High-Dose Buprenorphine Initiation in the Emergency Department Among Patients Using Fentanyl and Other Opioids

Design

Multi-center, retrospective cohort

N= 896

Objective

To compare high-dose buprenorphine treatment initiation, response, and follow-up treatment engagement between patients who did and did not report fentanyl use at California Bridge emergency departments (EDs)

Study Groups

Fentanyl user (n= 87)

Non-fentanyl user (n= 809)

Inclusion Criteria

All patients with opioid use disorder (OUD), regardless of chief concern, current treatment, withdrawal, or treatment desires

Exclusion Criteria

Methadone users, incomplete data

Methods

Data from electronic health records (EHRs) of eligible patients with OUD who presented to 16 California Bridge EDs were extracted. Patients considered fentanyl users based on EHR data (no toxicology testing was performed). Follow-up was assessed at 7 to 14 days (7-day follow-up) and 25 to 37 days (30-day follow-up) based on EHR documentation of buprenorphine or behavioral treatment through confirmation from the patient, outpatient practitioner, or the prescription drug monitoring program.

Duration

Data collection: January 1 to April 30, 2020

Follow-up: 30 days

Outcome Measures

Baseline Characteristics*

Fentanyl user (n= 87)

Non-fentanyl user (n= 809)

Median age (interquartile range), years

Female

White

Other substance use

Methamphetamine or stimulants

Alcohol or benzodiazepines

Heroin or pain medication

40.2%

33.3%

71.3%

38.9%

29.3%

100%

Baseline visit reason

Opioid withdrawal

Recent opioid use or high

Overdose

Seeking medication-assisted treatment

Other opioid use related

46.0%

10.3%

26.4%

27.6%

11.5%

50.7%

4.3%

9.6%

27.9%

14.2%

Total buprenorphine dose

2-7 mg 

8-16 mg

17-24 mg 

>24 mg

9.1%

63.6%

22.7%

4.5%

8.5%

81.0%

5.8%

4.7%

Median buprenorphine prescription dose, (range), mg/d

16 (0 to 32)

16 (2 to 32)

Buprenorphine prescription days

1-3

4-7

8-14

>14

7.0%

53.5%

23.3%

16.3%

6.2%

65.6%

20.4%

7.8%

*Data were adjusted for several confounders: age, sex, race and ethnicity, housing status, methamphetamine use, and alcohol and benzodiazepine use

Results

Endpoint

Fentanyl user (n= 87)

Non-fentanyl user (n= 809)

Response to administered buprenorphine

Improved condition

Induced sedation

Precipitated withdrawal

72.7%

0

4.5%

72.5%

0.2%

1.3%

Follow-up treatment engagement

7-14 days

30 days

50.6%

41.4%

45.6%

37.2%

No differences in follow-up engagement by patients with self-reported fentanyl use (adjusted odds ratio, 1.09), and precipitated withdrawal was rare (n=8 patients [1.6%]).

Adverse Events

Observed adverse events for fentanyl users and non-fentanyl users included headache, nausea or vomiting, and itchiness (n= 1 [2.3%] vs. n= 3 [0.7%], respectively).

Study Author Conclusions

In this cohort study, no differences were observed in follow-up engagement by patients with self-reported fentanyl use. These findings show that high-dose buprenorphine administered in the ED for patients in withdrawal is useful in a fentanyl-exposed population.

InpharmD Researcher Critique

Although data was adjusted based on several confounding factors, results are still limited due to retrospective design. The number of fentanyl users and non-fentanyl users was not balanced. Furthermore, both fentanyl use and follow-up engagement were determined through clinical documentation without confirmation, potentially leading to underestimating the results.

High-Dose Buprenorphine Induction in the Emergency Department for Treatment of Opioid Use Disorder

Design

Single-center, retrospective review

N= 391

Objective

To examine the safety and tolerability of high-dose (> 12 mg) buprenorphine induction for patients with opioid use disorder (OUD) presenting to an emergency department (ED)

Study Groups

N= 391

2-6 mg (n= 55)

8 mg (n= 136)

10-12 mg (n= 22)

16 mg (n= 106)

20-24 mg (n= 122)

≥ 28 mg (n= 138)

Inclusion Criteria

All patients treated with sublingual (SL) buprenorphine; aged ≥ 18 years

Exclusion Criteria

Not specified

Methods

Data were collected from electronic health records (EHR) for all ED patients with OUD treated with buprenorphine at a single, safety-net hospital in California. The high-dose ED buprenorphine induction pathway included a dose option up to 32 mg SL to increase the magnitude and duration of opioid withdrawal suppression. A high-dose sublingual buprenorphine induction protocol was clinically implemented and outcomes were reported according to total SL buprenorphine dose (range, 2 to > 28 mg).

All patients determined to be clinically appropriate for buprenorphine induction received an initial buprenorphine dose (4 to 8 mg SL) and were reassessed in 30 to 45 minutes. Patients with improvement in withdrawal symptoms after the initial dose and same-day access to a dispensed buprenorphine prescription after discharge were offered to continue the standard-dose.

High-dose buprenorphine induction (defined as more than 12 mg of SL-buprenorphine during the ED stay) to achieve minimal to mild withdrawal (Clinical Opioid Withdrawal Scale [COWS] score < 8) was based on the patient’s history, vital signs, physical examination findings, clinical judgment using scoring systems such as the COWS, and evaluation of complicating factors (age ≥ 65 years; altered mental status; viable pregnancy; methadone use; intoxication with alcohol, benzodiazepines, or other sedatives; post overdose reversal with naloxone; anticipated surgery; long-term opioid therapy for pain; or any serious acute medical illness, such as heart failure, liver failure, kidney failure, or respiratory distress).

Duration

Study period: January 1, 2018 to December 31, 2018

Data collection: April 2020 to March 2021

Outcome Measures

Baseline Characteristics*

16 mg (n= 106) 

Median vital signs at triage

Systolic blood pressure, mmHg

Respiratory rate, breaths/min

Heart rate, beats/min

Oxygen saturation

133

18

84

99%

132

18

89.5

99%

132

18

87

98%

128

18

83.5

99%

128

18

88

99%

130

18

87

99%

0.75

0.26

0.16

0.29

Chronic obstructive pulmonary disease

2.9%

3.6%

2.2%

4.5%

3.8%

1.6%

0.76

Supplemental oxygen

11%

4.5%

3.8%

1.6%

0.72%

0.01

Among all participants with a median (interquartile range [IQR] age of 36 (29 to 48) years, 68.3% were male and 43.5% were Black. Homelessness (22.5%) and psychiatric disorders (41.2%) were common. 

Emergency Severity Index were not significantly different between the groups.

A high dose of sublingual buprenorphine (> 12 mg) was administered including 138 doses (23.8%) ≥ 28 mg.

Results

Endpoint

2-6 mg (n= 55)

8 mg (n= 136)

10-12 mg (n= 22)

Precipitated withdrawal

Return to ED within 24 h

Hospitalization

Precipitated Withdrawal: n= 5 cases (event rate, 0.8%) of documented precipitated withdrawal occurred (4 cases occurred after usual dosing of 8 mg and, thus, were unrelated to high-dose buprenorphine; one patient tolerated a dose of 8 mg and experienced precipitated withdrawal after administration of an additional 24 mg of buprenorphine).

No significant association with total buprenorphine dose and reported vital signs, including blood pressure, respiratory rate, heart rate, and oxygen saturation were observed. No documentation of decreased respiratory rate were reported in the highest dose group of 28 mg or higher.

No patient was administered naloxone at any time after buprenorphine administration. 

Adverse Events

Common Adverse Events: nausea or vomiting (4% for 8 mg, 6% for 10 to 12 mg, 5% for 16 mg, 2% for 20 to 24 mg, 2% for ≥ 28 mg)

Serious Adverse Events (Grade 4) occurred in 3 patients; none were associated with buprenorphine administration, including sedation, hypoxia, and/or naloxone rescue in the ED or 24 hours after discharge.

Percentage that Discontinued due to Adverse Events: Not disclosed

Study Author Conclusions

These findings suggest that high-dose buprenorphine induction, adopted by multiple clinicians in a single-site, urban emergency department, was safe and well tolerated in patients with untreated opioid use disorder. There were no documented episodes of respiratory depression or excessive sedation, and precipitated withdrawal was rare (0.8% of cases) and was not associated with dosing.

InpharmD Researcher Critique

Given the retrospective nature of this single-center study, a comparative assessment of this high-dose buprenorphine clinical pathway versus conventional strategies remained undetermined. Further prospective studies performed in multiple sites would enrich the outcomes of this study.

Single high-dose buprenorphine for opioid craving during withdrawal

Design

Double-blind, randomized trial

N= 90

Objective

To evaluate the effect of a single, high dose of buprenorphine on craving in opioid-dependent patients over 5 days of abstinence from use of other opioids

Study Groups

Buprenorphine 32 mg (n= 30)

Buprenorphine 64 mg (n= 30)

Buprenorphine 96 mg (n= 30)

Inclusion Criteria

Daily opioid abuse for at least one year; opium, heroin, or prescribed opioids and met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for opioid use disorder (severe form)

Exclusion Criteria

Substance use disorders involving drugs other than opioids (excluding tobacco), organic mental disorders, major medical diseases (hepatic, renal, cardiovascular, pulmonary, gastrointestinal, or malignant diseases), or any type of psychosis

Methods

Eligible patients were randomly assigned to receive a single sublingual dose of buprenorphine at 32, 64, or 96 mg. The study took place in an inpatient psychiatric ward, with the necessary precautions and continuous monitoring of respiratory and cardiovascular parameters. Buprenorphine, administered as a single dose, was given sublingually to patients experiencing moderate opiate withdrawal.

Initial assessments of craving were collected, and subsequent evaluations occurred over the following 5 days after buprenorphine administration. The level of opioid craving was determined based on patients' self-reports. Urine drug toxicology was performed using thin-layer chromatography (TLC) before the single dose administration, twice weekly during the 5-day trial, and at the trial's conclusion. To ensure safety, adverse effects, vital signs, respiration, and gastrointestinal impacts were continuously monitored for the first day, followed by assessments every 6 h.

Duration

Five days

Outcome Measures

Baseline Characteristics

Buprenorphine 32 mg (n= 30)

Buprenorphine 64 mg (n= 30)

Age, years

Drug abuse, years

Job

Unemployed

Employed

Self-employed

40%

6.7%

53.3%

63.3%

10%

23.3%

40%

6.7%

53.3%

Education

Unable to read/write

Primary school

High school

University education

3.3%

36.7%

40%

20%

3.3%

26.7%

56.7%

13.3%

0

33.3%

50%

13.3% 

Marital status

Married

Single

50%

50%

70%

30%

46.7%

53.3%

All the patients had normal liver and kidney function before enrollment.

Results

Endpoint

Buprenorphine 32 mg (n= 30)

Buprenorphine 64 mg (n= 30)

Buprenorphine 96 mg (n= 30)

Craving scores

Baseline

Day 1

Day 2

Day 3

Day 4

Day 5

7.23 ± 3.51

4.46 ± 3.95

2.56 ± 3.23

1.70 ± 2.39

1.23 ± 1.86

0.7 ± 1.14 

6.93 ± 3.54

4.96 ± 2.9

3.03 ± 2.23

0.9 ± 1.37

0.3 ± 0.749

0.1 ± 0.402 

7.56 ± 3.53

4.00 ± 2.75

1 ± 1.74

0.366 ± 0.927

0.233 ± 0.727

0

Post-hoc t-test p-values of the three groups

Adverse Events

Two patients (both in the 96-mg group) developed significant hypotension (blood pressure of 75/50 and 80/45, respectively) and were treated with hydration. Two subjects (both in the 32-mg group) developed nausea. Five (two in the 64-mg group and three in the 96-mg group) developed both nausea and vomiting. No severe respiratory, cardiovascular, or gastrointestinal adverse effects were observed.

Study Author Conclusions

A single, high dose of buprenorphine can reduce craving during opioid withdrawal; additional studies with follow-up are warranted to evaluate safety.

InpharmD Researcher Critique

“Macrodosing” Sublingual Buprenorphine and Extended-release Buprenorphine in a Hospital Setting: 2 Case Reports

Design

Case presentation 1

A 26-year-old female with a history of fentanyl daily use for about 7 years was admitted to the emergency department (ED). She was stable on methadone treatment for 7 months until she was admitted to a residential treatment program for cocaine use where, without any methone treatment, she relapsed to intravenous fentanyl 0.5 to 0.6 g/day. After several weeks, she took one dose of buprenorphine/naloxone (8 mg/2 mg) to manage her withdrawal symptoms. However, one hour later, she presented to ED to manage her opioid withdrawal symptoms.

With stable vital signs at presentation, she initially received a dose of 4 mg buprenorphine/naloxone. However, her withdrawal symptoms worsened (Clinical Opiate Withdrawal Scale [COWS] score 19). After receiving clonidine 0.1 mg, sublingual (SL) lorazepam 1 mg, ondansetron 8 mg, and olanzapine ODT 5 mg, she received another dose of 4 mg/1 mg buprenorphine/naloxone (at 9 am) followed by another 8 mg/2 mg dose 20 minutes later, another 8 mg dose an hour later, and a 4 mg/1 mg dose at 1:00 PM (total ED dose of buprenorphine/naloxone 28 mg/7 mg) resulting in a better COWS score (COWS 5 at 3:00 PM, and COWS 2 at 6:00 PM). With stable vital signs and no evidence of respiratory depression or drowsiness, her assessments did not show a need for further doses of buprenorphine/naloxone for the rest of the day. The next morning, she received 32 mg/8 mg of buprenorphine/naloxone followed by a subcutaneous injection of 300 mg buprenorphine ER 4 hours later. Eventually, she was referred to the community withdrawal program and received a second buprenorphine ER injection 4 weeks later.

Case presentation 2

A 46-year-old male with a history of fentanyl use for 5 years (average daily dose of 1 g for the last 2 years) presented to ED. He had experienced several overdoses that required reversal with naloxone. Although he had several attempts to be treated with methadone and buprenorphine SL, no opioid agonist treatment was achieved during the past 2 years. His last fentanyl use was at 10:30 PM; 30 minutes later, his initial COWS score at ED presentation was 0. However, 18 hours later, repeat COWS score was 25. 

The following day, he was administered 16 mg of buprenorphine/naloxone SL at 5:00 PM, followed by two consequent 8 mg doses at 6:00 and 7:00 PM (a total of 32 mg over 2 hours). Finally, his assessed COWS score was 0. The next morning, he received a dose of 32 mg. Five hours later (29 hours after his first buprenorphine SL dose), he was administered buprenorphine ER 300 mg injection with a second dose given 28 days later. Since then, he has not reported fentanyl use, any side effects, or withdrawal symptoms.

Study Author Conclusions

In both cases, their withdrawal symptoms quickly resolved, without sedation or precipitated withdrawal. Both patients followed up with the outpatient clinic for another injection of extended-release buprenorphine.

High-dose sublingual buprenorphine/naloxone followed by early administration of extended-release buprenorphine quickly and safely relieved withdrawal symptoms in two fentanyl users who presented to the hospital emergency department. This novel approach shows promise in improving treatment retention rates for patients using fentanyl. Further research is required to evaluate the safety and effectiveness of this approach.