a b s t r a c t

Introduction: Buprenorphine precipitated Opioid withdrawal (BPOW) is an uncommon complication of bupre- norphine initiation in the emergency department (ED), but it can produce significant discomfort and be distressing to patients. As EDs continue to care for those with Opioid use disorder (OUD), clinicians should be aware of how to prevent and treat BPOW.

Objective: This narrative review provides an evidence-based update of the epidemiology, prevention strategies, and management of BPOW for the emergency clinician.

Discussion: BPOW is a rapid worsening of opioid Withdrawal symptoms upon initiating buprenorphine. BPOW can be prevented by waiting for the onset of moderate Clinical Opioid Withdrawal Scale (COWS) > 13 opioid withdrawal symptoms and a sufficient amount of time since last full opioid agonist use before buprenorphine ad- ministration. Risk factors for BPOW include chronic fentanyl use, methadone use, and concurrent benzodiazepine use. Alternative dosing strategies such as low-dose or “microdosing” and high-dose or “macrodosing” are options for buprenorphine that may impact the development of BPOW. The strategy of treating BPOW with more bupre- norphine has a pharmacological basis and has been effective in case reports. Additional management is symptom-based and supportive. Although most cases have a benign course, patients may be significantly less likely to use buprenorphine for OUD in the future or seek care for substance use disorder.

Conclusions: Appropriate initiation of buprenorphine is important to prevent BPOW. Dosing buprenorphine should be based on the patient’s patterns of opioid use and response to therapy. Management of BPOW should be symptom-based but include additional buprenorphine and adjunctive medications.

Published by Elsevier Inc.

1. Introduction

Buprenorphine is a highly effective medication for the treatment of Opioid use disorder in those with active opioid withdrawal (using the clinical opioid withdrawal scale [COWS]) and can reduce the morbidity and mortality associated with OUD [1-3]. A landmark study by D’Onofrio et al. in 2015 demonstrated reduced days of illicit opioid use and higher rates of engagement in outpatient addiction treat- ment following buprenorphine treatment in the emergency depart- ment (ED) [4]. In this study, 34% of patients presented to the ED seeking treatment for OUD, 25% reported only using prescription drugs, and 57% were not in severe enough withdrawal at the time of

* Corresponding author at: 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, USA.

E-mail addresses: [email protected] (A. Spadaro), [email protected] (B. Long), [email protected]. (J. Perrone).

presentation and took their first dose at home [4]. Additionally, all pa- tients in the buprenorphine arm received a brief intervention in the ED to enhance motivation to receive treatment for OUD [4]. Since the publication of this 2015 randomized controlled trial (RCT), many EDs have developed protocols for buprenorphine initiation, and other studies have demonstrated several aspects of ED buprenorphine initiation that are important for success such as handoff to a bridge clinic, post ED visit telephone calls, and active assistance navigating out- patient services [5-8]. In addition, retrospective studies have shown that buprenorphine initiation reduces repeat ED visits and all-cause hospitalizations [9-11].

Based on this literature and its efficacy, buprenorphine initiation in the ED is a vital component of managing those with OUD, as the ED serves as a critical access point within the healthcare system for these patients. Multiple protocols have been developed for buprenorphine use in the ED [5,12], and major clinical societies including the American College of Emergency Physicians (ACEP), American Academy of Emergency Medicine (AAEM), and American College of Medical

https://doi.org/10.1016/j.ajem.2022.05.013 0735-6757/Published by Elsevier Inc.

Toxicology (ACMT) support using buprenorphine in the management of OUD in the ED [13-15].

However, there is significant variation in buprenorphine administra- tion strategy in the ED setting. A 2021 study evaluated 31 protocols among different EDs. Thirty of 31 sites required a COWS score docu- mented prior to administration, 27 sites recommended a minimum COWS score of 8, with 3 sites recommending a minimum COWS score of 5, 11, or 12 [5]. For sites that did have recommendations for periods of abstinence prior to buprenorphine initiation, most recommended 12 h for short-acting opioids, 24 for long-acting opioids, and 48-72 h for methadone, with initial doses of buprenorphine ranging from 2 to 16 mg (most commonly 4 mg) [5]. Half of the protocols recommended an initial buprenorphine dose based on the severity of withdrawal, with 4 mg for COWS 8-12 and 8 mg for COWS >12 [5]. Of note, these proto- cols were developed before fentanyl became more prevalent in the drug supply. Surveys of emergency clinicians have also found many feel un- prepared in initiating buprenorphine and that lack of comfort with bu- prenorphine is a barrier to prescribing [16,17]. Additionally emergency clinicians may have the misconception that they cannot administer bu- prenorphine in the ED without an X-waiver [12]. However, short term treatment with direct administration of an opioid approved for use in maintenance or detoxification (e.g. methadone and buprenorphine) is allowed under the Drug Addiction Treatment Act of 2000, and the pa- tient may return to the ED daily to receive the medication for up to 72 h under the “3-day rule” [12].

While buprenorphine is safe and can reduce mortality in those with OUD, it may result in buprenorphine precipitated opioid withdrawal (BPOW). This syndrome is caused by the abrupt displacement of opioid agonist binding at the opioid receptor by exposure to the partial opioid agonist buprenorphine in a patient with Opioid dependence and resid- ual opioid effects from a full agonist [12]. Precipitated opioid with- drawal can also be induced by a less commonly used partial agonist nalbuphine or the opioid antagonists naltrexone and naloxone [12]. This manuscript reviews the pathophysiology of buprenorphine induc- tion and a potential complication, BPOW, not to discourage clinicians from prescribing buprenorphine, but to make them more comfortable with the nuances of its use.

1. Methods

This narrative review provides a focused overview of BPOW for emergency clinicians. The authors searched PubMed for English lan- guage articles 1977 to 2022 using the keyword and Medical Subject Heading “Buprenorphine Precipitated Withdrawal”, “Buprenorphine Precipitated Opioid Withdrawal”, or “BPOW” for production of this nar- rative review, including all papers that were observational studies, sys- tematic reviews, meta-analyses, narrative reviews, clinical guidelines, case reports, and case series. non-English language articles were ex- cluded. Initial literature search revealed 143 full text articles. Article in- clusion was determined by author review and consensus based on clinical relevance to ED evaluation and management. Additional articles relevant to buprenorphine initiation but not necessarily about precipi- tated withdrawal were selected based on author consensus. A total of 46 articles were determined to be of relevance to emergency clinicians by author consensus and included in this narrative review. Of the 46 ar- ticles included in this review, there were 2 randomized controlled trials, 14 observational studies, 3 society guidelines, 18 case series or case reports, and 9 review articles.

1. Discussion
   1. Pathophysiology

Buprenorphine has a unique pharmacologic profile as a partial mu- opioid receptor agonist with high affinity for the mu-opioid receptor but low intrinsic activity [12]. Buprenorphine also has antagonist

activity at the kappa-opioid and delta-Opioid receptors, which are in- volved in the spinal analgesic and dysphoric effect of agonists [18]. The partial agonism of the mu-opioid receptor relieves cravings, de- creases withdrawal symptoms, and treats pain with a ceiling effect on respiratory depression and euphoria compared to full opioid agonists [1,2]. Buprenorphine’s high affinity for the mu-opioid receptor causes it to displace lower affinity full agonists (e.g., heroin) which can lead to symptoms of withdrawal in patients with opioid dependance who have adapted to the presence of full agonism, as the partial agonism of buprenorphine will not be strong enough to prevent withdrawal symp- toms from the acute displacement of the full agonist [19]. Full mu- opioid agonists signal through both a G-protein and a beta-arrestin pathway [19]. The beta-arrestin pathway causes mu-opioid receptor down regulation contributes to physiological dependence and tolerance with chronic use, requiring higher doses of full agonists to achieve the same level of mu-opioid receptor activity [18]. Buprenorphine does not appear to signal through this beta-arrestin pathway contributing to its overall lower abuse potential [18]. Positron emission tomography (PET) studies of human subjects receiving buprenorphine indicate that there are threshold mu-opioid receptor availabilities needed to achieve withdrawal suppression and blockade of typical abused opioids, with lower concentrations needed to achieve withdrawal suppression [20]. BPOW symptoms start to develop 10-15 min after sublingual buprenor- phine and can last 8-24 h [2]. Anxiety, nausea, vomiting, diarrhea, and agitation can develop during BPOW [2]. BPOW is typically defined as an increase in COWS of 6 or more after receiving buprenorphine [21]. BPOW usually develops acutely after the administration of buprenor- phine, helping to distinguish from protracted withdrawal which is typ- ically defined as persistent withdrawal symptoms for 24 h after buprenorphine induction, although there are not well defined clinical criteria to distinguish the two entities [21]. Underlying psychiatric ill- ness such as schizophrenia, medical conditions such as gastroenteritis, or Substance use disorders such as benzodiazepine use disorder should be considered in patients who develop agitation, diarrhea, or anxiety after the administration of buprenorphine [21]. There have been case reports of Takotsubo cardiomyopathy and pulmonary edema from mas- sive Catecholamine release with BPOW [22-24]. Therefore, to avoid BPOW, patients seeking buprenorphine treatment must wait until they start experiencing withdrawal before initiating treatment [12]. Ad- ditionally, BPOW may discourage patients from continuing buprenor- phine [25]. Discontinuation of buprenorphine, even in the short term, has been associated with increased mortality [26]. Inducing or manag- ing a patient who experiences precipitated withdrawal may discourage ED clinicians from initiating buprenorphine in future patients with OUD.

• 1. Epidemiology and risk factors

In order to avoid BPOW, buprenorphine is typically not initiated until patients experience moderate to severe withdrawal, often defined as a COWS of 13 or greater; mild withdrawal is defined as a COWS 5-12 [2,21,27]. This presents a challenge for the initiation of buprenorphine for clinicians hoping to start buprenorphine during the acute care visit and for patients who want to minimize the amount of time they are experiencing withdrawal. Use of longer acting opioids such as metha- done and use of benzodiazepines has been associated with complicated inductions [21]. In one of the largest retrospective studies of buprenor- phine initiation in the office setting, close to 10% of patients experienced a complicated induction, although 90% of cases of BPOW occurred in patients using methadone [21]. A retrospective study including a convenience sample of buprenorphine inductions in the ED in the pre-fentanyl era found a BPOW rate of 0.8% [28]. There are additional concerns that the increasing prevalence of fentanyl in the illicit opioid supply can complicate buprenorphine induction [25,27,29-32]. Fentanyl is a highly lipophilic mu-opioid agonist, and although typically used as a short acting analgesic, it demonstrates prolonged renal clearance with chronic use [33]. One study estimated a higher odds of developing

Table 1

Conditions associated with the development of BPOW.

Table 3

Buprenorphine dosing regimens.

Medical Conditions

Chronic kidney disease, cirrhosis (through impaired CYP450 metabolism)

Standard Dose Regimen 1st dose:

COWS 8 to 12 and low risk of BPOW use 4 mg of

Opioid Use Methadone, fentanyl (chronic use)

Other Substance Use Benzodiazepine use

precipitated withdrawal when buprenorphine was started within 48 h of last fentanyl use compared to starting buprenorphine within 48 h of last methadone use (OR 3.3), despite its reputation as a long acting opioid [34]. Table 1 lists conditions associated with BPOW [21,33], and Table 2 lists patient characteristics associated with lower risk of BPOW [12,21,29].

• 1. Prevention strategies

The optimal strategy to prevent BPOW is appropriate patient assess- ment and selection when initiating buprenorphine. Guidelines can as- sist in determining patients appropriate for buprenorphine initiation [2,12-15]. Table 3 demonstrates different dosing regimen strategies, in- cluding a standard dose, low-dose or microdosing, and high-dose or macrodosing regimens [4,5,12,27-31,35]. Most protocols utilize a stan- dard dose regimen based on patient presentation using COWS, with the dose dependent on the score. Patients who are anxious or who re- port prior BPOW need additional reassurance that if BPOW occurs, they can be rapidly treated.

• • 1. Low-Dose or microdosing

An alternative strategy of preventing BPOW is to start at small “microdoses” of buprenorphine prior to the development of withdrawal from full opioid agonist use [35]. The pathophysiologic basis of low-dose buprenorphine is that the low-dose has enough activity to prevent and reverse the down-regulation of mu-opioid receptors that occurs with full agonists, allowing for more receptor occupancy by buprenorphine when increased doses are used which more effectively treats with- drawal symptoms [15,18-20]. Low-dose buprenorphine was first de- scribed by Hammig et al. as the “Bernese method”, initially as a strategy to avoid waiting for withdrawal to develop rather than

Low-Dose or Microdosing Regimen

High-Dose or Macrodosing Regimen

buprenorphine

COWS >12 and low risk of BPOW use 8 mg of buprenorphine

If at high risk for BPOW defer first dose until COWS >13

2nd dose: Reassess 30-60 min after first dose and give additional 4-8 mg of buprenorphine if improved but still having withdrawal symptoms

Discharge? on total dose given, to be taken daily until follow up

For COWS <13

1st dose:

Give 0.5 mg of buprenorphine (1/4 of 2 mg sublingual strip)?? with up titration plan based on symptoms

Discharge with following plan:

Day 1: 0.5 mg buprenorphine every 6-12 h

Day 2: 1 mg buprenorphine every 12 h

Day 3: 2 mg buprenorphine every 12 h

Can continue increasing on daily basis to 12 mg twice daily based on withdrawal symptoms (likely done by outpatient provider)

1st dose:

For COWS 8 to 12 use 4 mg of buprenorphine For COWS >12 use 8 mg of buprenorphine Reassess 30-60 min

2nd dose: for those at risk of POW, develop POW after 1st dose, or high opioid tolerance give 8-24 mg buprenorphine every 30-60 min for maximum dose of 32 mg

Discharge on 16 mg buprenorphine daily

avoiding the risk of BPOW [35]. It is difficult to predict which traditional starting dose of buprenorphine avoids precipitated withdrawal. A case series by Antoine et al. describes 4 patients who used fentanyl primarily and were induced on buprenorphine [30]. Two patients experienced BPOW when started on 4 mg of buprenorphine, and 2 patients were started on a lower dose regimen of 2 mg and did not experience BPOW [30]. However a case series of 3 patients who primarily used fen- tanyl reported 2 cases of BPOW with starting doses of 2 mg of buprenor- phine, indicating that 2 mg could still be too high a dose [32]. A feasibility study evaluated low-dose versus standard dose buprenor- phine [29]. Patients in the low-dose regimen received buprenorphine

0.5 mg twice daily and slowly increased to 12 mg twice daily by day 6, and the standard dose group received an initial dose of 2 mg and then up to 12 mg on the first day and staying at that dose thereafter [29]. More patients in the microdosing group 8/25 (32%) remained in therapy at 30 days compared to 5/21 (23.8%) in the standard dose group [29]. Of note in this study, if patients were in more severe withdrawal, defined

Table 2

Patient characteristics associated with low risk of BPOW.

No prior history of BPOW

History of previously tolerating buprenorphine

Short-acting opioid use (e.g., heroin) > 12 h ago (excluding chronic fentanyl use) Primarily using non-parenteral immediate release opioids (e.g. morphine IR,

Oxycodone IR)

Extended-release opioids (e.g., Oxycodone ER) > 24 h ago Methadone use >72 h ago

* Consider providing take home naloxone or discharging with a prescription for nal- oxone for all discharged patients with OUD.

?? Belbuca(TM), a buccal buprenorphine formulation that comes in 75 ug, 150 ug, 300 ug,

450 ug films can also be used, may have limited availability in outpatient pharmacies or hospital formularies.

as COWS >12, they were not eligible for the low-dose pathway [29]. A study of social media users who used low-dose buprenorphine to treat their OUD described self-guided low doses starting at 0.125-1 mg [31].

• • 1. High-Dose or macrodosing

A high-dose, or a “macrodosing” strategy, was described in 2021 to more rapidly stabilize patients on a dose of buprenorphine, rather than up titrate over 2-3 days [28]. This study was a retrospective chart review of patients in mild to severe opioid withdrawal at a center that had both a standard induction and high dose buprenorphine path- way [28]. The treating clinician determined clinical appropriateness of buprenorphine induction with initial doses of 4-8 mg and reassessment in 30-45 min, based on COWS score [28]. Additional doses up to 24 mg of buprenorphine were administered if withdrawal symptoms persisted on patient reassessment [20]. Of 579 patients there were 5 (0.8%) cases of BPOW [28]. Four of these cases occurred in patients who were treated on a standard induction pathway and received 8 mg total, and the fifth case occurred after a patient had received 32 mg of buprenorphine [28]. This study found a shorter length of stay in patients who were on the high-dose pathway, presumably due to faster control of withdrawal symptoms [28]. The results could be confounded by the non-random

nature of clinicians choosing the dosing regimen for their patients, but this could be a promising pathway for treatment of OUD. An additional case series of inpatients managed by an addiction medicine service re- ported on a buprenorphine induction method of starting with 16-20 mg of buprenorphine for patients with COWS >8 [36]. Of the 15 cases reported, there were no episodes of BPOW, 10 patients had relief of their withdrawal, and of the remaining 5 patients, 2 required an addi- tional 8 mg dose and 3 had persistent withdrawal [36]. Although the in- patient population is different than ED patients presenting with withdrawal, this provides additional evidence that a high dose of bupre- norphine did not lead to BPOW [36]. It also suggests that a high-dose buprenorphine pathway could start with 16 mg initially, rather than 4-8 mg [28,36]. High-dose buprenorphine should activate the majority of mu-opioid receptors even in patients with OUD who have chronic downregulation of their opioid receptors [37]. By activating a majority of the mu-opioid receptors, high-dose buprenorphine should cause enough agonism to prevent withdrawal [37]. A high-dose strategy may be more useful in a patient who will be discharged but will not have follow up within 24 h, as the higher dose may provide longer blockade from full-agonists and decrease withdrawal symptoms for a prolonged period of time [28]. Additionally, a low dose pathway might be considered in a patient who will be hospitalized and can be closely monitored, or in an outpatient with good follow up, a prior history of BPOW, and the ability to follow more complex tapering instructions [30,35].

• 1. Managing buprenorphine precipitated opioid withdrawal

While there are no randomized data to guide the management of BPOW, experience from the management of non-precipitated with- drawal as well as precipitated withdrawal from naltrexone and nalox- one can inform practice. Patient reassurance and a therapeutic alliance are an important foundation given that the first dose of buprenorphine caused these symptoms. Patients should be assured that treatment for precipitated opioid withdrawal is possible.

• • 1. Evidence for additional buprenorphine doses

Buprenorphine has been well established as an effective treatment for opioid withdrawal, and thus administering additional doses of bu- prenorphine may be used to treat precipitated withdrawal if the first dose of buprenorphine worsened symptoms [12]. A case report of BPOW from a failed low-dose buprenorphine cross-taper in a patient using fentanyl reported improvement in symptoms with 0.6 mg/kg IV ketamine and an additional 16 mg of buprenorphine [37]. Additionally, a case series of BPOW in patients using fentanyl reported improvement in 2 of the 3 cases with additional doses of buprenorphine, with the third case managed with hydromorphone [32]. Extrapolating from the management of naltrexone induced precipitated opioid withdrawal, 3 case reports and a case series described the use of buprenorphine to treat precipitated withdrawal, with resolution of precipitated with- drawal within hours using doses of 4-22 mg [38-41]. Buprenorphine has also been described as a treatment for naloxone precipitated opioid withdrawal in a case report in the ED [42]. There is a case series from the pre-hospital literature that describes 3 cases of precipitated withdrawal from naloxone, treated with 16 mg of buprenorphine with symptom improvement [43]. Another case report of a patient on methadone in precipitated opioid withdrawal from naltrexone reported improvement with 16 mg of buprenorphine [44]. In case reports of buprenorphine to manage BPOW, doses of 8-16 mg improved symptoms within 1-2h of receiving the additional doses.^27,436 Case reports of treating BPOW suggest starting doses of 8-24 mg of buprenorphine is likely a safe and effective option [27,38-46].

• • 1. Adjunctive medications

Non-opioid adjunctive medications to manage BPOW can be chosen based on the symptoms that occur during BPOW [12]. Expert reviews of

Table 4

Adjunctive medications for BPOW.

Symptom Medication

Nausea Ondansetron, Metoclopramide, Prochlorperazine

Diarrhea Loperamide

Abdominal Cramping Dicyclomine, Hyoscyamine

Myalgias Acetaminophen, Ibuprofen, Ketorolac

Anxiety Hydroxyzine, Clonidine, Diazepam, Lorazepam, Midazolam Agitation Haloperidol, Droperidol, Ketamine, Lorazepam

the management of OUD and society guidelines make recommenda- tions for different medications, although little high-quality evidence ex- ists [2,12,14]. Caution is needed when combining high doses or intravenous doses of benzodiazepines (e.g. 4 mg of intravenous lorezapam) with higher doses of buprenorphine (e.g. 16 mg buprenor- phine), as respiratory depression can occur [37,46]. Case reports de- scribe using ketamine and propofol for severe precipitated opioid withdrawal, although Close monitoring is needed [14,32,46]. A case re- port found that ketamine, at a dose of 0.2-0.3 mg/kg, might be particu- larly helpful in BPOW due to synergistic mu-opioid agonism with buprenorphine, antagonism at the N-methyl-D-aspartate (NMDA) re- ceptor decreasing hyperalgesia, and resensitizing the cell membrane to increase expression of previously downregulated mu-opioid recep- tors [37]. Table 4 provides a summary of medications that may be used for symptomatic therapy in BPOW. Some of the medications in Table 4 such as ondansetron and haloperidol can cause QTc prolonga- tion, and an EKG should be checked in accordance with hospital policy, particularly if the patient is on concurrent QTc prolonging medications such as methadone. Consider an outpatient prescription for naloxone for all patients with OUD who are discharged from the ED.

1. Conclusion

Buprenorphine is highly effective for the treatment of OUD but can cause precipitated opioid withdrawal in some patients. Longer acting opioid use such as methadone and chronic fentanyl use may increase the risk of BPOW. Low-dose or high-dose are alternative dosing options for preventing BPOW. BPOW can be managed with additional doses of buprenorphine, antiemetics, antihistamines, antispasmodics, ketamine, and benzodiazepines. Overall, BPOW is a relatively uncommon compli- cation from buprenorphine initiation and should not be a barrier to treating patients with OUD with buprenorphine.

Credit authorship contribution statement Anthony Spadaro: Validation, Visualization, Writing - original draft,

Writing - review & editing. Brit Long: Writing - review & editing, Visu-

alization, Validation, Supervision, Conceptualization. Alex Koyfman: Supervision, Validation, Visualization, Writing - review & editing, Con- ceptualization. Jeanmarie Perrone: Writing - review & editing, Writing - original draft, Visualization, Validation, Supervision.

Declaration of Competing Interest

None.

Acknowledgements

All authors conceived the idea for this manuscript and contributed substantially to the writing and editing of the review. This manuscript did not utilize any grants, and it has not been presented in abstract form. This clinical review has not been published, it is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including

electronically without the written consent of the copyright-holder. This review does not reflect the views or opinions of the U.S. government, Department of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.

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