Clinical trial NCT01967433
Conditions: Colonoscopy Adjunct Anesthesia Medication
Keywords: Fentanyl Midazolam Sedation Patient tolerance Duration of colonoscopy
Sponsor: University of Oklahoma
Start date: 2013-12-01; Completion date: 2018-07-01
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To access the efficacy of adding diphenhydramine as adjunct to improve sedation and to reduce the amount of standard sedatives used during colonoscopy in patients on chronic opioids.

Detailed description:
Specific Aims:

The primary aim of our study is to determine if addition of Diphenhydramine to Fentanyl and Midazolam will decrease the dose of Fentanyl and Midazolam used during colonoscopy in individuals on chronic opioids. Secondarily we will be looking at quality of sedation, duration of colonoscopy, time to reach cecum and adverse effects (hypoxia defined as O2 saturation less than 89% lasting for more than 30 seconds, hypotension defined as systolic BP less than 90 mmhg and use of reversal agents i.e Naloxone or Flumazenil).

Day of Procedure:

After consent is obtained the medical records of the patients will be reviewed and demographic information, co-morbidities, current medication will be extracted and recorded.

On the day of colonoscopy Alcohol use disorder inventory (AUDIT) will be used to screen for alcohol abuse. AUDIT was developed by World Health Organization and has been validated over a period of 2 decades. It consist of 10 questions, each question is scored 0-4 on the basis of subjects alcohol use. It takes about 2-4 minutes to complete. A score 10 or greater is highly specific or alcohol use.

Subjects will be checked in and prepared according to routine protocols of the VA medical center. Participants will be randomly assigned to receive either 50 mg of diphenhydramine or 10 ml of 0.9% sodium chloride. On the day of colonoscopy randomization will be performed by an independent investigator who is a pharmacist at VA medical center using the website http://www.randomization.com. She will also prepare and dispense medication. Each endoscopy team will consist of an attending gastroenterologist, gastroenterology fellow and two nurses. Medications will be administered by one of the nurses under the direct supervision of the physician.

At the start of procedure baseline vitals will be recorded as per our unit's policy. Research medication will be administered 3 minutes prior to administration of other medications. Neither the patient nor the medical staff including the endoscopist will be aware of the contents of the vial. Conscious sedation will be achieved using a combination of intravenous midazolam and fentanyl as standard sedative. Rarely, additional diphenhydramine will be given, on the basis of the judgment of the endoscopist. During the procedure vital signs including oxygen saturation will be monitored at 3-5 minute interval. Procedure related complications, including hypotension, desaturation and cardiac arrhythmia will be managed according to our endoscopy unit policy and protocols.

Following the procedure, the nurse and the fellow or the attending will individually rate the quality if sedation on a ten-point Likert scale. Qualitative assessment will also be made (Under-sedated, adequately sedated, or over-sedated).

Recovery time will be recorded.

Day Following the Colonoscopy Twenty-four hour discharge a follow up call will be made and the patients will be asked to evaluate the level of sedation on a 10-point scale (1, inadequate; 10 completely without discomfort); pain (1, no pain; 10 severe pain), and amnesia (10, no memory of the procedure; 1 complete memory).

Arms: arm 1: Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives arm 2: 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives
Interventions: intervention 1: Diphenhydramine intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Title: Use of Diphenhydramine as an Adjunctive Sedative for Colonoscopy in Patients 
Chronically on Opioids 
NCT: NCT01967433 
Date: 11/15/17 


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RESEARCH PROTOCOL OUTLINE
Title: Use of Diphenhydramine as an Adjunctive Sedative for Colonoscopy in Patients 
Chronically on Opioids 
Principal Investigator: Salman Nusrat, MD., Dept. of Medicine, Sect. of Digestive Diseases, 
Assistant Professor of Medicine
Co-Investigator: Mohammad Madhoun, M.D., Dept. of Medicine, Sect. of Digestive       Diseases, 
Assistant Professor of Medicine
William Tierney, M.D., Dept. of Medicine, Sect. of Digestive Diseases, 
Professor of Medicine. 
Donna Zink, M.S., Clinic Project Coordinator, Dept. of Medicine, Sect. of   
Digestive Diseases
Abstract: 
Specific Aims: To access the efficacy of adding diphenhydramine as adjunct to improve sedation 
and to reduce the amount of standard sedatives used during colonoscopy in patients on chronic 
opioids. Background: Large number of colonoscopies are performed each year. Use of Sedation 
increases tolerance and improves outcomes. With increasing use of opioids among general 
population patient often require large amount of fentanyl and midazolam for adequate sedation. 
Although effective, these medications have the potential to cause hypotension and respiratory 
depression especially in high doses. Diphenhydramine with its CNS depressant effect can 
theoretically provide synergistic effects.  We hypothesis use of diphenhydramine will decrease the 
amount of fentanyl and midazolam (versed) used during colonoscopy and will decrease the 
duration the procedure and the number adverse effects. Methods: Patient on chronic opioids 
scheduled to undergo colonoscopy will be randomized to receive 50mg of diphenhydramine or 
placebo. Amount of sedatives, duration of procedure, adverse effect and quality of sedation (nurse, 
physician and patient) will be recorded. Two-sided t-test will be used to compare the means of 
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continuous variables in the two groups, and Chi-square test will be used to compare the categorical 
variables. A P value < 0.05 will be considered statistically significant.
A.
Specific Aims
The primary aim of our study is to determine if addition of Diphenhydramine to Fentanyl and 
Midazolam will decrease the dose of Fentanyl and Midazolam (versed) used during colonoscopy 
in individuals on chronic opioids. Secondarily we will be looking at quality of sedation, duration 
of colonoscopy, time to reach cecum and adverse effects (hypoxia defined as O2 saturation less 
than 89% lasting for more than 30 seconds,  Hypertension 20 mmhg increase in BP from baseline 
provided this is >140 systolic and 90 diastolic, Hypotension 20 mmhg decrease in BP from 
baseline provided this <100 systolic or 60 diastolic, Bradycardia a decrease in HR of > 20 provided 
this is less than 60, Tachycardia a increase in HR of >20 provided this greater than 100 and use of 
reversal agents i.e Naloxone or Flumazenil).
B. Background and Significance 
According to an estimate more than 15 million colonoscopies are performed in United States. 
Patient tolerance is important for successful and safe completion of endoscopic procedure. 
Sedation not only reduces associated anxiety and pain but also results in increased compliance and 
willingness to undergo repeat procedures. i ii During the last two decade sedation frequency has 
increased both for diagnostic and therapeutic procedures.iii Failure to achieve adequate sedation 
has been a long-standing challenge in the field of gastrointestinal endoscopy. This results in 
patients discomfort, unsatisfactory examination, incomplete procedures, waste of time and 
financial loss. Although results have been conflicting factors predictive of difficult sedation 
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include excessive alcohol use (>40g/day), psychotropic medication, opioid use and anxiety (3-5).iv 
v Results of the 2010 National Survey on Drug Use and Health (NSDUH) showed that an estimated 
22.6 million (8.9%) of Americans, aged 12 or older, were current or past month illicit drug users. 
The escalating use of therapeutic opioids shows hydrocodone topping all prescriptions with 136.7 
million prescriptions in 2011, with all narcotic analgesics exceeding 238 million prescriptions. 
Benzodiazepines along with opioids are commonly used for endoscopic sedation.vi viiHowever, 
because of increasing use of both prescription and non-prescription opioids amongst general 
population and the associated cross tolerance with currently used sedatives, use of 
diphenhydramine hydrochloride as an adjunctive sedative has been explored and has shown 
promise. viii ixDiphenhydramine hydrochloride, an ethanolamine, belongs to the class of histamine 
1 antagonist. It is commonly used as an anti-allergic and has CNS depressants effects.x  However, 
no study has specifically looked at the use of diphenhydramine as an adjunctive sedative in high 
risk patients i.e. patient on opioids. We Hypothesis addition of diphenhydramine to midazolam 
and fentanyl would decrease the usage of benzodiazepines and opioids without compromising the 
success of the procedure. Thus our study will help identify a medication combination which is 
effective and save in this challenging population. 
C. Preliminary Studies 
Study by Raymond H et al showed addition of diphenhydramine resulted in 10.1% reduction in 
meperidine and 13.7% reduction in midazolam dose. Sedation scores significantly favor 
Diphenhydramine. However, only 7/130 patients in the diphenhydramine group were on chronic 
opioids. 
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D. Research Design and Methods
Study Design: 
Prospective Randomized Double Blind Study 
Study Center: 
Data will be collected from the Oklahoma City Veteran Affair Medical Center (VAMC)
Study Population:
Inclusion Criteria 
1. Patients aged 18-75 years undergoing screening, surveillance, diagnostic and 
therapeutic colonoscopy 
2. Patient on chronic opioids defined as at least 5 mg of morphine or its equivalent at least 
3 days per week for more than 3 months 
Exclusion Criteria 
1) Inability to execute informed consent 
2) Allergy to Diphenhydramine, fentanyl or midazolam 
3) Known or suspected pregnancy 
4) Endoscopic procedure without sedation
5) Patient scheduled to have other endoscopic procedures on the same day
6) Prior alimentary tract surgery 
7) Severe cardiopulmonary disease (ASA IV)
8) MOI use within 2 weeks of procedure
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Recruitment and Consent:
Charts of patients scheduled for colonoscopy at VA Medical Center Oklahoma will be reviewed 
by provider involved in the care of these patients to identify patient who meet the inclusion criteria. 
Patients will be consented on the day of the procedure by one the team members in a private room. 
Day of Procedure:
After consent is obtained the medical records of the patients will be reviewed and demographic 
information, co-morbidities, current medication will be extracted and recorded.
On the day of colonoscopy Alcohol use disorder inventory (AUDIT) will be used to screen for 
alcohol abuse. AUDIT was developed by World Health Organization and has been validated over 
a period of 2 decades. It consist of 10 questions, each question is scored 0-4 on the basis of subjects 
alcohol use. It takes about 2-4 minutes to complete. 
Subjects will be checked in and prepared according to routine protocols of the VA medical center. 
Participants will be randomly assigned to receive either 50 mg of diphenhydramine or 10 ml of 
0.9% sodium chloride. On the day of colonoscopy randomization will be performed by an 
independent investigator who is a pharmacist at VA medical center using the website 
http://www.randomization.com. She will also prepare and dispense medication. Each endoscopy 
team will consist of an attending gastroenterologist, two nurses either with or without a 3rd year 
gastroenterology fellow. Medications will be administered by one of the nurses under the direct 
supervision of the physician.
At the start of procedure baseline vitals will be recorded as per our unit’s policy. Research 
medication will be administered within 3 minutes prior to administration of other medications. 
Neither the patient nor the medical staff including the endoscopist will be aware of the contents of 
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the vial. Conscious sedation will be achieved using a combination of intravenous midazolam 
(versed) and fentanyl as standard sedative. During the procedure vital signs including oxygen 
saturation will be monitored per standard operating procedures of the endoscopy lab. Procedure 
related complications, including hypotension, desaturation and cardiac arrhythmia will be 
managed according to our endoscopy unit policy and protocols.
Following the procedure, the nurse and the fellow or the attending will individually rate the quality 
if sedation on a Likert scale (optimal sedation score of 7). Qualitative assessment will also be made 
(Under-sedated, adequately sedated, or over-sedated).  
Recovery time will be recorded. 
Day Following the Colonoscopy 
Twenty-four hour discharge a follow up call will be made and the patients will be asked to evaluate 
the level of pain (1, no pain; 10 severe pain), and amnesia (10, no memory of the procedure; 1 
complete memory). 
E. Statistical Analysis 
Sample Size Calculation: Using a mean dose of 94 mcg ± 29.1 for fentanyl (Robertson, DJ et al.) 
and considering a 15 mcg decrease in dose as significant a sample size of 120 will give a power of 
80% at an alpha of 0.05
SAS software (SAS Institute, Cary, NC, USA) will be used for performance of data analyses. 
Continuous variables will be reported as mean ± SD and categorical variables as percentages. Two-
sided t-test will be used to compare the means of continuous variables in the two groups 
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(diphenhydramine versus placebo), and Chi-square test will be used to compare the categorical 
variables. A P value < 0.05 will be considered statistically significant.
F. Gender/Minority/Pediatric Inclusion for Research 
This protocol includes all adult (over age 18) patients who will be having a colonoscopy as an 
outpatient.  No distinctions based on race or gender is relevant.
G. Human Subjects
Criteria for inclusion and exclusion is described are listed above. 
After obtaining consent medical records will be reviewed. Data will be gathered during and after 
colonoscopy as described above. 
The patient will be consent on the day of procedure by a team member in a private setting. 
Information about the study will be provided over the phone in advance and a copy of consent 
will be mailed to the identified patients for review at least a week prior to the scheduled 
colonoscopy. A contact number will be provided to address any questions or concerns. 
Risk and side effects related to Diphenhydramine as an adjunct to sedation: <1% (Limited to 
important or life-threatening). Side effects include dry mouth, pupillary dilation, urinary 
retention, constipation, hallucinations and delirium. Most of these side effects are temporary. QT 
prolongation leading to cardiac arrhythmia and torsades de pontes is extremely rare. xi Study by 
Raymond H, et al showed complication rate was not significantly different between patient 
receiving (midazolam + meperidine + Placebo) and   (Midazolam + meperidine + 
diphenhydramine). In addition all complications were mild. 
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H. Data and Safety Monitoring 
All data will be abstracted without personnel identifiers like name, social security number, date 
of birth, medical record number and assigned a code number.  The list that matches names with 
the code number will be kept in a locked file in the research team’s office (VA OKC Room # 
6A-143).  The research records will be kept in a password-protected computer file that only the 
study team will have access to. The personal computers used will be encrypted to ensure VA 
policies are met. All mobile devices will be encrypted and that the encryption will be FIPS 140-2 
validated.  Sensitive information will be transmitted to other research members using secure e-
mail only. Research data stored on a mobile device will be backed up regularly and stored 
securely within VA’s protected environment. Study personnel once they are not a part of the 
research team will lose access to any research study data. 
Destruction of Research Records:  All data used and maintained as part of a research protocol 
will be retained indefinitely until scheduled for destruction in accordance with Records Control 
Schedule (RCS) 10-1.  At the completion of the study, the research records will be maintained in 
password protected computer file to which only the research team will have access to.   
Any theft or loss of data or storage media, unauthorized access of sensitive data or storage 
devices or non-compliance with security controls will be reported to VA research office and IRB 
within 5 days of the event by the PI. 
REFERENCES
i Abraham NS, Fallone CA, Mayrand S, Huang J, Wieczorek P, Barkun AN.Sedation versus no 
sedation in the performance of diagnostic upper gastrointestinal endoscopy: a Canadian 
randomized controlled cost-outcome study. Am J Gastroenterol. 2004 Sep;99(9):1692-9.
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ii Zubarik R, Ganguly E, Benway D, Ferrentino N, Moses P, Vecchio J. Procedure-related 
abdominal discomfort in patients undergoing colorectal cancer screening: a comparison of 
colonoscopy and flexible sigmoidoscopy. Am J Gastroenterol. 2002 Dec;97(12):3056-61.
iii Bergeron P, Enns J, Delima L, Dupuis JY, Wynands JE. Effects of routine premedication for 
cardiac catheterization on sedation, level of anxiety and arterial oxygen saturation. Can J Cardiol. 
1995 Mar;11(3):201-5.
iv  Cook PJ, Flanagan R, James IM. Diazepam tolerance: effect of age, regular sedation, and 
alcohol. Br Med J (Clin Res Ed). 1984 Aug 11;289(6441):351-3.
v Peña LR, Mardini HE, Nickl NJ. Development of an instrument to assess and predict 
satisfaction and poor tolerance among patients undergoing endoscopic procedures. Dig Dis Sci. 
2005 Oct;50(10):1860-71.
vi Keeffe EB, O'Connor KW. 1989 A/S/G/E survey of endoscopic sedation and monitoring 
practices. Gastrointest Endosc. 1990 May-Jun;36(3 Suppl):S13-8.
vii Hirsh I, Vaissler A, Chernin J, Segol O, Pizov R. Fentanyl or tramadol, with midazolam, for 
outpatient colonoscopy: analgesia, sedation, and safety. Dig Dis Sci. 2006 Nov;51(11):1946-51. 
Epub 2006 Sep 29.
viii  Tu RH, Grewall P, Leung JW, Suryaprasad AG, Sheykhzadeh PI, Doan C, Garcia JC, Zhang 
N, Prindiville T, Mann S, Trudeau W. Diphenhydramine as an adjunct to sedation for 
colonoscopy: a double-blind randomized, placebo-controlled study. Gastrointest Endosc. 2006 
Jan;63(1):87-94.
ix Roach CL, Husain N, Zabinsky J, Welch E, Garg R. Moderate sedation for echocardiography 
of preschoolers. Pediatr Cardiol. 2010 May;31(4):469-73. doi: 10.1007/s00246-009-9622-z. 
Epub 2010 Jan 3.
x Hofmeister EH, Egger CM. Evaluation of diphenhydramine as a sedative for dogs. J Am Vet 
Med Assoc. 2005 Apr 1;226(7):1092-4
xi Husain Z, Hussain K, Nair R, Steinman R. Diphenhydramine induced QT prolongation and 
torsade de pointes: An uncommon effect of a common drug. Cardiol J. 2010;17(5):509-11
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