Medetomidine Webinar – Questions and Answers

General questions

Question: Medetomidine as a veterinary drug has an approved reversal agent (atipamezole)- has consideration been given to using this reversal agent for human overdose reversals? Are there policy changes that support implementation of a medetomidine reversal?

Atipamezole can reverse the acute effects of medetomidine or dexmedetomidine by displacing these drugs from alpha-2 adrenergic receptors. However, atipamezole is not approved for use in humans by the US Food and Drug Administration (FDA). In addition, in patients who are dependent on medetomidine, giving atipamezole can lead to hypertension, tachycardia (heart rate over 100 beats per minute), and other signs and symptoms of medetomidine withdrawal. Medetomidine withdrawal has the potential to be life-threatening, and therefore the administration of atipamezole and subsequent possible induction of withdrawal could be dangerous.

The FDA is responsible for reviewing safety and efficacy data on new drugs and their website has information on how this process works and how they can be contacted for further information.

Question: Have they (speakers from Pennsylvania) had any mass hospitalizations? For example, days when they've had a spike in admissions.

While there has not been a specific day with an increase in presentations for medetomidine withdrawal in Philadelphia, the Philadelphia Department of Public Health reported seeing a 134% increase in the number of emergency department (ED) visits across the city's EDs for withdrawal from the first quarter 2024 to the first quarter 2025.

As described in an MMWR report, in Chicago on Saturday, May 11, 2024, there were 50 emergency medical services (EMS) responses, mostly clustered on Chicago's West Side, for suspected opioid-involved overdoses. Across three Chicago Emergency Departments over that weekend and the following week, from May 11-17, 181 patients were treated for suspected opioid-involved overdose. Consistent with opioid overdose, most patients had altered mental status, most had pinpoint pupils, and many had hypoxemia (low oxygen levels). Less consistent with previous experience with opioid overdose, many patients had only partial improvement of symptoms with naloxone, and many had bradycardia, with some requiring atropine for bradycardia. Initial toxicologic tests from samples of bagged powders held by five of the patients being treated for overdose in the emergency department (ED) detected medetomidine mixed with fentanyl, in varying concentrations and ratios. Among the 38 patients determined to have confirmed or probable overdoses involving medetomidine mixed with opioids, 16 were admitted to the hospital.

Question: Do you think the decrease in overdose deaths is due to the lower level of opioids found in the drug supply as a result of the increased presence/addition of xylazine and medetomidine?

There are likely multiple reasons for the decrease in overall opioid-related overdose deaths seen nationally starting in 2023. The reasons for changes in fentanyl's share of the drug supply are unclear. It is possible that replacement of fentanyl with other substances including xylazine and medetomidine reflects reduced fentanyl or precursor availability in the illegal drug supply chain.

Recent Publication: Dowell D, Nataraj N, Rikard M, Park J, Zhang K, Baldwin G. Why have overdose deaths decreased? Widespread fentanyl saturation and decreased drug use among key drivers. The Lancet Regional Health – Americas, Volume 0, Issue 0, 101226. doi: 10.1016/j.lana.2025.101226

Question: How addictive is medetomidine?

Medetomidine is a mixture of levomedetomidine and dexmedetomidine. A withdrawal syndrome associated with dexmedetomidine use is reported in the medical literature and emerging evidence suggests a withdrawal syndrome associated with medetomidine as well. Addictive potential is likely related to various factors such as concentration, dose, length of use, route of exposure, purity of drugs and others.

Question: Have you seen any fatalities attributed solely to medetomidine?

Testing limitations make it difficult to attribute any reported fatalities in CDC's SUDORs data solely to medetomidine.

Question: Have there been any reported fatalities?

Doctor Perrone and Doctor Huo have reported some fatalities after hospitalized patients experienced complicated withdrawal, though it is difficult to pinpoint these deaths as being caused solely by medetomidine withdrawal.

Question: Have patients reported getting a free sample, of a substance that might have contained medetomidine, prior to hospitalizations?

Doctor Perrone and Doctor Huo report hearing that from some of their patients.

Diagnosis and treatment

Question: Naloxone dose in case series is just over 5 mg; was that intranasal formulation? (references slide)

We cannot confirm the formulation in the case series, as the authors do not report on that.

Question: Can you please repeat the description of delirium seen with medetomidine withdrawal?

From webinar (Dr. Huo): "The delirium that we've seen has been hypoactive. It almost feels like the patient is just too sick to talk.... They're really not talking much, and they're lying there, looking very uncomfortable, diaphoretic (sweating heavily), shaking."

Question: Can you please confirm if the lack of respiratory depression is not typical from medetomidine alone (probably in combination with other sedating substances)?

Medetomidine does not cause respiratory depression, though it can cause significant central nervous system depression through agonism at the alpha-2 receptor (thereby inhibiting norepinephrine release) and compromise respiratory status in that manner. Therefore, naloxone, an opioid antagonist, does not reverse the effects of medetomidine. Naloxone should be given whenever there is respiratory depression in an overdose that may involve opioids. In overdoses where the patient is experiencing respiratory depression and medetomidine is suspected to be involved, naloxone should be given, as to date, these overdoses have also involved opioids such as fentanyl, and naloxone will reverse the respiratory depression contributed by opioids.

Question: Can you confirm that in the case there was little/no contribution of imidazoline effect either toxicity or withdrawal?

The alpha-2 agonism effects are likely contributing to sedation and bradycardia (slow heart rate) as a result of use or excess drug dose and is likely mediating the withdrawal syndrome.

Question: Can you define severe hypertension and the frequency of severe hypertension? The slide presented stated sickest patients.

The case series that Philadelphia presented described the median values and range of blood pressures that were observed. Based on these numbers, many patients met criteria for severe hypertension. Several met criteria for hypertensive emergencies. There were three patients with imaging-confirmed Posterior Reversible Encephalopathy Syndrome (PRES) (though there were more patients who experienced altered mental status and blood pressures of >180/20, without imaging confirmation of PRES). Only health system C collected data on troponins; they found that 39 patients had positive high-sensitivity troponins, 10 patients had normal/negative troponins, and 10 patients did not have a troponin level checked.

Question: Dr. Huo mentioned the frequent need for treatment for severe hypertension. Any particular agents to be used, or avoided?

Doctor Perrone and Doctor Huo report using intravenous and titratable antihypertensive medications such as nicardipine and rarely esmolol. In most cases, though, aggressive use of dexmedetomidine is sufficient to control severe hypertension, and they have started using higher dosing of dexmedetomidine and boluses to be able to do so.