a b s t r a c t

Background: The safety of combining buprenorphine with a benzodiazepine or barbiturate in the treatment of concurrent alcohol and Opioid withdrawal has not been well established. In this study we examine a cohort of patients treated with buprenorphine and phenobarbital or benzodiazepines for co-occurring opioid and alcohol withdrawal.

Methods: This is a retrospective cohort study of ED patients treated for opioid and alcohol withdrawal from Jan- uary through December 2018. The primary outcome was unexpected airway intervention, or the administration of naloxone for respiratory depression.

Results: There were 16 patients treated for opioid and alcohol withdrawal. The mean age was 44.3 (standard de- viation [SD] 13.1), 12 (75.0%) were male, and 8 (50.0%) of the patients were admitted to the hospital. For opioid withdrawal, six patients received intravenous buprenorphine, with doses between 0.3 mg to 1.8 mg; 12 patients received Sublingual buprenorphine, with doses between 4 mg to 32 mg. For alcohol withdrawal, 10 patients re- ceived lorazepam with doses between 1 mg and 8 mg; 10 patients received phenobarbital with doses between 260 mg to 1040 mg. There were no unexpected airway interventions related to medications used for opioid or alcohol withdrawal. One patient with severe pneumonia was an expected intubation for respiratory failure.

Conclusions: We describe a cohort of patients treated for opioid and alcohol withdrawal in the ED. There were no serious adverse events related to the medications used to treat opioid or alcohol withdrawal. Further work should assess optimal use of medical therapy for opioid and alcohol withdrawal and the transition to mainte- nance treatment for Substance use disorders.

(C) 2020

1. Introduction

Opioid and Alcohol use disorders are epidemics in the United States affecting millions of individuals. Alcohol is associated with 88,000 US deaths annually, making alcohol the third leading preventable cause of death in the United States. [1] Opioid use disorder has been declared a public health emergency, with over 47,000 opioid involved drug over- dose deaths per year in the United States. [2] Emergency department (ED) providers frequently manage alcohol and opioid withdrawal. There is uncertainty, however, on the best practices for the medical management of co-occurring opioid and alcohol withdrawal, as the medications involved with treating these withdrawal syndromes – opi- oid agonist or partial agonists and Sedative-hypnotic medications – can lead to respiratory and cardiovascular compromise. Until recently, ben- zodiazepine use was considered a contraindication for buprenorphine

* Corresponding author at: Alameda Health System, Highland Hospital, Department of Emergency Medicine, 1411 East 31st Street, Oakland, CA 94602, USA.

E-mail address: smahmoud@alamedahealthsystem.org (S. Mahmoud).

treatment, however emergency clinicians do not infrequently face the clinical reality that alcohol withdrawal and opioid withdrawal com- monly occur and that treatment of severe alcohol withdrawal com- monly necessitates Large doses of benzodiazepines or phenobarbital. [3] For ED patients, buprenorphine and methadone are the preferred treatment options for opioid withdrawal, and benzodiazepines and bar- biturates are the main treatments used for alcohol withdrawal. Metha- done has fallen out of favor among ED providers more recently, as the safety profile and effectiveness of buprenorphine has been demon- strated in the literature specifically in the ED setting [4,5]. Buprenorphine, as a partial agonist at the u-opioid receptor, also has a unique “ceiling effect” on respiratory depression and sedation; how- ever, it is unclear as to whether this safety profile remains in the setting of concurrent treatment for alcohol withdrawal with benzodiazepines

or phenobarbital. [6,7]

To our knowledge, there have been no reports in the literature discussing the management of patients presenting with both alcohol and opioid withdrawal in the emergency department, or the risks posed by administering buprenorphine along with other sedatives or

https://doi.org/10.1016/j.ajem.2020.12.074

0735-6757/(C) 2020

anxiolytics. Herein, we describe a retrospective cohort study of patients who received treatment for acute opioid and alcohol withdrawal syn- dromes in a single, urban ED. We sought to determine the rate of emer- gent interventions, defined as unexpected airway intervention or naloxone reversal, that were temporally related to the administration of medications for the treatment of opioid or alcohol withdrawal.

1. Methods
   1. Study design

This is a retrospective cohort study of patients who were treated for alcohol withdrawal and opioid withdrawal during the same emergency department visit between 1/1/2018 and 12/31/2018. This study was ap- proved by the Highland Hospital – Alameda Health System (AHS) Insti- tutional Review Board with a waiver of written informed consent. The primary outcome was documentation of an adverse event potentially attributable to the combination of buprenorphine and a benzodiazepine or phenobarbital. We defined an adverse event as documented clinically significant respiratory depression, use of reversal agents such as nalox- one or flumazenil, supportive airway interventions such as addition of supplemental oxygen, bag-valve-mask ventilation, or any unexpected advanced airway maneuver (endotracheal intubation or placement of a supraglottic airway) within 2 h of treatment with either buprenorphine, a benzodiazepine, or phenobarbital. We followed STROBE guidelines for observational studies.

• 1. Study setting and population

Highland Hospital is a large urban, safety net teaching hospital in Oakland, California with an accredited Emergency Medicine residency program. The Highland Hospital ED has a well-established program for the initiation of buprenorphine for patients with opioid use disorder and linkage to long term addiction treatment, as well as harm reduction initiatives for patients who use injection drugs.

• 1. Selection of participants

Adult patients >=18 years were eligible for inclusion if they were treated with buprenorphine for opioid withdrawal and if they were treated with either lorazepam or phenobarbital for alcohol withdrawal as documented by the clinician. We obtained data from the electronic health record (Wellsoft Corporation, Somerset, NJ) for all patients who received buprenorphine during their ED visit as part of a larger cohort study on patients being treated for opioid withdrawal. We did not in- clude patients who received methadone, as we sought to describe the interaction of buprenorphine with medications for alcohol withdrawal. Within this cohort of patients, we selected patients who received a ben- zodiazepine or phenobarbital, as these are the medications used to treat alcohol withdrawal in the ED at our institution. Patients were excluded if they were given a sedative-hypnotic (either a benzodiazepine or bar- biturate) for reasons other than alcohol withdrawal.

• 1. Data abstraction

We conducted an initial pilot abstraction period of 50 charts to en- sure internal validity, and created a standardized data abstraction form. The data abstraction form contained variables related to the patient’s ED visit, including clinical and demographic information, as well as detailed data regarding the patient’s substance use treatment. This chart review contained specific adverse events related to intoxica- tion or over-sedation with buprenorphine or other medications co- administered during the ED visit. If not documented, adverse events were considered to be absent. Two research assistants blinded to the study hypothesis conducted the chart reviews, and the principal inves- tigator reviewed additional charts to generate a value for inter-rater

reliability. Frequent meetings were held between abstractors and dur- ing abstraction to clarify any data points, which were adjudicated by committee from study staff.

• 1. Data analysis

Descriptive analyses were performed for all variables. Categorical data are reported as numbers and percentages and continuous data are reported as means with standard deviation (SD). When appropriate, absolute differences in proportion with 95% confidence intervals (CI) were calculated. Cohen’s kappa statistic for interrater reliability was found to be 0.9-0.1 (p < 0.001) for primary and secondary reviewers over the master cohort of patients administered buprenorphine. All analysis was performed in Stata version 13.1 (Statacorp, College Station, TX).

1. Results

There were 640 patients that received buprenorphine in the ED, 54 of whom were also administered either phenobarbital or lorazepam. There were 37 patients who were excluded because they were given a sedative-hypnotic for anxiety, all of whom were given oral lorazepam; 1 patient was excluded for presenting with opioid and benzodiazepine withdrawal. This left a cohort of 16 patients treated for both opioid and alcohol withdrawal in the ED. Characteristics of patients included can be found in Table 1. The mean age was 44.3 (standard deviation [SD] 13.1), 12 (75.0%) were male, 5 (31.2%) were Black, 4 (25.0%)

were Hispanic/Latino, and 6 (37.5%) were white; 8 (50.0%) of the pa- tients were admitted to the hospital. Of the patients admitted to the hospital, 5 were admitted to the medical/surgical floor, 1 was admitted to the step-down unit, and 2 were admitted to the intensive care unit (ICU). One of the patients who was admitted to the ICU was intubated for pneumonia. The ED length of stay for patients who were discharged from the ED was 466 min.

Table 2 shows the doses of buprenorphine, lorazepam, and pheno- barbital that were administered to each patient. 6 patients received in- travenous buprenorphine, doses ranged from 0.3 mg to 1.8 mg (median 0.3, IQR 0.3-0.9); 12 patients received SL buprenorphine, doses ranged from 4 mg to 32 mg (median 12 mg, IQR 7-16). 10 patients received in- travenous lorazepam, doses ranged from 1 mg to 8 mg (median 3, IQR

Table 1

Characteristics of patients being treated for alcohol and opioid withdrawal.

	Patients N = 16* (%)
Age, mean (SD), y	44.3 (13.0)
Age 25-34	4 (25.0)
Age 35-44	5 (31.3)
Age 45-54	3 (18.8)
Age 55-70	4 (25.0)
Race/Ethnicity Black	5 (31.3)
Hispanic/Latino	4 (25.0)
White	6 (37.5)
Other	1 (6.3)
Gender Male	12 (75.0)
Female	4 (25.0)
Insurance Public	15 (93.7)
None	1 (6.3)
Disposition Med/Surgical Admit	5 (31.3)
Step Down Admit	1 (6.3)
ICU Admit	2 (12.5)
Discharge	8 (50.0)

SD, standard deviation; y, year; ICU, intensive care unit; Med/Surgical, medical surgical floor unit.

Table 2

Medications and disposition for patients treated for alcohol and opioid withdrawal.

pharmacotherapy involved, though there were also patients in the study who received more than 520 mg of phenobarbital and more

Patient Buprenorphine Lorazepam

IV

	SL (mg)	IV (mg)		(mg)		(mg)
A	–	0.3		–		1040	Discharge
B	16	–		1		–	Med/Surg
C	32	–		–		260	Discharge
D	–	0.3		–		1040	Med/Surg
E?	–	0.3		5		–	ICU
F	16	–		2.5		1040	Med/Surg
G	16	–		0		520	Discharge
H	12	0.3		3		0	Discharge
I	8	–		–		260	Discharge
J	0	1.8		3		520	ICU
K	6	–		1		–	Discharge
L	4	0.9		8		1040	Step Down
							Unit
M	8	–		6		–	Discharge
N	4	–		4		–	Med/Surg
O	24	–		–		1040	Discharge
P	12	–		3		260	Med/Surg
Median	12	0.3		3 (2.5-5)		780
(IQR)	(7-16)	(0.3-0.9)				(260-1040)

Phenobarbital IV

Disposition

than 8 mg of buprenorphine and were able to be discharged home. It is likely that in the setting of uncomplicated withdrawal syndromes, the severity of alcohol withdrawal or other underlying acute medical presentations are the driver of admissions from the ED.

In this manuscript, we also note that the medications were adminis- tered over prolonged ED visits, suggesting that patients with alcohol and opioid withdrawal present a challenging clinical scenario for clini- cians even when they are managed as outpatients. The average length of stay in the cohort was nearly 8 h, and providers should recognize that the dosing of medications for alcohol and opioid withdrawal should be carefully administered in divided doses. Four patients in our cohort were treated with intravenous and SL buprenorphine, which has not previously been described in the emergency medicine literature. Future work should examine the relative benefits of treating patients for opioid withdrawal with intravenous buprenorphine in the acute care setting. Intravenous buprenorphine seems to have a similar safety profile to SL buprenorphine, with faster peak plasma levels, which may be useful for patients with severe symptoms in the ED. [8]

It is important to note that buprenorphine is used for both acute opi-

SL, sublingual; IV, intravenous; mg, milligrams; IQR, interquartile range.

Med/Surg indicates an admission to the medical/surgical floor unit, ICU indicates an ad- mission to the intensive care unit, and Step Down Unit indicates an admission to the step down unit.

* Patient required intubation for pneumonia and acute respiratory distress syndrome.

2.5-5), and 10 patients received intravenous pHenobarbital, doses ranged from 260 mg to 1040 mg (median 780 mg, IQR 260-1040).

There was only 1 patient who required intubation within 30 min of buprenorphine administration, though this was an expected intubation due to progressive pneumonia. The patient who was intubated used 2 g of intravenous heroin per day, and drank an unspecified amount of alco- hol daily. The patient was admitted for pneumonia, and progressed to have acute respiratory distress syndrome and septic shock. The pro- viders documented planning for intubation due to hypoxic respiratory failure after the patient failed non-invasive ventilation, and then or- dered 0.3 mg intravenous buprenorphine for opioid withdrawal 29 min prior to intubation, and two doses of lorazepam intravenously

– 1 mg 45 min prior to intubation, 2 mg 34 min prior to intubation. The patient received an additional 2 mg of lorazepam more than three hours after intubation. The care team noted the patient’s Work of breathing did not change after treatment with buprenorphine or loraz- epam, and used etomidate and rocuronium for rapid sequence intubation.

1. Discussion

In this retrospective cohort study, we describe the clinical course and pharmacologic details of patients’ treatment for both opioid and alcohol withdrawal in the ED. Patients were treated with a range of doses of both medications; the median dose of SL buprenorphine was 12 mg, the median dose of IV buprenorphine was 0.3 mg, the median dose of lorazepam was 3.6 mg, and the median dose of phenobarbital was 520 mg. One patient was intubated within 2 h of buprenorphine and lorazepam administration, though this was determined to be due to the patient’s severe pneumonia and acute respiratory distress syn- drome, as opposed to the medications used for opioid and alcohol with- drawal. This is the first manuscript to describe the treatment of both withdrawal syndromes with relatively high doses of Pharmacologic therapy.

Patients with co-occurring opioid and alcohol withdrawal syn- dromes are often medically complicated to manage, and half of our study cohort required inpatient admission for further care, 1 of whom was admitted to the ICU. This may be due to the complex

oid withdrawal and maintenance therapy. While the medications de- scribed in this manuscript for alcohol withdrawal are not used for the treatment of alcohol use disorder, future work should consider optimal therapies for transitioning to pharmacotherapy and psychosocial thera- pies for patients with alcohol use disorder in addition to opioid use dis- order. In our ED, we have been implementing a protocol for the treatment of alcohol and opioid use disorders using buprenorphine and gabapentin; an approach that treats both use disorders and with- drawal syndromes, and may be a reasonable option for patients with lower acuity ED presentations. [9]

1. Limitations

Our study is limited in its observational design and took place at a single, urban ED. Our ED also has robust substance use treatment pro- grams, as well as a lower barrier substance use clinic for patients discharged from the ED staffed by two emergency physicians who are also board certified in addiction medicine. This limits the generalizabil- ity of our findings. There are also likely confounding variables that affect the treatment of patients with both alcohol and opioid withdrawal in the ED, and patients will likely require individualized therapy. Addition- ally, we are unable to quantify the level of alcohol or opioid withdrawal upon presentation to the ED, and present the amount of medications re- quired and disposition data as surrogates for disease severity.

1. Conclusion

In this retrospective cohort study, we describe a cohort of patients treated simultaneously for opioid and alcohol withdrawal in a single, urban ED. One patient required intubation, though this was determined to be secondary to severe pneumonia, and not oversedation. Future re- search should be directed at Optimal treatment strategies for patients with opioid and alcohol withdrawal that take into account maintenance therapy for their underlying substance use disorders.

Funding information

Not applicable.

Prior presentations

None.

Author contributions

SM: data curation, writing – original draft, writing – review and editing; ESA: conceptualization, visualization, writing – original draft and review and editing, formal analysis, methodology, supervision; AAH: conceptualization, visualization, supervision, writing – review and editing; AV: Data curation.

The authors have no commercial associations or sources of support that might pose a conflict of interest.

References

1. Centers for Disease Control and Prevention (CDC). Alcohol and Public Health: Alcohol-Related Disease Impact (ARDI). Average for United States 2006-2010 Alcohol-Attributable Deaths Due to Excessive Alcohol Use. Available at: https:// nccd.cdc.gov/DPH_ARDI/Default/Report.aspx?T=AAM&P=f6d7eda7-036e-4553- 9968-9b17ffad620e&R=d7a9b303-48e9-4440-bf47-070a4827e1fd&M=8E1C5233-

5640-4EE8-9247-1ECA7DA325B9&F=&D=. Accessed 1/18/17.

1. Wilson N, Kariisa M, Seth P, et al. Drug and opioid-involved overdose deaths–United States, 2017-2018. MMWR Morb Mortal Wkly Rep. 2020;69:290-7.
2. Long D, Long B, Koyfman A. The emergency medicine management of severe alcohol withdrawal. Am J Emerg Med. 2017;35(7):1005-11. https://doi.org/10.1016/j.ajem. 2017.02.002.
3. Herring AA, Perrone J, Nelson LS. Managing opioid withdrawal in the emergency de- partment with buprenorphine. Ann Emerg Med. 2019;73(5):481-7. https://doi.org/ 10.1016/j.annemergmed.2018.11.032.
4. D’Onofrio G, O’Connor PG, Pantalon MV, Chawarski MC, Busch SH, Owens PH, et al. Emergency department-initiated buprenorphine/naloxone treatment for opioid de- pendence: a randomized clinical trial. Jama. 2015;313(16):1636-44.
5. Food and Drug Administration. Food and Drug Administration drug safety Communi- cations: FDA urges caution about withholding opioid addiction medications from pa- tients taking benzodiazepines or CNS depressants. https://www.fda.gov/drugs/drug- safety-and-availability/fda-drug-safety-communication-fda-urges-caution-about- withholding-opioid-addiction-medications. Published September 20, 2017. Accessed

May 14, 2020.

1. Park TW, Larochelle MR, Saitz R, Wang N, Bernson D, Walley AY. Associations be- tween prescribed benzodiazepines, overdose death and buprenorphine discontinua- tion among people receiving buprenorphine. Addiction. 2020;115(5):924-32. https://doi.org/10.1111/add.14886.
2. Umbricht A, Huestis MA, Cone EJ, Preston KL. Effects of high-dose intravenous buprenorphine in experienced Opioid abusers. J Clin Psychopharmacol. 2004;24(5): 479-87.
3. Anton RF, Latham P, Voronin K, Book S, Hoffman M, Prisciandaro J, et al. Efficacy of gabapentin for the treatment of alcohol use disorder in patients with alcohol with- drawal symptoms: a randomized clinical trial. JAMA Intern Med. 2020;180(5): 728-36.