Addiction Medicine in Serious Illness: Chapter2 - Xylazine, Medetomidine (“Tranq”) and the Complex Sedative Crisis Within the Fentanyl Epidemic

Over the past 18 months in my hospital practice, I have encountered something that continues to reshape how we approach addiction medicine: the growing presence of veterinary sedatives — most notably xylazine and medetomidine — in the illicit fentanyl supply.

While this topic is not hospice-focused, it represents a major public health challenge that directly intersects with acute care, addiction medicine, and systems-based response. At SimsRx, we believe in discussing what clinicians are actually seeing at the bedside — and this is one of those realities.

What Is “Tranq”?

Xylazine — often called:

• Tranq

• Tranq dope

• Zombie drug

• Sleep-cut

• Horse tranquilizer

— is a non-opioid veterinary sedative increasingly found in illicit fentanyl.

Medetomidine, another veterinary alpha-2 agonist sedative, is now being detected in some regions as well. Both are alpha-2 adrenergic receptor agonists, similar in pharmacologic class to clonidine and dexmedetomidine — but far more potent and not approved for human use.

Importantly:

• These agents are not opioids

• Naloxone does not reverse their sedative effects

• They are frequently mixed with fentanyl without the user’s knowledge

Incidence and Exposure Trends

Across many regions in the United States, xylazine exposure in fentanyl-related overdoses has risen dramatically. Many patients using fentanyl today are unknowingly exposed to sedative compounds in addition to opioids.

The clinical implication:

We are no longer treating “opioid withdrawal” alone.

We are treating combined opioid + sedative withdrawal syndromes.

The Clinical Reality: Severe Sedative Withdrawal

When patients stop using fentanyl contaminated with xylazine or medetomidine, they may experience a withdrawal syndrome that is:

• Severe

• Prolonged (up to 5–7 days or longer)

• Poorly understood

• Frequently mismanaged

Tell-Tale Clinical Signs of Alpha-2 Agonist Withdrawal

Because xylazine and medetomidine are alpha-2 agonists, withdrawal reflects adrenergic rebound:

• Severe hypertension

• Tachycardia

• Diaphoresis

• Anxiety and agitation

• Tremors

• Insomnia

• Restlessness

• Hyperreflexia

• Nausea/vomiting

• Severe subjective distress

Patients often describe it as:

“Worse than heroin withdrawal.”

Unlike pure opioid withdrawal — which is intensely uncomfortable but rarely medically dangerous — alpha-2 agonist withdrawal can be physiologically destabilizing.

Routine Testing Is Rarely Done

One of the greatest challenges:

• Xylazine is not routinely included on standard urine drug screens.

• Medetomidine testing is even less common.

• Many clinicians are unaware they are treating sedative withdrawal.

As a result:

• Patients are labeled “treatment resistant.”

• Withdrawal severity is underestimated.

• Inadequate regimens are used.

• Patients leave AMA due to uncontrolled symptoms.

This fuels mistrust and reinforces the fear that seeking treatment will only worsen suffering.

Why Traditional MOUD Alone Is Not Enough

Medications for opioid use disorder (MOUD) — such as buprenorphine or methadone — treat opioid withdrawal.

They do not treat sedative withdrawal.

However, because xylazine is commonly found in fentanyl, clinicians often initiate MOUD as monotherapy. When severe adrenergic symptoms persist, the assumption may be:

“The buprenorphine isn’t working.”

In reality, the opioid component may be improving — but the sedative withdrawal remains untreated.

You must manage both syndromes simultaneously.

Mechanism: Alpha-2 Agonism and Rebound

Xylazine and medetomidine suppress sympathetic outflow through central alpha-2 receptor agonism.

When abruptly removed:

• Catecholamines surge

• Sympathetic tone increases

• Blood pressure and heart rate spike

• Severe agitation and autonomic instability occur

This is similar in principle to clonidine withdrawal — but often more severe.

Treatment Strategies

1. Alpha-2 Agonist Replacement

Because the withdrawal mechanism is adrenergic rebound, treatment often includes:

• Clonidine

• Tizanidine (Zanaflex)

• Dexmedetomidine (Precedex) in severe cases

Clonidine and tizanidine can blunt sympathetic overactivity and reduce:

• Hypertension

• Tachycardia

• Anxiety

• Autonomic symptoms

However, outpatient management is often insufficient for severe cases.

2. Hospital Admission and Precedex Infusion

In moderate-to-severe withdrawal:

• Patients frequently require hospital admission.

• Dexmedetomidine (Precedex) infusions may be necessary to stabilize autonomic symptoms.

• Continuous monitoring is often required.

This is not standard opioid detox.

This is medical management of adrenergic instability.

Withdrawal can persist for up to a week, requiring careful tapering of alpha-2 agents to avoid rebound symptoms.

Leveraging Buprenorphine Microinduction During Severe Withdrawal

One of the most effective strategies I have used in practice is:

Initiating buprenorphine via microinduction during the acute withdrawal phase.

Why?

• It allows stabilization of the opioid component without precipitated withdrawal.

• It enables gradual receptor occupancy while sedative withdrawal is being managed.

• It transitions the patient toward long-term MOUD during hospitalization.

This approach allows us to:

1. Control sedative withdrawal medically.

2. Initiate therapeutic buprenorphine.

3. Discharge the patient on stable MOUD.

This will be the focus of our next chapter — a deeper discussion of buprenorphine microinduction in complex withdrawal states.

Why Methadone May Be Problematic

Many of these patients present with:

• Severe hypertension

• Tachycardia

• Electrolyte abnormalities

• Prolonged QTc intervals

Methadone — while effective for opioid use disorder — can:

• Prolong QTc further

• Increase arrhythmia risk

• Be difficult to titrate in unstable patients

In the context of adrenergic instability and electrolyte disturbances, methadone may be contraindicated or require extreme caution.

This is not a blanket rule — but a clinical reality we must assess carefully.

The Human Side: Why Patients Avoid Treatment

Many patients using fentanyl contaminated with xylazine:

• Have experienced horrific withdrawal.

• Were told “it’s just opioid withdrawal.”

• Were inadequately treated.

• Left the hospital suffering.

They are scared.

If we do not understand this syndrome, we reinforce that fear.

When we manage both components properly, something remarkable happens:

• Trust builds.

• Symptoms improve.

• Engagement in treatment increases.

Final Thoughts

The illicit drug supply has changed.

Our clinical approach must change with it.

Xylazine and medetomidine exposure have transformed withdrawal management from a primarily opioid-centered model into a complex, dual-syndrome challenge requiring:

• Recognition

• Alpha-2 agonist management

• Hospital-level stabilization when needed

• Strategic buprenorphine initiation

In our next chapter, we will explore buprenorphine microinduction in detail — including protocols, timing, and how to safely initiate therapy during severe withdrawal states.

At SimsRx, we believe clinical excellence must evolve with emerging realities. If we are going to reduce suffering, we must first understand what patients are truly experiencing.

Donald F. D’Aquila, PharmD, MBA, BCGP, RRT
Founder, SimsRx
Medicine Minds Blog Series