Newsletters

POSTED: December 3rd, 2024
POSTED IN: 2024 Quarter 4, EM Pulse - The Official Newsletter of MOCEP,

by Evan Schwarz, MD, FACEP

After an extended hiatus, we’re back to discuss the toxicologic issues of the day! Since it’s been a while, we’ll start with updates on what is in the drug supply. I think the last time we addressed this, we discussed the rise of fentanyl analogs and xylazine. We may have even written about designer benzodiazepines such as bromazolam.¹ Bromazolam was first synthesized in 1976 and never was approved for human use.² It’s seizure by law enforcement has continuously risen since 2016. It is generally detected alongside opioids such as fentanyl, which is concerning as the combination of an opioid and benzodiazepine drastically increase the risk of overdose. At least one case series associated it with hyperthermia and seizures in three patients.³

More recently, nitazenes, a very potent opioid class, were found as adulterants in the drug supply. Nitazenes are actually an old class of opioids initially develop in a Swiss pharmaceutical laboratory in the 1950s.⁴ Due to their potency and high risk of addiction, they were never approved for human use. While nitazenes were first identified in the drug supply as far back as 1999, it was in 2019 when they really emerged in the illicit drug supply. Since then, the number of nitazenes found in the drug supply have only continued to increase. While some are scheduled, many are not, although none are explicitly legal for human use. As mentioned, they are very potent, which has garnered attention for potentially increasing the chance of overdose, particularly when found as an adulterant in non-opioids such as methamphetamine. Importantly, potency does not mean nitazenes are resistant to naloxone. To date, there is no evidence that naloxone will not reverse respiratory depressant effects from nitazenes, if administered in a timely manner.

Medetomidine was also detected in the drug supply recently. If medetomidine sounds familiar, it should, as it is a racemic mixture of levomedetomidine and dexmedetomidine. While medetomidine is only approved for veterinary use, dexmedetomidine is used as a sedative in hospitals and emergency departments every day. Since 2023, It has been increasingly found in the illicit drug supply⁵ with large outbreaks reported in Philadelphia, Pittsburgh, and Chicago in 2024 and first reported in human biologic samples in 2024.⁶  Medetomidine is expected to have similar clinical effects to dexmedetomidine. Importantly, it is not expected to cause wounds, which are associated with xylazine, a well-known adulterant with a very similar mechanism of action to medetomidine.

As opioids in the drug supply continue to increase in potency and more designer sedatives adulterate the drug supply, there is an increasing focus on improving the management of these patients. Normally, this involves a rant against the need for high dose opioid antagonists and certain long-acting antagonists. Instead, we’ll briefly discuss several studies evaluating the use of naloxone in cardiac arrest. Adults with nontraumatic out of hospital cardiac arrest (OHCA) were included as part of a retrospective cohort study in California.⁷ They compared patients that received naloxone to those that did not with the primary outcome of discharge from the hospital. Importantly, naloxone was administered at the discretion of the paramedics on scene. A drug-related arrest was determined by the treating EMS clinicians. However, this was not confirmed by hospital discharge diagnosis, hospital records, or any form of drug screen. How and when naloxone was administered was also not standardized. A total of 8,195 patients were included in the final analysis between 2015-2023. Of these, 715 (8.7%) were identified as a drug-related arrest. Naloxone was administered to 1,165 patients (14.2%). Demographics between the group that received naloxone and those that didn’t were substantially different. The authors determined that the group that received naloxone was more likely to obtain return of spontaneous circulation (ROSC) [34.5% vs 22.9%; p<0.001] and survive to hospital discharge (15.9% vs 9.7%; p<0.001). Overall, the authors concluded that naloxone was beneficial in both drug-related and non-drug related cardiac arrests.

A separate analysis included 769 consecutive  patients between 2017 and 2022 with OHCA in Camden County in New Jersey, an area with a large number of opioid overdoses.⁸ This retrospective study included patients treated by a single, hospital-based ambulance service who administered naloxone for any suspected opioid overdose. Like the prior study, the decision to administer naloxone was at the discretion of the EMS clinician. The authors compared patients that received naloxone to those that did not. Like the prior study, the two groups differed in a number of characteristics. However, in this study they did not find a difference in ROSC,  hospital discharge, or neurologically-intact survival between groups.

So, what does this mean? For me, I view naloxone as a critically useful drug but as a luxury so you don’t have to continuously bag the patient. What these patients die from is hypoventilation leading to a hypoxic arrest. As such, as long as the patient is being oxygenated and ventilated adequately, that is the critical intervention and not naloxone. Importantly, the patient must have some form of circulation for the naloxone to work. As such, standard resuscitation focusing on good CPR and resuscitation would appear to be what is important, much more than administering naloxone to this population, at least until better studies say differently. Now, you may ask, “well, what is the downside?” Well, if you have a lot of people helping and many extra hands, then it probably isn’t a big deal to also throw in some naloxone. However, if there aren’t that many people involved with the resuscitation or everyone is really busy or, for example, at my hospital where a single pharmacist is preparing all medications, then it is probably best to limit all non-necessary things and decrease the cognitive load of everyone and save naloxone for patients not in cardiac arrest.

References:

1. Aldy, K, Mustaquim D, Campleman S, et al. Notes from the Field: Illicit Benzodiazepines Detected in Patients Evaluated in Emergency Departments for Suspected Opioid Overdose-Four States, October 6, 2020-March 9, 2021. MMWR Morb Mortal Wkly Rep 2021;70(34):1177-9.
2. Manchester KR, Lomas EC, Waters L, et al. The Emergence of New Psychoactive Substance (NPS) Benzodiazepines: A Review. Drug Test Anal 2018;10(1):37–53.
3. Ehlers PF, Deitche A, Wise LM, et al. Notes from the Field: Seizures, Hyperthermia, and Myocardial Injury in Three Young Adults who Consumed Bromazolam Disguised as Alprazolam-Chicago, Illinois, February 2023; MMWR Morb Mortal Wkly Rep 2024;72(5253):1392-3.
4. Drug Enforcement Administration. Benzimidazole-Opioids Other Name: Nitazenes. January 2024. https://www.deadiversion.usdoj.gov/drug_chem_info/benzimidazole-opioids.pdf. Accessed on October 29, 2024.
5. Sisco E, Appley M. Identification of the Veterinary Sedative Medetomidine in Combination with Opioids and Xylazine in Maryland. J Forensic Sci 2023;68(5):1708-12.
6. Schwarz ES, Buchanan J, Aldy K, et al. Notes from the Field: Detection of Medetomidine Among Patients Evaluated in Emergency Departments for Suspected Opioid Overdoses-Missouri, Colorado, and Pennsylvania, September 2020-December 2023. MMWR Morb Mortal Wkly Rep 2024;73(30):672-4.
7. Dillon DG, Montoy JCC, Nishijima DK, et al. Naloxone and Patient Outcomes in Out-of-Hospital Cardiac Arrests in California. JAMA Netw Open 2024;7(8):e2429154.
8. Quinn E, Murphy E, Du Pont D, et al. Outcomes of Out-of-Hospital Cardiac Arrest Patients Who Received Naloxone in an Emergency Medical Services System with a  High Prevalence of Opioid Overdose. J Emerg Med 2024;67(3):e249-58.