What Should You Know About Nitazenes?

Imagine a synthetic narcotic 40 times more potent than fentanyl, one with respiratory depressant effects 50 times greater than morphine—a drug so powerful that after it was discovered physicians decided against using it in clinical practice because its therapeutic range was so narrow, patients were in constant danger of overdosing.

Nitazene (and its analogs, etonitazene, metonitazene, and isotonitazene) is that drug. Discovered by Swiss pharmaceutical manufacturers in the 1950s, it was deemed not practical for use in clinical medicine because of its great potential for overdose.

The formulary for this drug rested on a shelf for decades until it turned up recently in forensic samples in the US and Europe of people who had died from opioid overdoses. Isotonitazene alone is believed to have contributed to more than 40 deaths in Cook County, Illinois and Milwaukee County, Wisconsin in the first seven months of 2020.¹ This has raised alarm bells around the world. The opioid epidemic hasn’t gone away. COVID-19 may have bumped it down a spot on the list of public health emergencies, but make no mistake, opioids and the opioid epidemic will return to No. 1 when COVID is over.

Nitazene may be found as a powder or liquid. It may be injected through subcutaneous, intramuscular, and intravenous routes. In a powder form it may also be snorted, and it can be formed into pills and taken orally. It produces a robust response, featuring the same typical mu-opioid receptor agonist effects as fentanyl or morphine. This makes nitazene an excellent analgesic. The difficulty with it is that up to 50% of patients who had it administered in a controlled clinical setting had severe respiratory depression.

Nitazene has been placed on the Schedule I list of drugs, meaning it has no current acceptable medical use and a high potential for abuse. As nitazene analogs find their way into the drug supply, the potential for an increase in deaths from opioid overdoses may rise.

The signs and symptoms of nitazene overdose are the same as they are for other opioid overdoses. Decreased level of consciousness, respiratory depression, and pinpoint pupils are hallmarks. Patients who are unconscious, hypotensive, or bradycardic are in a pre-cardiac arrest phase and need to be managed aggressively.

Use of multiple substances—alcohol and cocaine, for example—may complicate the clinical picture. Gear resuscitation in these circumstances to supportive care, maintaining blood pressure, heart rate, and oxygenation. If someone is known to have used opiates and does not respond to naloxone (or their response is not as vigorous as expected), consider other causes, including hypoglycemia, other depressants, alcohol, trauma, and stroke.

Treatment

Regardless of the opioid ingested, management of the airway and oxygenation are keys to successful resuscitation. When you arrive on scene, you don’t know how long a patient has been hypoxic. A concentrated effort at management in this regard is critical.

Insert a nasopharyngeal airway (NPA), but if you’re going to administer intranasal naloxone, do that first. I prefer NPAs since I don’t know how long I will need to bag a patient, and patients given 2–4 mg of nasal naloxone will, after 2–4 minutes, regain consciousness and respirations simultaneously. An oral airway will cause them to vomit, but if I use lidocaine jelly to insert the NPA, even conscious patients tolerate it well.

Ventilate but do not hyperventilate. Use 100% oxygen with a BVM and nice, controlled ventilations, 10–12 per minute. Use good technique, two-rescuer if possible. You do not want to overinflate the patient and cause gastric distension. Watch the patient for those first signs of reversal: an increase in respiratory rate, their eyelids start to flutter. When you see that increase in respiratory rate, stop bagging the patient if they have a good rate and can maintain their own airway. Then transition to supplemental oxygen.

Naloxone will work on nitazene and its analogs. Nalorphine, the opioid-reversal agent that preceded naloxone, worked well against it in clinical studies. You may have already had patients who have overdosed on nitazene analogs that have been mixed with heroin or fentanyl and been successfully reversed with naloxone.

Some patients may need to have additional doses of naloxone administered when they have overdosed on nitazenes. I prefer to start an IV and administer 0.4–0.8 mg naloxone IVP and bring patients up slowly. I do this for a couple of reasons. One, I can bring patients up to a rousable state—not one where they are fully conscious, but they can maintain their own airway and ventilate themselves on their own. They will not go into full withdrawal as we see sometimes when we administer an intranasal dose of 2–4 mg. It also reduces vomiting.

The other reason is that if I bring a patient out too quickly, they will be confused and disoriented. The patient will go from a dreamlike state to one where they are fully awake with 3 or 4 uniformed individuals in the room, typically scaring them. With smaller doses I can talk to the patient as they regain consciousness, and it is more controlled. I have had better success this way.

Wooden Chest Syndrome

Wooden chest syndrome (WCS), previously observed in fentanyl overdoses, has also been observed with etonitazene. WCS is a skeletal muscle rigidity of the chest wall that presents as episodic breath-holding spells, tense abdominal muscles, a firmly locked jaw, and stiff extremities. Hypertension and hypoxia are also common during these episodes.

The breath-holding is a direct result of extended chest wall skeletal muscle contraction, which results in ineffective ventilation, whether it is spontaneous breathing or assisted with a BVM. If you are using a BVM to oxygenate a WCS patient, expect extremely high resistance. This will make bagging and oxygenating them difficult at best.

You cannot overdose from touching nitazene. We have seen the hysteria that has arisen from fentanyl, the misconceptions that as a fine powder it can be airborne and inhaled or absorbed through the skin. We have seen people who have been around fentanyl and reported headaches, rapid respiratory rates, and panic—none of these are symptoms of opioid overdose. You cannot overdose on fentanyl or nitazene by touching them.

Systems of Care

The treatment and management of patients suffering from addiction and overdose requires systems of care. Increased access to naloxone in your community is important but not the only option. Once you have treated patients in the field, do you have designated receiving centers? If patients refuse care after being resuscitated, can EMS provide suboxone? Can patients receive follow-up care, either through community paramedics or another type of intervention?

Remember, opioid addiction is a chronic, incurable medical disease that takes on average 8 years to control. EMS is an integral part of these patients’ systems of care. Work with your medical director, receiving hospitals, and local harm-reduction groups. This is a collaborative effort, regardless of the substance.

Reference

1. Shover CL, Falasinnu TO, Freedman RB, Humphreys K. Emerging Characteristics of Isotonitazene-Involved Overdose Deaths: A Case-Control Study. J Addict Med. 2021; 15(5): 429–31. doi: 10.1097/ADM.0000000000000775

Resources

American Academy of Orthopaedic Surgeons. Emergency Care and Transportation of the Sick and Injured. 12th ed. Jones & Bartlett Learning; 2021

Chapleau W, Burba A, Pons P, Page D. The Paramedic. McGraw-Hill; 2011

Drug Enforcement Administration, Diversion Control Division, Drug & Chemical Evaluation Section. Isotonitazene. Published August 2020

Expert Committee on Drug Dependence. Critical Review Report: Metonitazene. World Health Organization. Accessed March 23, 2022

Gerard D. A Combined Effort Against the Opioid Crisis, EMS World. Published July 27, 2019. www.hmpgloballearningnetwork.com/node/158032

Krotulski AJ, Papsun DM, Walton SE, Logan BK. Metonitazene in the United States—Forensic toxicology assessment of a potent new synthetic opioid using liquid chromatography mass spectrometry. Drug Test Anal. 2021; 13(10): 1697–711. doi: 10.1002/dta.3115. Epub 2021 Jun 22

Montanari E, Madeo G, Pichini S, Busardò FP, Carlier J. Acute Intoxications and Fatalities Associated with Benzimidazole Opioid (Nitazene Analog) Use: A Systematic Review. Ther Drug Monit. 2022. doi: 10.1097/FTD.0000000000000970. Online ahead of print

Mueller F, Bogdal C, Pfeiffer B, Andrello L, Ceschi A, Thomas A, Grata E. Isotonitazene: Fatal intoxication in three cases involving this unreported novel psychoactive substance in Switzerland. Forensic Sci Int. 2021; 320: 110686. doi: 10.1016/j.forsciint.2021.110686

National Association of Emergency Medical Technicians. AMLS: Advanced Medical Life Support. 3rd ed. Jones & Bartlett; 2021

Daniel R. Gerard, MS, RN, NRP, is EMS coordinator for Alameda, Calif. He is a recognized expert in EMS system delivery and design, EMS/health-service integration, and service delivery models for out-of-hospital care.