Trial Outcomes & Findings for Diphenhydramine as an Adjunctive Sedative in Patients on Chronic Opioids (NCT NCT01967433)

Results Overview

Moderate sedation (using the American Society of Anesthesiologists definition of maintaining purposeful response to verbal or tactile stimulation, adequate ventilation requiring no airway protection, and maintenance of cardiovascular function) was then achieved using incremental doses of the combination of intravenous midazolam (1 mg) and fentanyl (25 μg) given every 2 to 3 minutes. To minimize any crossover, additional diphenhydramine was not permitted.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

120 participants

Primary outcome timeframe

From induction (first dose of sedative) to end of procedure

Results posted on

2020-03-11

Participant Flow

Participant milestones

Participant milestones
Measure	Diphenhydramine Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives Diphenhydramine Allocated: 61 Lost to follow up: 0 Analyzed: 61	Placebo 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives Placebo Allocated: 59 Lost to follow up: 0 Analyzed: 58
Overall Study STARTED	61	59
Overall Study COMPLETED	61	58
Overall Study NOT COMPLETED	0	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Diphenhydramine as an Adjunctive Sedative in Patients on Chronic Opioids

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Diphenhydramine n=61 Participants Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives	Placebo n=58 Participants 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives	Total n=119 Participants Total of all reporting groups
Age, Continuous	60.7 years STANDARD_DEVIATION 9.3 • n=5 Participants	60.1 years STANDARD_DEVIATION 9.7 • n=7 Participants	60.37 years STANDARD_DEVIATION 9 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	57 Participants n=5 Participants	56 Participants n=7 Participants	113 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	45 Participants n=5 Participants	46 Participants n=7 Participants	91 Participants n=5 Participants
Race/Ethnicity, Customized Race · Others	16 Participants n=5 Participants	12 Participants n=7 Participants	28 Participants n=5 Participants
Region of Enrollment United States	61 participants n=5 Participants	58 participants n=7 Participants	119 participants n=5 Participants

PRIMARY outcome

Timeframe: From induction (first dose of sedative) to end of procedure

Moderate sedation (using the American Society of Anesthesiologists definition of maintaining purposeful response to verbal or tactile stimulation, adequate ventilation requiring no airway protection, and maintenance of cardiovascular function) was then achieved using incremental doses of the combination of intravenous midazolam (1 mg) and fentanyl (25 μg) given every 2 to 3 minutes. To minimize any crossover, additional diphenhydramine was not permitted.

Outcome measures

Outcome measures
Measure	Diphenhydramine n=61 Participants Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives Diphenhydramine	Placebo n=58 Participants 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives Placebo
Dosage of Fentanyl	125.4 (μg) Standard Deviation 56.2	126.9 (μg) Standard Deviation 53.5

SECONDARY outcome

Timeframe: During the colonoscopy and 24 hours after discharge

Quality of sedation will be accessed by the nurse and the physician at the end of procedure. Name: 10 point visual analogue scale Minimum score: 1 (worse) Maximum score: 10 (better)

Outcome measures

Outcome measures
Measure	Diphenhydramine n=61 Participants Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives Diphenhydramine	Placebo n=58 Participants 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives Placebo
Quality of Sedation Physician rating	6.2 score on a scale Standard Deviation 1.1	5.3 score on a scale Standard Deviation 1.2
Quality of Sedation Nurse rating	5.6 score on a scale Standard Deviation 1.5	5.1 score on a scale Standard Deviation 1.4

SECONDARY outcome

Timeframe: Time from induction (first dose of sedative) to discharge

Induction period (time from first dose of fentanyl to scope insertion), procedural time (time from scope insertion to scope out), and recovery time (time from scope out to discharge) were recorded by the nursing staff in their standard documentation.

Outcome measures

Outcome measures
Measure	Diphenhydramine n=61 Participants Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives Diphenhydramine	Placebo n=58 Participants 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives Placebo
Duration of Procedure Procedure time	34.8 minutes Standard Deviation 19.5	34.7 minutes Standard Deviation 17.8
Duration of Procedure Recovery	34.4 minutes Standard Deviation 9.2	32.4 minutes Standard Deviation 5.9
Duration of Procedure Induction	6.4 minutes Standard Deviation 3.2	6.3 minutes Standard Deviation 2.8

SECONDARY outcome

Timeframe: From induction (first dose of sedative) to discharge

Following adverse events will be recorded: (1)Hypoxia defined as O2 saturation less than 89% lasting for more than 30 seconds, (2)hypotension defined as systolic BP less than 90 mmhg and (3)use of reversal agents i.e Naloxone or Flumazenil

Outcome measures

Outcome measures
Measure	Diphenhydramine n=61 Participants Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives Diphenhydramine	Placebo n=58 Participants 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives Placebo
Number of Participants With Adverse Events Hypotension	12 Participants	22 Participants
Number of Participants With Adverse Events Hypertension	5 Participants	3 Participants
Number of Participants With Adverse Events Desaturation	0 Participants	0 Participants
Number of Participants With Adverse Events Apnea	0 Participants	0 Participants
Number of Participants With Adverse Events Arrhythmia	0 Participants	0 Participants
Number of Participants With Adverse Events Reversal agent use	0 Participants	0 Participants
Number of Participants With Adverse Events Tachypnea	0 Participants	0 Participants

SECONDARY outcome

Timeframe: About 24 hours after the procedure

At 24 hr follow up patients were asked to rate the level of pain during the procedure using 10 point scale. 10 point visual analogue scale minimum= 0 (better) maximum =10 (worse)

Outcome measures

Outcome measures
Measure	Diphenhydramine n=61 Participants Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives Diphenhydramine	Placebo n=58 Participants 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives Placebo
24 Hour Follow up Pain Score	2.0 score on a scale Standard Deviation 2.17	3.09 score on a scale Standard Deviation 3.95

SECONDARY outcome

Timeframe: From induction (first dose of sedative) to end of procedure

Moderate sedation (using the American Society of Anesthesiologists definition of maintaining purposeful response to verbal or tactile stimulation, adequate ventilation requiring no airway protection, and maintenance of cardiovascular function) was then achieved using incremental doses of the combination of intravenous midazolam (1 mg) and fentanyl (25 μg) given every 2 to 3 minutes. To minimize any crossover, additional diphenhydramine was not permitted.

Outcome measures

Outcome measures
Measure	Diphenhydramine n=61 Participants Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives Diphenhydramine	Placebo n=58 Participants 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives Placebo
Dosage of Midazolam	4.9 mg Standard Deviation 2.1	5.0 mg Standard Deviation 1.9

SECONDARY outcome

Timeframe: At about 24 after the procedure

Patient were also asked to rate amnesia on a 10 point scale 24 after discharge. minimum= 0 (worse) maximum =10 (better)

Outcome measures

Outcome measures
Measure	Diphenhydramine n=61 Participants Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives Diphenhydramine	Placebo n=58 Participants 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives Placebo
24 Hour Follow up Amnesia Score	7.8 score on a 10 point point scale Standard Deviation 3.4	6.5 score on a 10 point point scale Standard Deviation 3.8

Adverse Events

Diphenhydramine

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Diphenhydramine n=61 participants at risk Diphenhydramine 50 mg IV 3 minutes prior to administration of other sedatives	Placebo n=58 participants at risk 0.9% sodium chloride 10 ml IV 3 minuted prior to administration of other sedatives
General disorders Hypertension	8.2% 5/61 • Number of events 5 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)	5.2% 3/58 • Number of events 3 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)
Cardiac disorders Hypotension	19.7% 12/61 • Number of events 12 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)	37.9% 22/58 • Number of events 22 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/61 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)	0.00% 0/58 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)
Respiratory, thoracic and mediastinal disorders Apnea	0.00% 0/61 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)	0.00% 0/58 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)
Cardiac disorders Arrhythmia	0.00% 0/61 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)	0.00% 0/58 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)
General disorders Reversal Agent	0.00% 0/61 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)	0.00% 0/58 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)
Respiratory, thoracic and mediastinal disorders Tachypnea	0.00% 0/61 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)	0.00% 0/58 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)
Cardiac disorders Bradycardia	0.00% 0/61 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)	0.00% 0/58 • Preprocedure, procedural, post procedure and 24 hr follow up Hypoxia (defined as O 2 saturation less than 89% lasting for more than 30 seconds), hypertension (20 mm Hg increase in blood pressure from baseline, provided this is \>140 mm Hg systolic and 90 mm Hg diastolic), hypotension (20 mmHg decrease in blood pressure from baseline, provided this is \<100 mm Hg systolic or 60 mm Hg diastolic), bradycardia (a decrease in heart rate of \>20 bpm, provided this is less than 60), tachycardia (an increase in heart rate of \>20 bpm, provided this \>100 bpm)

Additional Information

Salman Nusrat

University of Oklahoma Health Sciences Center and VAMC, Oklahoma City

Phone: 4052715428

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place