‘Dope’ is no longer heroin in an increasing number of our communities. The biggest change has been the gradual replacement of diacetylmorphine (heroin) by fentanyl and other synthetic opioids. Due in large part to the proliferation of anonymous chemical factories able to produce industrial volumes of inexpensive synthetic opioids without opium or other controlled precursors, fentanyl spilled into the United States, Canada, and Europe, heroin soon fell to market forces [1, 2]. Along the same time, a veterinary sedative, xylazine, became popular in Puerto Rico in individuals who used injection drugs [3]. An alpha-2 receptor agonist mechanistically similar to clonidine, dexmedetomidine, and tetrahydrozoline, xylazine made its way to the U.S. and settled in the metropolitan areas of the Northeast, especially my community, Philadelphia. The combination of the two now represents more than 98% of samples tested by the City of Philadelphia and has been given the moniker ‘tranq dope’ [4]. 

Case

A patient arrives via EMS from the bus station complaining of fever, vomiting, and back pain. Their back has worsened significantly over the past 24 hours with radiation down the left leg. They report insufflating ‘a bundle’ of tranq dope per day. They report occasional cocaine and amphetamine use more than 72 hours ago, but no other substances. They report an allergy to ‘bupe,’ describing a prior episode of ‘precipitated withdrawal’ when given buprenorphine, despite already withdrawing.

Vital signs

• T 39.5C
• BP 180/90
• HR 140
• RR 24 (oxygen saturation 99% room air)

Exam

• General: Diaphoresis, piloerection, psychomotor agitation, and actively vomiting
• Eyes: Dilated pupils
• Cardiac: No murmur
• Back: Focal tenderness at L1 and L2
• Neurologic: L hip flexion weakness
• Extremities:
  • Several necrotic, ulcerative wounds on their arms and legs without secondary signs of infection
  • Lymphedema of distal arms and legs with early venous stasis changes

Breaking down the case

“A Bundle”

• Understanding how much patients use can help us understand how likely their withdrawal is to be severe.
• Our experience: A Philadelphia Bundle is 14 bags, most other cities are 10 bags. One bag has been approximated anywhere from 25-100 morphine milligram equivalents (MME), meaning use of a bundle (or two) a day is equivalent to use of hundreds to thousands of MME, vastly more than has ever been encountered in human history. Anyone using “bundles” (or more than a few bags per day) is at risk of significant withdrawal if they abruptly stop.
• Clinical impact: This patient is likely having severe symptoms of withdrawal from cessation of their regular use.

The Wounds

• Common among patients who use xylazine, the necrotic and exudative wounds are still not fully understood [5-8], but are likely due in part to direct cytotoxic effects of the drug and its impurities, as well as possible nutritional deficiencies common in those with dependence.
• Our experience: Oddly, though injection drug use is certainly associated with wound location, injection use is not required for their development, and they have been noted in patients who solely insufflate or smoke their substances. While superinfection is common due to the myriad social determinants of health challenges individuals who use these drugs face in trying to care for them — when the wounds look uninfected, they typically are and respond better to local wound care, nutritional support, and long-term monitoring than obligatory IV antibiotics or surgical debridement. The wounds themselves may not be infected or require surgical management themselves, but can act as an entry point to deeper infections. We treat with wound care and reserve surgical management only for limbs that are no longer viable. IV antibiotics do not help treat the wounds unless there is evidence of other skin/soft tissue infection (City of Philadelphia’s excellent wound care guide).
• Clinical impact: The case patient’s wounds were cleaned and dressed with petroleum jelly based wound ointments and enzymatic salves for the necrotic portions. Inpatient wound care teams provided long-term support and a nutrition consult ordered protein, micronutrient, and vitamin supplementation.

Lymphedema (Puffy Hands & Feet)

• Our experience: After we noted a cohort of admissions for suspected endocarditis were found to be reassuringly negative, we noted this physical exam finding as strikingly common. Evaluation for nephrotic syndrome due to viral hepatitis, endocarditis, venous thromboembolism or other cause of chronic lymphedema is reasonable.
• Clinical impact: The patient’s DVT ultrasounds were negative. A trans-esophageal echocardiogram showed a normal ejection fracture, normal right ventricular function, and no vegetations.

Bupe Allergy

• Buprenorphine induction has been the mainstay of emergency department treatment of opioid use disorder for more than a decade [11, 12].
• Our experience: It was not long ago that we instructed our staff that: ‘COWS >8, give ’em 8 (mg of buprenorphine).’ We witnessed our prior protocols become ineffective, even at very large doses (16 mg over 2 hours with adjuncts) in patients who were already in severe withdrawal. Similarly, dramatic but idiosyncratic episodes of ‘precipitated withdrawal’ were noted in some patients who had used tranq dope in the past 48-72 hours. Patients with moderate withdrawal became dramatically worse within short periods, noted both in the community and in our department [13, 14]. Confounding this is a high-quality analysis in an area with high fentanyl and unknown xylazine intensity not demonstrating this phenomenon [15]. Akin to real-life ghost stories told by patients, the risk is not insignificant, and the concern warranted by patients. We have seen cases of esophageal rupture from vomiting and stress cardiomyopathy in association with these phenomena. While fentanyl is more lipophilic than other opioids, and a depot effect may play a role in long term users, this condition, its pathophysiology, and its relation to xylazine or other contaminants remains unknown.
• Clinical impact: Rather than arguing with the patient about the likelihood of this phenomenon occurring and whether this is a true allergy, the patient is informed that they do not need to immediately start treatment to receive care in the hospital. That discussion can be deferred until the patient is stable, the risk of such an event is mitigated, and other medications can be given for their withdrawal symptoms and pain.

Multi-Substance Use

• Substances such as cocaine, amphetamines, and benzodiazepines often are used concurrently, which can confound the management plan. Urine/serum toxicology screening can show additional substances that they don’t know they’ve been using, which can help them receive recovery services when medically stable. Of note, screening is often required for insurance approval for substance use treatment.
• Our experience: Traditionally, ED physicians do not like ordering urine drug screens (UDS). Whether due to the non-specific nature of the results, a low likelihood of changing management, or a genuine concern that ordering UDS is a form of stigmatizing patients, it has been a change of practice for us to encourage ordering (and provide EHR decision support) for UDS testing in patients who use drugs. Bundled ordering has not only opened our eyes to the use patterns in our community, but has streamlined the referral to substance use treatment for thousands of patients in our health system. Pairing fentanyl screening to our standard UDS has also allowed us to see the ubiquity of its use; patients are now routinely screening negative for conventional opiates despite using enormous amounts of tranq dope.
• Clinical impact: For the patient case, the UDS was negative for conventional opiates but positive for cocaine. You call the lab and request fentanyl testing, which is a send-out test. A social worker stops you in the hall and thanks you for ordering the UDS as they go see the patient.

How to Think About This Case of Tranq Dope Withdrawal

The patient is likely experiencing opioid withdrawal [MDCalc Clinical Opioid Withdrawal Scale (COWS) score] and some degree of xylazine withdrawal. We recently published a retrospective observational study of a novel implementation medication order set for fentanyl & xylazine withdrawal, which provide insights into managing this case [16].

1. Xylazine withdrawal is controversial.

There are no prospectively developed or articulated xylazine withdrawal scales. Some experts wonder if what we deem xylazine withdrawal is actually due in large part to the large doses of synthetic opioids consumed, or due to coexisting stimulant withdrawal. We have certainly seen patients who have pain which is controlled and still have psychomotor agitation and sympathetic activation, leading some to require ICU admission for dexmedetomidine and/or ketamine infusion. In our study, we used COWS alone in the ED, which does utilize restlessness, anxiety, and tachycardia as part of the formula, as the sole evaluation tool for tranq dope withdrawal.

2. Medication opioid use disorder (MOUD) induction needs to be done carefully.

We advocate for an approach that uses low dose (or micro-induction) of buprenorphine. We use a product that contains solely buprenorphine at a range of low doses, called Belbuca. This allows us to administer a safe dose of buprenorphine. This low dose initiation strategy did not result in any cases of precipitated withdrawal, and still provided kappa opioid receptor antagonism, which is postulated to help modulate psychological components of dependence.

Alternatively, one can cut the 2 mg Suboxone (buprenorphine + naloxone combination) strips into 4 pieces after waiting for a longer washout period (72-96 hours of abstinence from non-medical opioids) before starting the induction. Or one can start methadone induction.

3. Short-acting, full mu agonist opioids are part of the solution.

In our study, we administer full mu agonists for tranq dope withdrawal, but others in our community also use a combination of short and long-acting full mu agonists.

In our study protocol, dosing started at oxycodone 10 mg PO (update: I now recommend 20 mg) or hydromorphone 2 mg IV for more severe cases. These doses do not come close to replacing their daily opioid use. Some patients require re-dosing in the ED. Most admitted patients end up on patient-controlled analgesia (PCA) pumps early in their course of admission when their use patterns are severe (≥ 1 bundle/day).

4. Acknowledge that short-acting opioids are insufficient on their own.

In our study order set, we intentionally incorporated the concepts of potentiation and synergism to stretch the effects of short-acting opioids (oxycodone PO or hydromorphone IV) while also treating the associated symptoms of opioid and xylazine withdrawal. We also incorporated:

• Ketamine
• Neuroleptic medications (droperidol IV and olanzapine ODT)
• Alpha 2 agonists (tizanidine and guanfacine)
• Diphenhydramine
• Lactated ringers IV solution

Differentiation was based on severity, presence of an IV, and concern for prolongation of the QTc >450 msec (Table 1).

We did not use clonidine, despite its known alpha agonist utility in opioid withdrawal, due to the undifferentiated nature of our patients receiving the pathways, not wanting to give an antihypertensive agent to patients who sometimes are experiencing shock and other critical illness. Clonidine is often added back to their regimens inpatient as their vital signs tolerate.

When patients received treatment with one of our four our pathways, there was an association with a significant decrease in post-treatment COWS scores and the risk of patient-directed discharge (renamed from ‘against medical advice’ disposition to remove the stigmatizing connotation [17]) .

Table 1. Multimodal medication options for fentanyl-xylazine withdrawal management in London et al. 2024 study [16]. Prolonged QTc was defined as >450 msec.

5. Treatment protocol update: Adding gabapentin with concurrent stimulant use

In our study, more than 70% of our patients used multiple substances, including cocaine and amphetamines [16]. Because the withdrawal syndromes from stimulants can also produce anxiety and sympathetic activation, we have now added GABAergic medications (gabapentin 300 mg PO) to our pathways, given the commonality of coexisting stimulant use disorders.

6. When all else fails, choose harm reduction.

Even in the best-case scenarios, some patients may not be able or willing to stay for their full treatment. While we may not convince them, it does not mean we cannot make a positive contribution to their health. Consider the following discharge adjuncts to give the patient:

• Nasal naloxone
• Fentanyl test strips
• Wound care supplies
• Safe injection equipment
• Connection to syringe service programs or other community groups (which are both likely less expensive than the hospital and less traumatizing for patients)

Case Conclusion: Tranq dope withdrawal and spinal epidural abscess

For the patient with back pain and severe tranq dope withdrawal symptoms, you order the following:

• Buprenorphine 150 mcg buccal
• Hydromorphone 2 mg IV
• Ketamine 10 mg IV
• Olanzapine 10 mg ODT
• Tizanidine 4 mg PO
• Diphenhydramine 25 mg IV
• Gabapentin 300 mg PO (given UDS being for cocaine)
• IV fluids 1 L bolus

With an unknown QTc interval, you avoid droperidol IV. Your patient ultimately is diagnosed with a spinal epidural abscess requiring operative care. Post-operatively, the care team includes an addiction medicine consultant and certified recovery specialist (an individual with lived experience of addiction, who advocates for and connects others to recovery services; also called peer recovery specialists or recovery coaches [20, 21]).

The patient’s buprenorphine doses are titrated up as their pain stimulus decreases. They are also given screening exams for viral hepatitis, HIV and STIs, and are offered PrEP (pre-exposure prophylaxis for HIV). Despite myriad challenges due to out of state insurance, the patient is connected with a rehabilitation center that provides both physical and substance recovery services. A dedicated addiction and medical bridge clinic is available to the patient following their rehabilitation stay, connecting them to long term care, including treatment for their newly diagnosed hepatitis C. They reconnect with family and community members who were lost to them, building a sustainable support system.

Last Words

Substance use disorders (SUD) are similar to other chronic relapsing medical conditions such as diabetes mellitus, congestive heart failure/cardiomyopathy, chronic obstructive pulmonary disorder, and cancer. While all share a combination of genetic, developmental, and cognitive risk factors, only SUD has been demonized societally as a behavioral failure, rather than just another consequence of cascading social and medical determinants of health.

Treating patients with SUD can be incredibly challenging, especially without a foundation in trauma-informed care principles [20]. Stigma occurs on both sides of the therapeutic relationship, and the poor coping strategies that lead individuals to use injection drugs can malign even tolerant clinicians in such highly charged situations. Strategies to mitigate these challenges include adding certified recovery specialists to care teams, standardizing/improving withdrawal management, and having a holistic addiction medicine team that can provide patient-centered, tailored MOUD and comorbidity guidance.

We are now seeing further contamination in our drug supply, such as other veterinary sedatives (such as medetomidine), novel benzodiazepines (such as bromazolam) and even an industrial solvent (called BTMPS or Tinuvin 770). Psychosis is now being witnessed with naloxone reversal in some cases, and the impact of these novel contaminants on withdrawal syndromes and wounds remain unknown.

If this is reaching your community and you have additional questions, feel free to contact me. I am happy to help how I can.

References

1. Reuter P, Pardo B, Taylor J. Imagining a fentanyl future: Some consequences of synthetic opioids replacing heroin. International Journal of Drug Policy. 2021 Aug 1;94:103086. PMID 33423915
2. Pesce A, Bevins N, Tran K, Thomas R, Jensen K. Changing Landscape of Fentanyl/Heroin Use and Distribution. Annals of Clinical and Laboratory Science. 2023 Jan 1;53(1):140-2. PMID 36889767
3. Torruella RA. Xylazine (veterinary sedative) use in Puerto Rico. Substance Abuse Treatment, Prevention, and Policy. 2011 Dec;6:1-4. PMID 21481268
4. Education, T.C.F.F.S.R. Drug Checking Quarterly Report (Q3 2022). Philadelphia, Pennsylvania, USA. 2022; 06/26/2023.
5. Wei J, Wachuku C, Berk-Krauss J, Steele KT, Rosenbach M, Messenger E. Severe cutaneous ulcerations secondary to xylazine (tranq): a case series. JAAD Case Reports. 2023 Jun 1;36:89-91. PMID 37274146
6. Sloan B. This month in JAAD Case Reports: August 2023: Xylazine and skin necrosis. Journal of the American Academy of Dermatology. 2023 Aug 1;89(2):231. DOI:
7. Papudesi BN, Malayala SV, Regina AC. Xylazine toxicity. 2023 [book]. PMID 37603662
8. Rose L, Kirven R, Tyler K, Chung C, Korman AM. Xylazine-induced acute skin necrosis in two patients who inject fentanyl. JAAD Case Reports. 2023 Jun 1;36:113-5. PMID 37288443
9. Bishnoi A, Singh V, Khanna U, Vinay K. Skin ulcerations caused by xylazine: A lesser-known entity. Journal of the American Academy of Dermatology. 2023 Aug 1;89(2):e99-102. PMID 37054812
10. Janardan A, Ayoub M, Khan H, Jha P, Dhariwal MS. Mysteriously puffy extremities: an unintended consequence of intravenous drug abuse. Cureus. 2022 May;14(5). PMID 35774687
11. D’Onofrio G, Chawarski MC, O’Connor PG, et al. Emergency department-initiated buprenorphine for opioid dependence with continuation in primary care: outcomes during and after intervention. Journal of general internal medicine. 2017 Jun;32:660-6. PMID 28194688
12. D’Onofrio G, O’Connor PG, Pantalon MV, et al. Emergency department–initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial. JAMA. 2015 Apr 28;313(16):1636-44. PMID 25919527
13. Sue KL, Cohen S, Tilley J, Yocheved A. A Plea From People Who Use Drugs to Clinicians: New Ways to Initiate Buprenorphine Are Urgently Needed in the Fentanyl Era. J Addict Med. 2022;16(4):389-391. PMID 35020693.
14. Starting Bupe From Fentanyl Can Be a Nightmare. Microdosing Methods Help, 2020.
15. D’Onofrio G, Hawk KF, Perrone J, et al. Incidence of precipitated withdrawal during a multisite emergency department–initiated buprenorphine clinical trial in the era of fentanyl. JAMA Network Open. 2023 Mar 1;6(3):e236108-. PMID 36995717
16. London K, Li Y, Kahoud JL, et al. Tranq Dope: Characterization of an ED cohort treated with a novel opioid withdrawal protocol in the era of fentanyl/xylazine [published correction appears in Am J Emerg Med. 2024 Oct 8:S0735-6757(24)00523-0. doi: 10.1016/j.ajem.2024.10.006]. Am J Emerg Med. Published online September 4, 2024. doi:10.1016/j.ajem.2024.08.036. PMID 39260041.
17. Lee CD, Mello MM, Bradfield O, Beach MC. Discharging Patients Against Medical Advice. N Engl J Med. 2023;388(13):1230-1232. doi:10.1056/NEJMclde2210118. PMID 36988605
18. Vakkalanka P, Lund BC, Arndt S, et al. Association Between Buprenorphine for Opioid Use Disorder and Mortality Risk. Am J Prev Med. 2021;61(3):418-427. doi:10.1016/j.amepre.2021.02.026. PMID 34023160
19. London K, Matsubara J, Christianson D, Gillingham J, Reed MK (September 12, 2024) Descriptive Analysis of Emergency Department Patients With Substance Use Disorders As Seen by Peer Recovery Specialists in Philadelphia. Cureus 16(9): e69274. DOI
20. Bartholow LAM, Huffman RT. The Necessity of a Trauma-Informed Paradigm in Substance Use Disorder Services. J Am Psychiatr Nurses Assoc. 2023;29(6):470-476. PMID 34334012