By Ioana Cozma

Last updated: 29 January 2024 & medically reviewed by Morgan Blair

Synthetic opioids, also known as benzimidazole opioids, nitazenes, and Frankenstein opioids are opioids synthesized in a lab to have the same effects as natural opioids. While initially designed to treat pain-related conditions, synthetic opioids have become widely abused leading to most being made illegal. Some commonly abused synthetic opioids include carfentanil, protonitazene, and isotonitazene, as well as fentanyl, which is widely recognized as a central component in the continuing overdose crisis.

Key takeaways:

  • New synthetic opioids have been initially developed as pain relievers.

  • These drugs look like white powders and can be inhaled, ingested, or injected.

  • Novel synthetic opioids are considerably more potent than morphine.

  • Carfentanil is approved for use with severe restrictions, while protonitazene and isotonitazene are illegal.

  • Severe side effects range from respiratory difficulties to fast-onset overdose.

Synthetic Opioids

What are synthetic opioids?

Synthetic opioids have played a key role in the overdose crisis since the early 2010s, culminating with 73,654 opioid-related fatalities in 2022.[1]

Fentanyl was the predominant synthetic opioid during this era, marking the “third wave” of the opioid epidemic. While fentanyl abuse and overdose remain prominent, new synthetic opioids such as nitazenes have fueled greater increases in the death toll from opioid-related overdoses.

Related: Vaccine Could Prevent Fentanyl from Entering the Brain and Prevent Relapses and Overdoses

Initially introduced in the mid-1980s as an anesthetic for large animals like elephants, carfentanil is an extremely potent fentanyl derivative. Carfentanil is currently used for positron emission tomography imaging due to its high affinity for mu-opioid receptors (MOR).[2]

Meanwhile, protonitazene and isotonitazene are part of a unique group of synthetic opioids known as benzimidazoles. Developed in the 1950s as new pain relievers, these drugs have recently come under the spotlight as emerging designer synthetic opioids.[2]

These drugs have a similar appearance but have different side effects and methods of consumption. Carfentanil and isotonitazene appear in pill, powder, and liquid forms, while protonitazene is rarely manufactured in liquid form. As such, these new synthetic opioids can be ingested, injected, inhaled, or combined with other illicit drugs.[2]

How strong are synthetic opioids?

Carfentanil is one of the strongest synthetic opioids derived from fentanyl. Some sources claim it is 1000 times stronger than morphine and with a 50 times larger affinity for the mu-opioid receptor in the brain.[2] However, other sources claim that carfentanil is 10,000 more potent than morphine and 100 times stronger than fentanyl.[3]

Its uses as an anesthetic for large animals and high potency led to carfentanil being dubbed as “drop dead” and “elephant tranquilizer” on the streets.

Protonitazene is three times more potent than fentanyl, so its life-threatening effects emerge fast, even at small doses.[4]

Attorney General Ashley Moody states the drug may be fatal even when accidentally inhaled or touched.[5] The World Health Organization (WHO) reports that isotonitazene is 500 more powerful than morphine.[6]

While carfentanil is legal in the United States with strict restrictions, isotonitazene and protonitazene are not.

The legal status of drugs, including synthetic opioids, is determined by their classification under the Controlled Substances Act (CSA). The CSA categorizes substances into different schedules (I-V) based on their potential for abuse, currently accepted medical use, and accepted safety levels under medical supervision.

Carfentanil is classified as a Schedule II controlled substance in the U.S., recognized as having a high potential for abuse. However, carfentanil may have currently accepted medical uses with severe restrictions.[6]

Isotonitazene and protonitazene are Schedule I controlled substances in the U.S. This class of drugs is considered to have a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision. Therefore, the production, distribution, and possession of isotonitazene and protonitazene without appropriate authorization is illegal.[2]

What are the effects of synthetic opioids?

New synthetic opioids bind to and activate mu-opioid receptors in the brain, reducing stress and anxiety. These drugs also stimulate particular brain regions involved in reward processing, creating a sense of euphoria. Like all opioids, synthetic opioids diminish the perception of pain by reducing the activity of pain pathways.[8]

However, the potency of synthetic opioids, particularly compounds like carfentanil, protonitazene, and isotonitazene, amplifies the risk of adverse effects.

All opioids have the potential to suppress the brain’s ability to regulate breathing. In the case of novel synthetic opioids, even small doses may significantly depress the respiratory system. The results are decreased oxygen intake and, ultimately, apnea, where breathing stops altogether. Respiratory failure may also lead to overdose and, unfortunately, death.[8]

Related: International Overdose Awareness Day 2023

In the long term, given their potency, new synthetic opioids may cause physical dependence faster than other opioids. To avoid withdrawal symptoms, people may need to consume higher doses.[2]

Chronic use might lead to changes in brain structures involved in judgment, decision-making, learning and memory, and behavior regulation. Likewise, the extreme potency might exacerbate the risk of damage to vital organs, especially when combined with other substances or taken in large amounts over time.

What are the risks of synthetic opioids?

Among the major risks of these synthetic opioids is their extreme potency. As these drugs are hundreds of times more potent than morphine and fentanyl, their side effects are intense and have a fast onset. Overdosing may also occur faster, leaving a narrow window between intoxication and life-threatening effects.[2]

Unfortunately, numerous reports show that novel synthetic opioids may be mixed into other drugs without the user’s knowledge. For example, they might be found in heroin, counterfeit prescription pills, or even in stimulants like cocaine. This increases the risk of overdose, as users may not be aware they are consuming such potent opioids.[8]

Moreover, the amount of synthetic opioids may vary even within a single batch of illicit drugs. One dose might contain a minimal amount, while the next could be lethal.

Many standard drug tests, especially rapid or older ones, might not detect newer synthetic opioids, though fentanyl test strips are highly effective and can save lives.

Other synthetic opioids

N-desethyl isotonitazene is another novel nitazene derivative first reported by NPS Discovery Florida in December 2022, though the substance was first identified in September 2022. Research suggests that N-desethyl isotonitazene is 20 times more potent than fentanyl.[9]

In a study on rats, this substance was able to provide pain relief with a dose ten times smaller than that of fentanyl and 1,400 smaller than morphine.[8]

Brorphine is another powerful novel synthetic opioid discovered in various drug seizures since 2019. Structurally similar to fentanyl and appearing as a grey powder, this opioid acts as a powerful CNS depressant, which can lead to respiratory failure.[10]

The Drug Enforcement Agency placed brorphine as a Temporary Schedule I Controlled Substance on March 1, 2023.[11]

The emergence of brorphine has led to concerns about other related compounds that might soon find their way into the illicit drug market. These derivatives could potentially share the high potency of brorphine, presenting similar risks.

What are the withdrawal symptoms from new synthetic opioids?

The general symptomatology of withdrawing from new synthetic opioids aligns with opioid withdrawal symptoms.

Early symptoms (within the first 24 hours after the last dose) include:

  • Agitation

  • Anxiety

  • Muscle aches

  • Increased tearing

  • Insomnia

  • Runny nose

  • Sweating

Further symptoms include:

  • Abdominal cramping

  • Diarrhea

  • Dilated pupils

  • Goosebumps

  • Nausea and vomiting

  • Rapid heartbeat

  • High blood pressure[2]

Although uncomfortable, opioid withdrawal is typically not life-threatening on its own, though complications may arise due to dehydration caused by diarrhea and vomiting. It is always advised to seek professional opioid use disorder treatment when attempting to stop synthetic opioid dependence. Inpatient and outpatient treatment programs can provide a structured medically assisted detox as well as psychotherapies and support groups that can help with ongoing recovery.