Our toxicology mini-fellowship meeting last week was all about bupe (buprenorphine)! Here is a brief review of the key points of discussion.
Why does this matter?
As emergency physicians, we are on the frontline in caring for patients with opioid use disorder (OUD). These patients come to the ED for acute care both related and unrelated to their substance use disorder – sometimes for withdrawal, sometimes for overdose, and other times for toe pain and headaches and chest pain, just like everyone else. They trigger our biases, challenge our compassion, and are often perceived as our most difficult patients. Those treated in the ED for opioid overdose have a staggeringly high one-year mortality of 5.5% [1]. In short, we have both the opportunity, and with buprenorphine in our toolbox, the means to work toward saving the lives of these patients.
Buprenorphine: pharmacology, safety, and efficacy
Buprenorphine has been approved for office-based medication-assisted treatment and opioid substitution therapy (MAT/OST) of OUD since 2000 [2]. Widespread use is limited by the requirement for practitioners to complete an 8-hour course and to add an X-waiver to their DEA license for outpatient prescribing. However, let that not deter you from learning to love it! Buprenorphine may be ordered for patients both in the ED and on the wards by non-X-waivered clinicians, and as we speak, a bipartisan-backed bill. The Mainstreaming Addiction Treatment Act (House Resolution 2482), seeking to X the X-waiver, is working its way through Congress.
What makes buprenorphine so effective? Its pharmacology! Buprenorphine, commonly known as “bupe”, is a partial agonist at the mu-opioid receptor. It displays minimal euphoric reward effects while creating a ceiling effect on both sedation and respiratory depression [3]. At doses of 8-16 mg, buprenorphine is effective at suppressing opioid withdrawal symptoms. In contrast to methadone, bupe does not prolong the QT interval [2]. These features likely play key roles in the significantly reduced rates of buprenorphine abuse and diversion, as well as the relative safety of its use [4].
Multiple randomized controlled trials have supported the safety and efficacy of MAT/OST with buprenorphine. In studies comparing bupe to placebo, clinically and statistically significant differences have been observed in admission and retention in addiction treatment programs [5], self-reported frequency of opioid use and cravings [5,6], and opioid-positive urine samples [6].
Across multiple studies, patients receiving buprenorphine for MAT have been found to have significantly reduced rates of all-cause and opioid-related mortality compared to patients not receiving MAT/OST [7,8]. Larochelle et al found a 12-month all-cause mortality of 3.0% (95% CI 2.2% to 3.9%) in patients receiving buprenorphine and 4.9% (95% CI 4.5%-5.3%) in patients not receiving MAT/OST [7]. From this data, we can calculate a number needed to treat (NNT) for MAT/OST of 55 (95% CI 34 – 174).
ED-based induction
While no definitive approach to ED dosing strategies exists, a reasonable approach is outlined in Herring et al [3]. Patients must be experiencing at least moderate symptoms of opioid withdrawal prior to initiation of buprenorphine to ensure that bupe-precipitated withdrawal is avoided. The clinical opioid withdrawal scale (COWS) is well-validated and displays good inter-rater reliability. With apps such as MDCalc, it is not difficult to calculate, however, visual analog scales of single questions such as “feeling sick” may perform just as well [9]. Most protocols use COWS of 7-8 as their cutoff for bupe administration.
*Image retrieved from Herring et al (3)
Doses of 2-4 mg of buprenorphine should be administered, and patients should be reassessed every 30-60 minutes for repeat dosing. A target of 16 mg should be achieved for most patients, which will result in protection from opioid withdrawal symptoms for up to 24 hours. Doses up to 32 mg can be considered for patients with significant barriers to follow-up in order to allow a longer duration of relief from withdrawal symptoms.
If the administration of buprenorphine does precipitate withdrawal symptoms, the treatment is – you guessed it – more buprenorphine! So, do not fear the bupe. Embrace the bupe.
Once a target dose of buprenorphine has been administered in the ED and clinical withdrawal is resolved, discharge planning hinges on the availability of an X-waivered prescriber and the timeliness of chemical dependency follow-up. Provide a prescription for 16 mg sublingual buprenorphine/naloxone daily for 3-7 days or until follow-up appointment (if known). If no X-waivered clinicians are available, patients may be instructed to return to the ED for daily doses of buprenorphine until follow-up is available. Some EDs maintain lists of X-waivered clinicians who are willing to co-sign prescriptions of buprenorphine for patients in need.
Kings County hot tips: We have Subutex (buprenorphine) sublingual tablets and Suboxone (buprenorphine-naloxone) sublingual films on formulary. The ED Leads team, if present, will also help walk you through the process. All patients should be endorsed to the chemical dependency team and referred for follow-up prior to their discharge to ensure a seamless transition of care.
Additional considerations
Buprenorphine is relatively safe in pregnancy and should be provided to pregnant women with OUD, an opinion recently supported by ACOG (10). The US Food and Drug Administration rates buprenorphine/naloxone category C (potential benefits should outweigh potential risks) (11). Neonatal abstinence syndrome does occur in infants of mothers treated with buprenorphine but tends to be less severe than in mothers taking full opioid agonists. Further, the benefits of OST are thought to far outweigh the risks of continued opioid use for both mother and fetus (10).
It has been suggested that the treatment of naloxone-precipitated withdrawal with buprenorphine could provide both symptomatic relief from withdrawal and a rapid transition to OST for patients requiring it (12). While some hospital systems have begun treating naloxone-precipitated withdrawal with high doses (16-24 mg) of buprenorphine, scant published evidence currently exists, and we await better data before adopting this practice.
SUMMARY/Take-Home Points
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♠ Buprenorphine is safe and highly efficacious in the treatment of opioid withdrawal.
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♠ Buprenorphine therapy demonstrates an all-cause and opioid-related mortality benefit to patients suffering from OUD.
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♠ Provide bupe at initial doses of 2-4 mg to patients experiencing at least moderate withdrawal symptoms and reassess at 30-60 minute intervals.
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♠ Use COWS or a simple visual analog scale (VAS) to assess the severity of withdrawal.
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♠ A target dose of 16mg of buprenorphine should be administered on induction to provide up to 24 hours of protection from withdrawal symptoms and cravings.
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♠ Consider higher doses (up to 32 mg) for patients with significant barriers to follow-up.
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♠ Know the chemical dependency follow-up available to your patients at your facility, and ensure an adequate supply of buprenorphine until follow-up is available.
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♠ Find out who has an X-waiver in your ED.
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♠ The use of buprenorphine for naloxone-precipitated withdrawal OR as rescue therapy for opioid overdose requires more evidence before it is widely accepted but is exciting nonetheless.
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References
1. 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
2. Nelson LS, Olsen D. Opioids. In: Howland MA, Hoffman RS, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank’s Toxicologic Emergencies. 11th ed. McGraw-Hill; 2019.
3. Herring AA, Perrone J, Nelson LS. Managing Opioid Withdrawal in the Emergency Department With Buprenorphine. Ann Emerg Med. 2019;73(5):481-487. doi:10.1016/j.annemergmed.2018.11.032
4. Yokell MA, Zaller ND, Green TC, Rich JD. Buprenorphine and buprenorphine/naloxone diversion, misuse, and illicit use: an international review. Curr Drug Abuse Rev. 2011;4(1):28-41. doi:10.2174/1874473711104010028
5. D’Onofrio G, O’Connor PG, Pantalon M V, et al. Emergency department-initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial. JAMA. 2015;313(16):1636-1644. doi:10.1001/jama.2015.3474
6. Fudala PJ, Bridge TP, Herbert S, et al. Office-based treatment of opiate addiction with a sublingual-tablet formulation of buprenorphine and naloxone. N Engl J Med. 2003;349(10):949-958. doi:10.1056/NEJMoa022164
7. Larochelle MR, Bernson D, Land T, et al. Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality: A Cohort Study. Ann Intern Med. 2018;169(3):137-145. doi:10.7326/M17-3107
8. Sordo L, Barrio G, Bravo MJ, et al. Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ. 2017;357:j1550. doi:10.1136/bmj.j1550
9. Tompkins DA, Bigelow GE, Harrison JA, Johnson RE, Fudala PJ, Strain EC. Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. Drug Alcohol Depend. 2009;105(1-2):154-159. doi:10.1016/j.drugalcdep.2009.07.001
10. Committee on Obstetric Practice. Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy. Obstet Gynecol. 2017;130(2):e81-e94. doi:10.1097/AOG.0000000000002235
11. Rappaport BA. SUPPLEMENT APPROVAL FULFILLMENT OF POSTMARKETING REQUIREMENT NDA 022410/S-004, S-017, S-018. Silver Spring, MD; 2014. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/022410Orig1s004,s017,s018ltr.pdf.
12. Haroz R, Carroll GG, Strayer RJ. Treatment Strategies for Precipitated Opioid Withdrawal after Naloxone Rescue. ACEP Now. https://www.acepnow.com/article/treatment-strategies-for-precipitated-opioid-withdrawal-after-naloxone-rescue/. Published 2020. Accessed August 20, 2020.
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