Recommended Citation: Wahrenbrock T and Nelson M. The Toxic Shelf - High-Dose Buprenorphine Induction for Withdrawal [Internet]. Cook County Emergency Medicine Residency;Available from: https://cookcountyem.com/blog/2023/10/6/toxicology-corner-high-dose-buprenorphine-induction-for-withdrawal
The Case:
A 48 yo M with a past medical history of hypertension and heroin use disorder presents to the Emergency Department (ED) with body aches and vomiting since this morning in the context of 14 hours since last heroin used. You note the patient is diaphoretic and restless with moderately dilated pupils, rhinorrhea, and a slight tremor. You are concerned the patient is in withdrawal. He is interested in getting into a medication-assisted treatment (MAT) program; however, he is currently undomiciled and does not know if he can follow up outpatient tomorrow. Here we discuss options to treat the patient's withdrawal and help bridge to outpatient MAT.
Pathophysiology of Opioids, Naloxone, Buprenorphine, and Suboxone, Naloxone:
Most clinically relevant opioids are μ-opioid receptor agonists acting in the central and peripheral nervous system. μ-opioid receptor agonism causes analgesia in addition to sedation, respiratory depression, bradycardia, nausea and vomiting, and a reduction in gastric motility (1). Naloxone is a competitive inhibitor of the µ-opioid receptor. It reverses the effects of opioids and can precipitate opioid withdrawal (2). Buprenorphine is a potent partial agonist that attaches to and partially activates opioid receptors to ease withdrawal symptoms and cravings (1).
Buprenorphine outcompetes naloxone at the μ-opioid receptor. This can relieve precipitated withdrawal in the naloxone-treated opioid overdose patient (2). Suboxone is a combination of buprenorphine and naloxone. Naloxone is not absorbed orally but is absorbed intravenously. If injected, suboxone can lead to withdrawal due to the effects of naloxone. However, if taken sublingually, it is useful in treating opioid use disorder and withdrawal (2).
High-Dose Buprenorphine Induction for Withdrawal:
A high dose of buprenorphine is defined as more than 12 mg of sublingual buprenorphine during the ED stay. Most providers use 8 - 12 mg of buprenorphine during induction based on the Department of Health and Human Services guidelines developed for office-based practice. Most overdose or withdrawal patients in the ED will require higher doses, up to 32 mg, for effective opioid agonist (i.e., heroin/fentanyl) blockade.
High-dose induction also allows for faster therapeutic levels. You can get a therapeutic level within 4 hours as opposed to 2-3 days with the typical outpatient induction pathway. This timing could help increase safety by decreasing overdose or re-use between ED discharge and continuation of treatment in an outpatient setting. Herring et al. looked at an ED high-dose buprenorphine pathway and evaluated its safety and tolerability in 579 ED visits. There was no documentation of respiratory depression or the need to administer naloxone after induction, and no patients were admitted for buprenorphine precipitated withdrawal (3).
Figure 1. High-Dose Buprenorphine Treatment Pathway available Herring AA, Vosooghi AA, Luftig J, et al. 2021 (3)
Buprenorphine Induction after Opioid Reversal with Naloxone:
Patients who have overdosed and been reversed with naloxone, who have no suspected co-ingestions, who are not on methadone, who have a normal mental status, and who have the ability to provide consent can be treated with buprenorphine in the ED. Because buprenorphine has a higher affinity for μ-opioid receptors than naloxone, buprenorphine yields an increase in μ-opioid receptor agonism that relieves withdrawal symptoms after opioid reversal with naloxone. In addition, buprenorphine prevents return of full agonist (i.e., opioid) toxicity even if there are high concentrations of full agonists in the system because of its high-affinity and longer-acting μ-opioid receptor occupancy (4).
Figure 2. Hypothesized opioid/agonist withdrawal outcomes in two patients treated with high-dose buprenorphine in an immediate or delayed fashion courtesy of https://bridgetotreatment.org/addiction-treatment/ca-bridge/
Why should we treat withdrawal with buprenorphine?:
Mortality of patients who present to the ED with nonfatal opioid overdoses is high, especially within the first month and particularly within the first two days after overdose (5). It has low risks and high benefits. “The number needed to treat (NNT) with buprenorphine to prevent one death in the year after overdose is 52.6 — lower than the number needed to treat for nearly any medication that we have embraced without hesitation” (6).
1 in 2 patients treated with high-dose buprenorphine induction (>16 mg) will continue treatment compared to 1 in 3 (7-16 mg) and 1 in 4 (2-6 mg) for medium-dose and low-dose, respectively. Many factors may prevent patients from following up for outpatient MAT, so induction with a therapeutic level could help prevent overdose during the critical time between discharge from the ED and outpatient follow-up (3).
Figure 3. Buprenorphine protocol for use immediately following reversal of opioid withdrawal courtesy of https://bridgetotreatment.org/addiction-treatment/ca-bridge/
Take Home Points:
Precipitated withdrawal and withdrawal due to opioid abstinence are both appropriate times to initiate buprenorphine treatment in the ED (3). Buprenorphine following naloxone-reversed opioid overdose is safe and effective due to buprenorphine’s high-affinity opioid agonist blockade and ceiling effect on respiratory depression (4). High-dose induction of buprenorphine is safe, rapidly addresses withdrawal, and could help bridge the gap to outpatient MAT in patients experiencing social determinants of health that may prevent prompt follow-up (i.e., patients without insurance/underinsured, undomiciled, psychiatric disorders, etc.) (3).
Authored by Taylor Wahrenbrock, MD
Edited by Michael Nelson, MD
References:
Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain. 2012;6(1):11-16. doi:10.1177/2049463712438493
Kumar R, Viswanath O, Saadabadi A. Buprenorphine. [Updated 2023 Apr 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459126/
Herring AA, Vosooghi AA, Luftig J, et al. High-Dose Buprenorphine Induction in the Emergency Department for Treatment of Opioid Use Disorder. JAMA Netw Open. 2021;4(7):e2117128. Published 2021 Jul 1. doi:10.1001/jamanetworkopen.2021.17128
Bridge to Care Explainer: Buprenorphine after Opioid Overdose: ODNaloxoneBup. https://bridgetotreatment.org/wp-content/uploads/protocol-packet.pdf
Weiner SG, Baker O, Bernson D, Schuur JD. One-Year Mortality of Patients After Emergency Department Treatment for Nonfatal Opioid Overdose. Ann Emerg Med. 2020;75(1):13-17. doi:10.1016/j.annemergmed.2019.04.020
Poorman E. The Number Needed to Prescribe - What Would It Take to Expand Access to Buprenorphine? [published correction appears in N Engl J Med. 2021 Jul 29;385(5):480]. N Engl J Med. 2021;384(19):1783-1784. doi:10.1056/NEJMp2101298