EMS brings in a patient who is reporting heroin withdrawal, so you reflexively give the patient an IV fluid bolus and Zofran, but he is now feeling worse. You try sublingual buprenorphine 8mg, and while the patient initially feels better, he is feeling even sicker a few hours later. What else may be going on? What other options are at your disposal to improve your patient’s symptoms?
Article:
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. 2024;85:130-139. doi:10.1016/j.ajem.2024.08.036
Background and Results:
Treating opioid use disorder is now harder than ever. With synthetic opioids like fentanyl and xylazine so widespread, caring for patients with opioid use disorder in the Emergency Department (ED) has become more challenging than ever. Fentanyl has largely replaced heroin in many places in the United States as the primary opioid in the non-medical drug supply chain. Xylazine, an alpha-two agonist sedative, has also found its way into the non-medical opioid supply. Xylazine is commonly mixed in with opioids to boost the depressive effects of opioids on the central nervous system and is frequently added to other illicit substances like cocaine as an adulterant. Xylazine has been linked to an increase in overdose deaths and has potentially lethal side effects, including hypotension, bradycardia, and bradypnea, as seen with opioids like heroin. Because xylazine is an alpha-two agonist and not an opioid, it cannot be reversed by naloxone, making it more challenging to manage in patients who present with overdoses.
Review of the literature demonstrated no standardized treatment plans to address xylazine withdrawal. Therefore, London et al. aimed to create a novel order set in hopes of reducing both COWS scores and rate of discharge in patients presenting with fentanyl and xylazine withdrawal.
This is a retrospective observational study after implementation of an order set to address acute fentanyl and presumed xylazine withdrawal in two urban hospitals in Philadelphia, PA. A set of Emergency and Addiction Medicine specialists convened to create four specific order pathways, which were developed into a wider set of guidelines that reflected consensus on treatment and evaluation of opioid and alpha-two agonist overdoses. The pathways were created with regards to severity of withdrawal, ability to gain IV access, and known or concern for prolonged QTc. The proposed order set was built into the electronic health record of the hospitals. The order set automatically ordered diagnostics (including urine immunoassay toxicological screening, which could test for fentanyl but not xylazine) and monitoring tests, such as ECGs and COWS scores. Their outcome measures included pre- and post-exposure COWS scores, disposition data, and any adverse events (events that occurred within 12 hours of administration of medication in the pathways). These pathways can be found in Figure 1.
There were 270 encounters during the study period where patients received treatment from one of the order sets and 177 who met all criteria for final analysis. The decrease in COWS score pre- and post-treatment was statically significant with a median pre-treatment COWS score of 12 and the median post-treatment COWS score of 4. They also looked at the impact of individual medications in the pathways and saw no statistically significant differences in COWS scores of any single medication being given or not given as compared to receiving all medications in the pathway. By using these pathways, the EDs had a significantly lower number of patients who left against medical advice (AMA) as compared to all patients who screen positive for opioid use disorder (3.9% versus 10.7%). However, the rate of AMA was still higher than the rate of the general census patients in the ED.
There were eleven patients who had adverse effects, though these all resolved without complication. There were two cases of dystonic reactions, two cases of fluid-responsive hypotension in patients with additional acute illness, three cases of asymptomatic bradycardia, one case of mild hypoxia requiring 2L of oxygen via nasal cannula, one patient that required non-invasive positive pressure ventilation in the setting of multifocal pneumonia, and one patient who had a seizure in the setting of concomitant benzodiazepine withdrawal. There were no cases of ventricular dysrhythmias, need for intubation, or precipitated withdrawal.
Discussion:
This paper presents a proposed pathway for treatment of presumed xylazine and fentanyl withdrawal in the ED. Overall, the researchers saw symptomatic improvement in patients, decreased rates of AMA, and no serious adverse reactions. However, there are several significant limitations of this study. For one, the researchers tested patients for fentanyl (100% positive testing rate), but they had no way to test for xylazine. It was presumed that this was an additional adulterant in patients who presented with opioid withdrawal because local data in Philadelphia, where the study took place, showed 98% of all non-medical opioid samples tested contained both fentanyl and xylazine.
Additionally, the amount of medication given was inconsistent. The specialists proposed multiple medications in each pathway, but there did not seem to be consensus on giving all of the medications versus one, as it was ultimately provider-dependent. The researchers reported that most patients received all medications in the delivered pathway, with the outlier being buprenorphine, which was provided in only around half of the cases. This is an unexpected finding given that buprenorphine is often considered a first-line medication for opioid withdrawal.
The researchers also did not specify why certain medications were placed into different pathways. For example, the mild and severe pathways both use a partial opioid agonist (buprenorphine), as well as a full opioid agonist (hydromorphone). However, the researchers do not clarify the rationale as to why patients in those groups received a low dose of buprenorphine in addition to a full opioid agonist. The dose of buprenorphine may also have been suboptimal, as the patients typically received 150mcg, which is a very low dose. For opioid withdrawal, full-dose or high-dose buprenorphine is more effective.
Overall, the proposed medications and pathways in this study are unlikely to be considered a reasonable treatment option for opioid and/or xylazine withdrawal. There are too many inconsistencies in medication selection and dosing to reliably depend on the data presented. To treat opioid and/or xylazine withdrawal, it would be better to continue providing higher and more adequate doses of buprenorphine, as well as an alpha-two agonist like clonidine as needed.
Expert Opinions from County-Trained Toxicologists and Addiction Experts:
Dr. Michael Nelson: I love the idea of this study, however these pathways are really suspect for management. If the patient is in significant opioid withdrawal, they should maximize the buprenorphine dose. They are giving extremely small doses of buprenorphine. Then they are giving full opioid agonists (oxycodone and hydromorphone). To make it "cleaner,” ideally they would maximize buprenorphine dose and then give an alpha-two agonist (e.g. clonidine, tizanidine) and none of the other stuff and see if that improves the outcomes or withdrawal symptoms. Their protocol is a bit too messy for my liking.
Dr. Toni Nemanich: Looking at the table, I think the study is flawed because they never treat with more than 150 mcg of buprenorphine even for "severe withdrawal." The adjuncts also seem too polypharmacy and rather random. It is interesting how they give alpha-two agonists like tizanidine and guanfacine, but odd that they don't use the more commonly used clonidine at all! I would not advise anyone to ever follow these doses in real patients. I would give proper loading doses of buprenorphine, followed by the usual adjuncts if needed (clonidine being the most relevant here, but also ondansetron, hydroxyzine, benzos, as appropriate). The agitation associated with xylazine withdrawal is usually responsive to benzos, and clonidine will help with HTN/tachycardia. Ketamine can be a helpful adjunct in most severe withdrawal syndromes, but I have never felt a need to use anything other than buprenorphine, clonidine, and benzos in opioid/xylazine withdrawal. COWS score should be at least 9 before loading with buprenorphine, and 8-16 mg should be given in that context. A lot of patients don't feel better because they aren't given enough buprenorphine, and it may have nothing to do with xylazine. Also, xylazine withdrawal tends to show up a little later. Typically, patients feel better after a loading dose of buprenorphine (I give 16mg followed by another 16mg 30 minutes later if they don't feel better.) They usually feel relief, but then if they go on to experience xylazine withdrawal, over the next 2-4 hours, they develop agitation that is usually responsive to benzos and clonidine. I think the proposed regimens above are overly complicated. Mechanistically, it doesn't make sense to me to give olanzapine at all. Also, I would reassure everyone that buprenorphine does not prolong the QTc! That's another thing that is overly overemphasized in this study.
Authored by Taylor Wahrenbrock, MD; Kathryn McGregor, MD; Eric Leser, MD; Michael Nelson, MD; and Antonia Nemanich, MD.
Further Reading:
Ayub S, Parnia S, Poddar K, Bachu AK, Sullivan A, Khan AM, Ahmed S, Jain L. Xylazine in the Opioid Epidemic: A Systematic Review of Case Reports and Clinical Implications. Cureus. 2023 Mar 29;15(3):e36864. doi: 10.7759/cureus.36864. PMID: 37009344; PMCID: PMC10063250
Gupta R, Holtgrave DR, Ashburn MA. Xylazine - Medical and Public Health Imperatives. N Engl J Med. 2023;388(24):2209-2212. doi:10.1056/NEJMp2303120