not realize it, and is going to stop breathing and die,” Holstege said.

Holstege is a professor of emergency medicine and pediatrics at the UVA School of Medicine and is board-certified in emergency medicine and medical toxicology. He remains clinically active in treating poisoned patients and has spent decades working in toxicology.

Orphines are synthetic opioids with chemical roots dating to the 1960s. Holstege said they currently have no legitimate medical use and are not approved by the U.S. Food and Drug Administration.

Like heroin, morphine and fentanyl, they can cause sedation, very small pupils and dangerously slowed breathing. In severe cases, a person can stop breathing and die.

The potency varies depending on the particular orphine involved. Some are more potent than morphine but less potent than fentanyl by weight, Holstege said. Others haven’t been adequately studied in humans and could potentially be more potent than fentanyl.

Small changes to their chemical structures can significantly change how they affect the body.

Fentanyl Test Strips Won’t Detect Them

One of Holstege’s biggest concerns is that detecting orphines isn’t easy.

Fentanyl test strips do not detect them.

Many hospitals face the same problem because commonly used drug screening methods don’t identify these emerging substances either.

Holstege said the Blue Ridge Poison Center covers 74 hospitals. UVA Health has advanced testing technology that could potentially identify some orphines, but even that depends on the specific substance and its chemical structure.

“We may have a patient that looks like an opioid overdose and is an opioid overdose, but it’s actually an orphine, and we don’t realize it,” Holstege said.

That makes determining how widespread the drugs have become difficult.

The Blue Ridge Poison Center routinely receives calls involving opioid overdoses, but without specialized testing, doctors may not know exactly which opioid caused them.

UVA Health has not yet identified an orphine case, Holstege said. It has, however, detected nitazenes, another class of synthetic opioids that emerged as the illicit drug supply changed.

Elsewhere in the country, laboratories and forensic investigators are beginning to find orphines, including in cases involving deaths.

Holstege believes the limitations of current testing could mean orphines are significantly underreported in both hospital cases and overdose deaths.

People May Not Know What They Are Taking

Another concern is that people may not be seeking out orphines.

The drugs have been found mixed with other illicit substances.

Someone might believe they are buying heroin or a prescription medication when the product actually contains an orphine. Holstege said the substances have also been found in combinations involving amphetamines and other stimulants.

Counterfeit prescription pills present another risk.

A pill can look like a legitimate medication even though it was produced illegally and contains something entirely different. Holstege said counterfeit medications have already been found containing fentanyl, and orphines could present a similar risk.

That means a pill’s appearance doesn’t guarantee what’s actually inside.

“It’s just an exceedingly dangerous time,” Holstege said.

Fentanyl test strips can provide information about whether fentanyl is present, but Holstege stressed that they cannot identify every dangerous opioid or other drug.

“That’s the big problem with the fentanyl test strips,” he said. “They’re only looking for fentanyl.”

Naloxone Can Help, But Overdoses May Be Complex

Naloxone, commonly known by the brand name Narcan, appears capable of reversing the opioid effects of orphines, Holstege said.

However, the amount needed may vary.

Doctors have encountered similar problems with especially potent fentanyl analogs, where regular doses of naloxone may not work as well.

Another complication is that illicit drugs increasingly contain several substances at once.

An orphine could be mixed with fentanyl, a novel benzodiazepine, xylazine, a stimulant or another substance.

Naloxone can reverse opioid effects, but it doesn’t reverse non-opioid drugs. Someone may therefore begin breathing better after receiving naloxone but remain unconscious, sedated or otherwise impaired because another substance is still affecting the body.

That uncertainty is one reason suspected overdoses require emergency medical attention even when naloxone has been administered.

Opioid Epidemic Continues To Change

Holstege said the appearance of orphines is part of a larger change in America’s opioid epidemic.

The first major wave involved prescription opioids. As access to prescription drugs tightened, heroin became increasingly prominent. Fentanyl and fentanyl analogs followed.

Now, Holstege said, the country is dealing with what has been described as a fourth wave — one characterized by numerous drugs and mixtures rather than a single substance.

Instead of encountering only heroin or fentanyl, someone may be exposed to a combination involving fentanyl, xylazine, an orphine or other drugs.

Fentanyl remains the most prominent illicit opioid based on available information, Holstege said, but he cautioned that fentanyl is also much easier to detect than many emerging substances.

“We are seeing a lot of opioid overdoses at the hospitals throughout Virginia,” he said. “We don’t always know what’s causing the opioid overdose.”

That inability to quickly identify emerging substances makes it harder for doctors and public health officials to determine what is circulating and warn communities about new threats.

Concerns Go Beyond Orphines

Holstege also raised concerns about kratom and other novel psychoactive substances.

He described kratom as a plant-based opioid and said healthcare providers are seeing addiction and adverse reactions involving kratom and related products.

New sedatives, stimulants, and hallucinogenic substances are also emerging.

Those producing illicit drugs can make relatively small changes to chemical structures and create new substances, posing an ongoing challenge for doctors, toxicologists, testing laboratories and law enforcement.

The risks aren’t limited to adults.

Holstege said counterfeit pills and illicit drugs are a concern for college and high school students and can reach children as young as middle-school age.

After more than 30 years in practice, Holstege said the current drug environment is among the most difficult he has encountered.

“There’s a whole host of substances that are really emerging in the market,” he said. “It’s a very challenging time.”

The Blue Ridge Poison Center provides confidential assistance 24 hours a day for people with questions about possible poisonings or drug exposures. Callers can speak with nurses experienced in poison cases or a medical toxicologist.

You can reach the center at 1-800-222-1222.

Anyone who is unresponsive or has severely slowed or stopped breathing following a suspected drug exposure requires immediate emergency medical assistance.