Clinical trial NCT02643355
Conditions: Substance Withdrawal Syndrome
Keywords: Narcotic Withdrawal Opiate Withdrawal Emergency Department
Sponsor: Hennepin Healthcare Research Institute
Start date: 2015-11-01; Completion date: 2017-06-21
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Withdrawal from opioids is a clinical scenario that emergency department physicians encounter frequently. Patients who present with opioid withdrawal display symptoms such as agitation, anxiety, myalgias, abdominal pain, diarrhea, nausea, and vomiting. Currently, the standard treatment for opioid withdrawal is clonidine (an alpha-2 adrenergic agonist), as well as supportive cares (anti-emetics, intravenous fluids). Olanzapine is an atypical antipsychotic that is given frequently in the ED for many of the same symptoms that are seen in patients who are experiencing opioid withdrawal, however its use in this toxidrome has never been studied. The hypothesis of this study is that olanzapine is a safe and efficacious option when compared to clonidine for the treatment of opioid withdrawal in the emergency department.

Detailed description:
This study will be a randomized control trial where patients will be randomized to receive intramuscular olanzapine or oral clonidine as the first intervention given for treatment of opiate withdrawal. This study will not be blinded.

Screening and enrollment: Research Associates will screen patients by review of the electronic medical record. When these patients are identified, the RA will approach the CITI trained ED provider who will obtain written informed consent. Allergies to either medication will be screened for in Epic by the research associates. Allergies will also be verified by the provider who is completing the consent.

Study protocol: If the patient consents to enroll in the study, the research associate will randomize the patient to receive olanzapine or clonidine as the first treatment intervention. The ED provider will then order that medication for the patient and will it be administered by nursing staff. At this time the provider may order the patient to have a peripheral IV placed and IV fluids administered at their discretion. No other supportive measures (anti-emetics, non-narcotic pain medications) may be given at this time.

Prior to medication administration, the research associate will assess the patient's withdrawal symptoms using the Clinical Opiate Withdrawal Scale for withdrawal symptoms. This is a validated tool used to assess degree of withdrawal symptoms by evaluating physiologic and symptomatic parameters. The medical provider will also obtain information regarding the patients opioid use history (what type of opioid used, chronicity of use, date and time of last use). After the study medication administration, patients will be observed for clinical improvement. At 30 minutes, additional medications or interventions may be prescribed at the discretion of the ED provider for symptom control, including crossover of the study medications. The research associate will record which other medications/interventions were ordered, the indication for these interventions, and times administered.

Symptoms will be re-assessed by the research associate using the COWS at 60 minutes, 120 minutes post administration of the initial treatment intervention, as well as at 4 hours post administration (approximately time of discharge from the emergency depatment). At these same time marks, sedation of the patient will be assessed using the overt agitation severity scale (OASS). Throughout the patient's ED stay, the research associate will be monitoring for adverse complications such as allergic reaction, dystonia, akathisia, respiratory complications, or hypotension.

The investigators will conduct preliminary data analysis after the first 25 and 50 patients are enrolled, respectively. Initial power analysis and sample size calculations delineated that the investigators would need 35 patients per arm to detect a 50% difference in the need for rescue medication at 1 hour between the two study medications.

Arms: arm 1: Drug of interest in the study - Olanzapine arm 2: Standard of care - clonidine
Interventions: intervention 1: Olanzapine intervention 2: Clonidine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL TITLE: Opioid Withdrawal 
 
Page 1 of 7 
 
 
An Open-Label Randomized Trial of Intramuscular Olanzapine 
versus Oral Clonidine for Symptomatic Treatment of Opioid 
Withdrawal in the Emergency Department 
 
Original Protocol: October 1, 2015 
Updated: May 9, 2019 
 
1.0 
Objectives 
1.1 Purpose: The purpose of this study is to compare olanzapine versus 
clonidine in the treatment of symptoms of opioid withdrawal in the 
Emergency Department (ED).  
2.0 
Background 
2.1 Significance of Research Question/Purpose: Opioid withdrawal is a 
commonly encountered clinical scenario in the ED. Patients in opioid 
withdrawal present with symptoms including nausea, vomiting, diarrhea, 
abdominal pain, anxiety, agitation, among others. Treatment for opioid 
withdrawal generally falls into two broad categories; it can be treated with 
classes of non-opiate medications and opiate medications.  There are 
certain environments, such as outpatient clinics that specialize in pain 
management and addiction, where the administration of opiates 
(methadone) or partial-opiate agonists (buprenorphine) may be the 
appropriate treatment for opioid withdrawal. The ED generally however 
does not have the resources to initiate these types of therapies, and the 
patients presenting to the emergency department are typically having a 
more acutely symptomatic withdrawal necessitating the need for non-
opiate adjuncts to achieve rapid relief. 
2.2 Preliminary Data:  At this time, many ED physicians treat withdrawal with 
clonidine, which has been studied extensively [1]. Clonidine is an alpha-2 
adrenergic agonist and is thought to blunt the symptoms of withdrawal by 
binding to central apha-2 receptors.  Other medications thought to be 
useful in opiate withdrawal include medications targeted at treating 
anxiety/agitation (benzodiazepines, diphenhydramine), anti-emetics 
(ondansetron, prochlorperazine), anti-diarrheals (loperamide), and non-
narcotic pain mediations (ibuprofen, acetaminophen). Although it has not 
been extensively studied, there is some literature to support that the use 
of atypical antipsychotics may be helpful in treatment of opiate withdrawal 
symptoms. These studies show that atypical antipsychotics may reduce 
opiate cravings, pain, and anxiety [2, 3] as well as gastrointestinal side 
effects [4]. Furthermore, we recently conducted a prospective evaluation 


PROTOCOL TITLE: Opioid Withdrawal 
 
Page 2 of 7 
 
of olanzapine in our ED and showed good efficacy in the treatment of 
nausea, vomiting, abdominal pain, and agitation, some of whom were in 
the ED for treatment of opioid withdrawal.  We also conducted a large 
retrospective review of over 700 ED patients who received olanzapine for 
various clinical indications and found that olanzapine administration is very 
safe, with very low rates of airway complications, dystonia, and allergic 
reaction.  
 [1] Gowing L, Farrell MF, Ali R, White JM. Alpha2-adrenergic 
agonists for the management of opioid withdrawal. Cochrane 
Database Syst Rev 2014 Mar 31;3:CD002024.  
[2] Pinkofsky HB, Hahn AM, Campbell FA, Rueda J, Daley DC, 
Douaihy AB. Reduction of opioid-withdrawal symptoms with 
quetiapine. J Clin Psychiatry. 2005 Oct;66(10):1285-8 
[3] Sarkar S, Mattoo SK. Newer approaches to opioid 
detoxification. Ind Psychiatry J. 2012 Jul;21(2):163-7. doi: 
10.4103/0972-6748.119652. 
[4] Mori T, Komiya S, Ohya J, Uzawa N, Sugiyama K, Saitoh Y, 
Shibasaki M, Suzuki T. Involvement of 5-HT2 receptors in the 
expression of withdrawal diarrhea in morphine-dependent mice. 
Eur J Pharmacol. 2014 Oct 5;740:160-7. 
3.0 
Study Outcomes 
3.1 Primary Outcome: The primary outcome is rescue sedation within 60 
minutes of drug administration 
3.2 Secondary Endpoint(s)/Event(s)/Outcome(s):  
Rescue Medication: 60 minutes, 120 minutes, Time of Disposition 
Clinical Opioid Withdrawal Scale: Baseline, 60 minutes, 120 minutes, Time 
of Disposition 
OASS Score:  Baseline, 60 minutes, 120 minutes, Time of Disposition 
Adverse Events: Dystonia, Akathisia, Wheezing, Rash/Hives, Hypotension, 
Aspiration 
Airway Events: Oxygen administration, Nasal/oral airway, Bag valve mask 
Serious Adverse Events: Death, Intubation 
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 Description: Study interventions will include: 
(1) Randomization of initial treatment for symptoms of withdrawal to 0.3 
mg of oral clonidine versus 10 mg of intramuscular olanzapine 
● Intramuscular Olanzapine: FDA-approved medication and dose  


PROTOCOL TITLE: Opioid Withdrawal 
 
Page 3 of 7 
 
● Oral clonidine: FDA-approved medication and dose 
4.2 Drug/Device Handling: This drug is being given open label. These drugs are 
routinely stored in the Department of Emergency Medicine Omnicell.  
There are no alterations to drug storage other than what is routine and 
standard of care for the Dept of Emergency Medicine. The drug will be 
administered or injected as it would be in routine clinical practice.  
 
5.0 
Procedures Involved 
5.1 Study Design: Open label, unblinded, randomized clinical trial  
5.2 Study Procedures: 
After patients are consented and enrolled procedures are as follows: 
(1) Research Associate randomizes patient (random assignments will be 
placed in opaque envelopes and the next sequential envelope will be 
opened) 
(2) Research Associate will inform provider which medication the patient is 
randomized to 
(3) Provider will notify patient which medication they are randomized to 
and they will order the medication in the electronic medical record 
(4) Nurse will administer the medication to patient 
(5) Research Associate will perform baseline assessment (COWS score, 
OAAS score) & will obtain demographic information and opioid use 
history information from patient 
(6) No medications should be given to the patient for 30 minutes after 
administration of the initial medication; after 30 minutes any 
medication or treatment can be given to the patient as needed. 
(7) Research Associate will perform assessment 60 minutes, 120 minutes 
after medication administration and at the time of disposition 
(discharge or admission) including COWS score, OAAS score, and the 
names of additional treatments given by the ED provider during that 
interval. 
(8) Research Associate will record clinical information related to the 
counter including disposition, laboratory values, adverse events, 
serious adverse events, airway events, and time in department. 
(9) Note: all medication choices administered except for the initial 
randomized medication are at the discretion of the treating physician; 
there is no research protocol to dictate additional treatments 
5.3 Study Duration: The study duration is from the time of enrollment to the 
time the patient is discharged or admitted to the hospital. The study 
duration does not extend past the patient’s ED encounter.  


PROTOCOL TITLE: Opioid Withdrawal 
 
Page 4 of 7 
 
5.4 Individually Identifiable Health Information: Identifiable Health Information 
will be obtained including Medical Record Number. This number is 
necessary in order to access the patient’s medical record. After this 
number is no longer needed, the database will be de-identified.  
 
6.0 
Sharing of Results with Participants 
6.1 Results will not routinely shared with participants but the patient will have 
contact information including phone numbers to contact the investigators 
to answer any questions about study results if they query.,  
7.0 
Study Population 
7.1 Inclusion Criteria:  
● Adult Patients (18 years of age and greater) 
● Patients must be in the ED for symptoms that may be caused by 
opioid withdrawal  
● The ED provider believes that medication treatment is indicated 
for the patient’s symptoms opioid withdrawal  
7.2 Exclusion Criteria:  
● Age < 18 years 
● Inability to provide informed consent 
● Allergy to either medication 
● Prisoner/Under Arrest 
● Known Pregnancy 
● Already received treatment from their ED provider for symptoms 
7.3 Screening: Patients will be screened by research associates and by ED 
providers for symptoms that could possibly be related to opioid 
withdrawal. An Opioid Use history may be elicited by the ED provider, or 
the patient may offer this history themselves. Screening will occur in the ED 
only. 
8.0 
Vulnerable Populations 
8.1 
Vulnerable Populations: No vulnerable populations will be approached 
for inclusion in this study. Patients in opioid withdrawal are healthy, and not 
impaired. By definition, they are not intoxicated.  
9.0 
Local Number of Participants 
9.1 Local Number of Participants to be Consented: Up to 70 
10.0 Local Recruitment Methods 


PROTOCOL TITLE: Opioid Withdrawal 
 
Page 5 of 7 
 
10.1 Recruitment Process: No external recruitment will occur, only patient’s 
who are in the ED will be approached for possible enrollment 
10.2 Identification of Potential Participants: Physicians will be actively searching 
for patients in the ED with symptoms of opioid withdrawal, and will be 
aware of this trial and will notify Research Associates if a patient may 
eligible to complete the screening process. Research Associates will also be 
screening patients in the ED that have chief complaints that may be related 
to opioid withdrawal (i.e. “nausea”, “vomiting”, “withdrawal”) but this is 
not an inclusive list of chief complaints. Identification will rely almost 
exclusively on ED provider identification of appropriate patients. 
10.3 Recruitment Materials: There are no recruitment materials.  
10.4 Payment: There will be no payments 
11.0 Withdrawal of Participants 
11.1 Withdrawal Circumstances: Patients can withdraw at any time. They can 
withdraw as soon as consent as signed up until the study is closed. They 
can even choose to withdraw after data collection is complete, and are 
provided with a phone number to contact if that be the case.  
11.2 Withdrawal Procedures: Patients must notify their doctor of the research 
associate to withdraw if they are in the ED still. If they are no longer in the 
ED they must call a phone number that is included in the consent form.  
11.3 Termination Procedures: Data will not be used if the patient requests it not 
be used. 
12.0 Risks to Participants 
12.1 Foreseeable Risks:  
It is possible that enrolling in the study could slightly delay getting a 
medication for treatment of the patient’s symptoms. 
There is a possible risk of breach of data confidentiality but this will be 
mitigated by storing all forms in locked storage facilities and electronic 
databases are encrypted and password protected 
Possible side effects of the two medications: 
Olanzapine: drowsiness, extrapyramidal side effects, dizziness, headache, 
respiratory depression, hypotension, among others 
Clonidine: drowsiness, headache, fatigue, abdominal pain, dry mouth, 
hypotension, among others 
Of note, these medications are also used frequently in the ED, so it is 
likely that either or both of these medications would be given as part of 
routine clinical care. 


PROTOCOL TITLE: Opioid Withdrawal 
 
Page 6 of 7 
 
12.2 Reproduction Risks: A known pregnancy will also be an exclusion criteria. 
We will not require a urine pregnancy test but one may be obtained at the 
discretion of the ED provider, as in many cases this will be part of usual 
care. Both study medications administered are considered pregnancy 
category C and are frequently used in the pregnant population as a 
standard of care. 
12.3 Risks to Others: N/A 
13.0 Potential Benefits to Participants 
13.1 Potential Benefits There is no direct benefit to the patient for being in this 
study 
14.0 Statistical Considerations 
14.1 Data Analysis Plan: Demographic data will be described using descriptive 
statistics, including means, medians, and proportions as appropriate. The 
primary outcome will be the rate of rescue medication given within 60 
minutes. This will be calculated as a proportion. The comparison of the 
primary outcome will be a calculation of the difference in proportions with 
associated 95% confidence intervals. A difference in proportions with 
associated 95% confidence intervals will also be calculated for secondary 
outcomes including rescue medication at 120 minutes and during the 
entire encounter. Adverse events will be reported as counts and 
proportions.  
14.2 Power Analysis: Sample size calculations were performed using estimates 
from a previous study looking at patients who received olanzapine in the 
ED for all indications. A subset of these patients received the olanzapine for 
opioid withdrawal and approximately 40% of those patients received 
rescue medications. We estimated that olanzapine would result in a 
relative reduction of rescue medication administration of 50% compared to 
clonidine. We would therefore need at least 56-70 patients total to achieve 
80%-90% power, respectively, with a two-sided alpha of 0.05.   
14.3 Data Integrity: Standardized data collection forms will be used to ensure 
data integrity. After a patient is enrolled and data is collected, a trained 
research coordinator will review the data collection forms. They will 
attempt to complete any missing data points using the patients’ medical 
record and via query of the patients treating physician if appropriate. The 
principal investigator will also review the database on a rolling (at least 
monthly) basis to ensure that data collection is complete. An interim data 
analysis will be performed.  
15.0 Confidentiality 


PROTOCOL TITLE: Opioid Withdrawal 
 
Page 7 of 7 
 
15.1 Data Security: Data will be stored on a password protected encrypted 
database that only the investigators and research coordinators have access 
to. Paper data collection forms are stored in a locked facility.  
16.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
 
All serious adverse events will be reviewed immediately by the 
investigators and reported the next business day IRB. All serious adverse 
events will also be reviewed by the listed Co-Investigators and the 
Research Director (this group will serve as a Data Safety Monitoring 
Board) to determine the extent to which it was related to the study drug 
and assess appropriateness of continuing the trial on a case-by-case 
basis.  All other non-serious adverse events will be reported on the 
annual report.  
 
An interim analysis will occur after the first 40 patients are enrolled by 
the lead investigator and will be presented to the listed Co-Investigators 
and the Research Director (this group will serve as a Data Safety 
Monitoring Board). Efficacy outcomes will be assessed, and safety 
outcomes will be assessed. If there are significant disparate safety 
concerns, then the study will be terminated. Significant safety concerns 
are defined as a rate of serious adverse events (mortality, intubation) 
that is significantly greater in one group than the other.   
 
Furthermore, a yearly continuing review form will be submitted by the 
investigators to the IRB.  
 
17.0 Provisions to Protect the Privacy Interests of Participants 
17.1 Protecting Privacy: Data will be stored on a password protected encrypted 
database that only the investigators and research coordinators have access 
to. Paper data collection forms are stored in a locked facility.  
18.0 Consent Process 
18.1 Consent Process (when consent will be obtained): Informed consent from 
the patient must be obtained for every patient or from their legally 
authorized representative. There will be no alterations in consent accepted 
for this trial. Consent will be obtained after the patient has been confirmed 
eligible. Consent will be obtained by the treating ED provider.