Cite as: Hamza O, Basharat A, Potru S. Xylazine, nitazenes, and the changing street drug landscape: what pain physicians should know. ASRA Pain Medicine News 2026;51. https://doi.org/10.52211/asra020126.008.

Introduction

Patients in acute and chronic pain may resort to self-medicating using illicit opioids, which are sometimes combined with other substances when bought from unregulated street suppliers. The street drug supply is increasingly contaminated with potent synthetic agents that complicate clinical care, becoming more frequent and complex each year. Xylazine, nitazenes, medetomidine, and related compounds are now common in heroin, fentanyl, stimulants, and counterfeit pills (labeled as one substance but actually containing different substances).^1-3 These contaminated or counterfeit substances carry unique risks, including refractory overdoses, complex withdrawal syndromes, and physiologic instability that defies typical reversal strategies.^1,2 For interventional pain physicians, this has immediate and critical implications. Contaminant exposure can blunt sedation responses, mimic infection or withdrawal, and elevate procedural risks. This review highlights the most clinically relevant adulterants (including newer compounds like nitazenes and medetomidine) and examines regional patterns to help guide risk assessment and care planning.

Common Contaminants in Street Drugs

Xylazine

Breaking headlines in recent years due to the widespread contamination of illicit opioid supplies, xylazine is a veterinary alpha-2 agonist increasingly found in the illegal opioid supply, particularly in the Northeast.¹ In Philadelphia, over 90% of opioid samples contained xylazine by 2021.¹ It induces sedation, bradycardia, hypotension, respiratory depression, and necrotic skin lesions. Its synergistic effect with fentanyl complicates overdose reversal, as naloxone does not address xylazine’s alpha-2 agonist effects.¹ For interventional pain physicians, xylazine exposure can prolong sedation, increase hemodynamic instability, and obscure the clinical picture during procedures. Prescribers should remain vigilant when managing pain in patients who obtain opioids from unverified sources, such as street opioids or diverted prescriptions. In acute or peri-procedural settings where opioid analgesia is clearly indicated, prescribing a regulated opioid may still be necessary. In these situations, clinicians should assume possible exposure to adulterants such as xylazine, increase monitoring, involve toxicology consultation, and consider non-opioid or multimodal alternatives where feasible. This creates an ethical dilemma: While prescribing a regulated opioid may address undertreated pain, clinicians cannot ensure that patients will stop using unregulated street opioids, thereby risking continued exposure to adulterants. On the other hand, patients may resort to buying illicit opioids because their prescriber is refusing to prescribe them, inadvertently exposing themselves to contaminants while trying to relieve their pain.

Nitazenes

Nitazenes are highly potent synthetic opioids, often hundreds to thousands of times stronger than morphine and up to tenfold stronger than fentanyl.² Isotonitazene and metonitazene are common street analogs of the same class that are frequently mixed with fentanyl or pressed into counterfeit pills but sold as fentanyl.² They were initially developed in the 1950s but never approved for the market. Overdose on these street analogs may be resistant to typical opioid reversal methods, requiring multiple doses of naloxone, making them especially dangerous and often refractory to treatment.² The true prevalence of nitazene contamination remains underestimated due to significant limitations in routine toxicology screens.²

Medetomidine

Medetomidine, another veterinary sedative, has emerged as a novel adulterant since 2022.³ It acts as an alpha-2 agonist, similar to xylazine, causing sedation, hypotension, bradycardia, early hypertension that often transitions to hypotension, and respiratory depression.³ No FDA-approved reversal agent currently exists, and human effects remain poorly understood but mirror those of other alpha-2 agonists (with variable hemodynamic and sedative effects). In Missouri and Colorado, medetomidine was identified in several patients presenting to emergency departments for opioid overdose in 2022–2023.³ Like xylazine, it can work synergistically with opioids but not respond to reversal agents like naloxone and complicate procedural interventions with its highly variable effects and timing.

Regional Differences in Drug Contaminants

Drug contamination patterns vary significantly by United States region. In the Northeast and non-West regions, over one-third of synthetic opioid deaths now involve cocaine; in the West, methamphetamine co-involvement exceeds 50%.⁵ Xylazine first appeared in Puerto Rico and Philadelphia and is now implicated in overdose deaths across at least 43 states.⁷ Vermont and Connecticut report some of the highest xylazine-related mortality rates, with approximately 9-10 deaths per 100,000 residents.⁷

Medetomidine was first identified in overdose clusters in Missouri and Colorado and has since been detected in Pennsylvania, Chicago, and Pittsburgh.³ Its spread mirrors that of xylazine, with a regional impact initially that has become nationwide.

Nationally, overdose deaths dipped slightly between 2022 and 2023. However, this masks sharp regional divergence: While fatalities fell by 7.5% in the Northeast, Midwest, and South, fatalities increased by 14% in the West.⁵Polysubstance use among many patients with substance use disorder (SUD) is now the norm. In one European drug consumption room, over 20% of users combined heroin and cocaine, the so-called “speedball”.⁶ Similar trends are seen among patients in the United States who self-medicate using any illicit substances (street opioids, cannabinoids, etc.) from unverified non-medical sources for chronic pain.^5,6

For interventional pain physicians, these regional patterns matter both in medication prescribing and in the procedure suite. A patient in Massachusetts may be exposed to xylazine and cocaine; one in California may face methamphetamine-opioid combinations. Sedation planning, anesthetic risk, and even the interpretation of wounds (eg, distinguishing skin necrosis from infection) all hinge on knowing local street drug trends.⁵

Emerging Contaminants and Clinical Clues

New synthetic adulterants continue to enter the street drug supply. Brorphine, a potent µ-opioid receptor agonist, was linked to overdose deaths after its emergence in 2019 and has since declined, though analogs are expected.⁴ Veterinary sedatives like detomidine and acepromazine, along with unregulated benzodiazepines, are growing threats with very limited human data.³ It does appear that the synergistic effects of alpha-2 agonists are more frequently being introduced into opioid-specific drug supplies, making management difficult; supportive care remains the mainstay until alpha-2 reversal agent strategies are validated or tested. While not currently used in practice, yohimbine, phenoxybenzamine, or other alpha antagonists may be considered to reverse the effects of xylazine and medetomidine, particularly for patients in severe hemodynamic crisis, which is typically hypotension but may rarely include an early hypertensive phase due to peripheral vasoconstriction.

Patients exposed to contaminated street drugs may present with altered sedation response, hemodynamic instability, or necrotic skin wounds that mimic infection.

Clinicians should suspect adulterant exposure in patients with sedation unresponsive to naloxone, bradycardia, hypotension, or prolonged respiratory depression.^1,3 Xylazine is strongly associated with deep necrotic skin ulcers.¹ In contrast, nitazenes act as potent opioids and present with profound respiratory depression but usually without hypotension, while acepromazine primarily produces vasodilatory hypotension often with reflex tachycardia. Detomidine and related agents may cause an initial transient hypertension followed by prolonged hypotension and bradycardia, a profile distinct from pure opioid intoxication. Polysubstance users, particularly those combining opioids with cocaine or methamphetamine, may first present with agitation and hypertension but then progress into hypotension once opioid and alpha-2 agonist effects predominate.^5,6 Taken together, hypotension is often the most reliable distinguishing factor separating pure opioid overdose from opioid-adulterant intoxication, and awareness of these clues can help interventional pain physicians anticipate complications during sedation or recovery.

Practical Considerations for Pain Physicians

Patients exposed to contaminated street drugs may present with altered sedation response, hemodynamic instability, or necrotic skin wounds that mimic infection.^1,3 These complications increase the risk of neuraxial or moderately sedated interventions. Blunted responses to naloxone are common, particularly with alpha-2 agonists.^1,3 Pre-procedure evaluation should include a targeted history for illicit substance use and consider contaminant exposure in anesthetic planning. Clinicians should also remain vigilant in prescribing other agents outside of the opioid class, such as gabapentinoids, duloxetine, mirtazapine, and others, to further minimize the risks mentioned above (excessive sedation, inaccurate pain responses pre-procedurally, neurocognitive changes, physiologic/symptomologic medication changes affecting patient vitals). For gabapentinoids and mirtazapine, this caution reflects their well-established additive sedative and respiratory-depressant effects when combined with opioids. In the case of duloxetine, sedation is minimal; however, vigilance remains warranted because duloxetine is a moderate CYP2D6 inhibitor that can inhibit the conversion of certain prodrug opioids (eg, codeine, tramadol, hydrocodone) into their active metabolites, thereby reducing analgesic efficacy or altering toxicity profiles.⁹ Duloxetine also has serotonergic activity, which can rarely contribute to serotonin toxicity when combined with serotonergic opioids (tramadol, methadone) or stimulant-adulterated opioids.¹⁰ Thus, while duloxetine itself is not sedating, its pharmacodynamic and metabolic interactions with opioids justify inclusion in the risk assessment.

Polysubstance use is now typical. As previously noted, nearly one-third of fentanyl-related deaths in non-Western regions involve cocaine, and over half in the West involve methamphetamine.⁵ Clinicians should assess for concurrent stimulant or sedative use, which may alter vital signs, sedation depth, or withdrawal trajectory. Early collaboration with toxicology and addiction medicine can optimize procedural safety and postoperative care in high-risk patients, and clinicians can still initiate medication treatment of opioid use disorder (with buprenorphine, for example) in the pain clinic for both harm reduction and analgesic benefits.

Current Challenges

Routine toxicology panels do not detect many emerging adulterants, including xylazine, nitazenes, and veterinary sedatives.^1-3 Confirmatory testing is slow, often unavailable in outpatient settings, and rarely impacts real-time clinical decisions. At present, detection of these substances is only possible through specialized “send-out” toxicology testing performed at reference or forensic laboratories, which use liquid chromatography and/or mass spectrometry methods. In practice, clinicians who suspect exposure must request a specialty confirmatory assay through their hospital’s laboratory services, which then forwards the specimen (typically urine or blood) to an external lab. Turnaround time is measured in days rather than hours, limiting its usefulness for acute care. Rapid point-of-care strips for xylazine and nitazenes exist in harm-reduction settings, but they are not FDA-approved for clinical use. As a result, diagnosis in the clinical setting still depends heavily on careful history and suspicion, with confirmatory testing serving more for documentation, public health surveillance, or medico-legal purposes than immediate patient management.

Reversal options are limited. Naloxone does not reverse alpha-2 agonists, and ultra-potent opioids may require multiple administrations of naloxone before seeing any symptom changes.^1-4 No targeted antidotes currently exist for these compounds.

Withdrawal syndromes can be atypical. For example, xylazine withdrawal resembles autonomic rebound rather than opioid withdrawal, complicating peri-procedural management.¹ Intoxication and withdrawal may overlap, blurring clinical presentations.

Street drug composition shifts regionally,⁵ limiting the utility of uniform protocols. Pain physicians may encounter unfamiliar substances due to geographic variation, underscoring the need for regional awareness.

Finally, most clinic workflows do not screen for non-opioid adulterants or adjust sedation planning accordingly. Formalized collaboration with toxicology and addiction medicine remains rare. Together, these gaps highlight the potential benefits of regional surveillance, rapid diagnostics, multidisciplinary pain and SUD treatment, and updated procedural safety frameworks.

Conclusion

Emerging contaminants like xylazine, nitazenes, and medetomidine have fundamentally changed the risks associated with illicit opioid use. Polysubstance exposure is now common, and many of these agents are resistant to standard reversal methods.^1-5 For pain physicians, staying current on regional drug trends and associated clinical clues is essential. These exposures can alter sedation responses, increase periprocedural risks, and mislead diagnosis or treatment plans. Anticipating these variables can help improve procedural safety and patient outcomes.

References

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8. Friedman J, Montero F, Bourgois P, et al. Xylazine spreads across the US: a growing component of the increasingly synthetic and polysubstance overdose crisis. Drug Alcohol Depend 2022;233:109380.https://doi.org/10.1016/j.drugalcdep.2022.109380
9. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet 2009;48(11):689-723. https://doi.org/10.2165/11318030-000000000-00000
10. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352(11):1112-20. https://doi.org/10.1056/NEJMra041867