A Dose Ranging Effect of Preoperative Diphenhydramine on Postoperative Quality of Recovery After Ambulatory Surgery

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01451762
• Collaborator: (none)
• Enrollment: 90
• Locations: 2
• Arms: 3
• Duration (Months): 12
• Patients Per Site: 45
• Patients Per Site Per Month: 3.7

Study Details

Study Description

Brief Summary

Pain after ambulatory surgery remains an unsolved problem in The United States and Europe. It is associated with delayed hospital discharge and it can result to an increased opioid consumption with adverse side effects. The concept of multimodal analgesic technique was introduced more than 15 years ago and several techniques have been studied over the years including non steroidal antiinflammatory drugs (NSAIDs), acetaminophen, gabapentoids, ketamine, local and regional anesthetic techniques. Histamine can have effects on polymodal nociceptors and C-fibers, producing pain which is further increased by neurogenically mediated release of substance P from afferent pain fibers. Several non-selective or H1 -selective histamine receptors antagonists have been demonstrated in animal models and clinical pain. Chia et al demonstrated that preoperative promethazine had opioid sparing properties without adverse sedative effects in patients undergoing abdominal hysterectomy.

Diphenhydramine is an anti-histamine drug who has been found to be effective in reducing postoperative nausea and vomiting after ambulatory surgery but its effects on postoperative pain and other important outcomes after ambulatory surgery such as time to meet discharge criteria have not being studied.

The MQOR 40 is a validated instrument that was specifically design to evaluate patient recovery after anesthesia and surgery. This instrument can be particularly valid to examine interventions which affect different spheres of patient recovery as is the case of diphenhydramine. The objective of this study is to determine a dose response effect of preoperative diphenhydramine on postoperative quality of recovery after ambulatory surgery. The use of preoperative diphenhydramine can improve patient's quality of recovery, decrease postoperative pain, opioid consumption and opioid related side effects after ambulatory surgery.

The research question: Does a preoperative dose of diphenhydramine improve postoperative quality of recovery after ambulatory surgery? The hypothesis of this study is that preoperative diphenhydramine will improve postoperative pain, Postoperative nausea and vomiting (PONV), sleep which will translate in a better overall quality of recovery.

Condition or Disease	Intervention/Treatment	Phase
Surgery; Pain	Drug: .9 normal saline; Drug: 25 mg diphenhydramine IV; Drug: 50 mg diphenhydramine IV	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Dose Ranging Effect of Preoperative Diphenhydramine on Postoperative Quality of Recovery After Ambulatory Surgery
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo .9 normal saline IV	Drug: .9 normal saline; .9 normal saline administered before surgery.
Active Comparator: 25 mg diphenhydramine IV 25 mg diphenhydramine IV administered before surgery	Drug: 25 mg diphenhydramine IV; 25 mg diphenhydramine IV administered before surgery
Active Comparator: 50 mg diphenhydramine IV 50 mg diphenhydramine IV administered before surgery	Drug: 50 mg diphenhydramine IV; 50 mg diphenhydramine administered IV before surgery

Outcome Measures

Primary Outcome Measures

1. Quality of Recovery 40 at 24 Hours [24 hours post operatively]

   Scores on QOR (quality of recovery) 40 questionnaire.The QoR-40 score, which ranges from 40 to 200, representing very poor to outstanding quality of recovery, respectively.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 18-64 years

• Patients undergoing ambulatory surgery

• ASA PS I, II.

Exclusion Criteria:

• Chronic opioid use

• pregnant patient or lactating patients

• allergy to diphenhydramine

• glaucoma

• uncontrolled hypertension

• asthma

• hyperthyroidism

• cardiovascular disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Prentice Womens HOspital	Chicago	Illinois	United States	60611
2	Prentice Womens HOsptial	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• Northwestern University

Investigators

• Principal Investigator: Gildasio De Oliveira, MD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003 Aug;97(2):534-540. doi: 10.1213/01.ANE.0000068822.10113.9E.
• Baird-Lambert J, Jamieson DD. Possible mediators of the writhing response induced by acetic acid or phenylbenzoquinone in mice. Clin Exp Pharmacol Physiol. 1983 Jan-Feb;10(1):15-20.
• Benhamou D, Berti M, Brodner G, De Andres J, Draisci G, Moreno-Azcoita M, Neugebauer EA, Schwenk W, Torres LM, Viel E. Postoperative Analgesic THerapy Observational Survey (PATHOS): a practice pattern study in 7 central/southern European countries. Pain. 2008 May;136(1-2):134-41. Epub 2007 Aug 20.
• Kehlet H, Dahl JB. The value of "multimodal" or "balanced analgesia" in postoperative pain treatment. Anesth Analg. 1993 Nov;77(5):1048-56. Review.
• Raffa RB. Antihistamines as analgesics. J Clin Pharm Ther. 2001 Apr;26(2):81-5. Review.
• Rumore MM, Schlichting DA. Analgesic effects of antihistaminics. Life Sci. 1985 Feb 4;36(5):403-16. Review.
• Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjörk HE. Specific C-receptors for itch in human skin. J Neurosci. 1997 Oct 15;17(20):8003-8.
• White PF, Kehlet H. Improving postoperative pain management: what are the unresolved issues? Anesthesiology. 2010 Jan;112(1):220-5. doi: 10.1097/ALN.0b013e3181c6316e. Review.

• Responsible Party: Gildasio De Oliveira, Gildasio De Oliveira, M.D. Principal Investigator, Northwestern University
• ClinicalTrials.gov Identifier: NCT01451762
• Other Study ID Numbers: STU00044695
• First Posted: Oct 14, 2011
• Last Update Posted: Mar 14, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by Gildasio De Oliveira, Gildasio De Oliveira, M.D. Principal Investigator, Northwestern University: pain; anesthesia; surgery; postoperative
• Additional relevant MeSH terms: Diphenhydramine; Promethazine

Study Results

Participant Flow

Recruitment Details	90 subjects were enrolled between September 2011 and September 2012.

Arm/Group Title	Placebo	25 mg Diphenhydramine IV	50 mg Diphenhydramine IV
Arm/Group Description	.9 normal saline IV	25 mg diphenhydramine IV administered before surgery	50 mg diphenhydramine IV administered before surgery
Period Title: Overall Study
STARTED	30	30	30
COMPLETED	27	24	24
NOT COMPLETED	3	6	6

Baseline Characteristics

Arm/Group Title	Placebo	25 mg Diphenhydramine IV	50 mg Diphenhydramine IV	Total
Arm/Group Description	.9 normal saline IV	25 mg diphenhydramine IV administered before surgery	50 mg diphenhydramine IV administered before surgery	Total of all reporting groups
Overall Participants	30	30	30	90
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	30 100%	30 100%	30 100%	90 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35 (8.36)	36.5 (10.7)	37 (8.3)	37 (9.1)
Sex: Female, Male (Count of Participants)
Female	30 100%	30 100%	30 100%	90 100%
Male	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	30 100%	30 100%	30 100%	90 100%

Outcome Measures

1. Primary Outcome

Title	Quality of Recovery 40 at 24 Hours
Description	Scores on QOR (quality of recovery) 40 questionnaire.The QoR-40 score, which ranges from 40 to 200, representing very poor to outstanding quality of recovery, respectively.
Time Frame	24 hours post operatively

Outcome Measure Data

Analysis Population Description

Primary outcome was QOR 40 a sample size of 23 per group was estimated to achieve 80% power to detect a 10 point difference in aggregated QOR040 score for the three groups. A 10 point difference represents a clinically relevant improvement in quality of recovery. TO account for drop outs lost to follow up 90 subjects were randomized.

Arm/Group Title	Placebo	25 mg Diphenhydramine IV	50 mg Diphenhydramine IV
Arm/Group Description	.9 normal saline IV	25 mg diphenhydramine IV administered before surgery	50 mg diphenhydramine IV administered before surgery
Measure Participants	27	24	24
Median (Inter-Quartile Range) [units on scale 40 (low) - 200 (high)]	164	169	172

Adverse Events

Time Frame	24 hours
Arm/Group Title	Placebo		25 mg Diphenhydramine IV		50 mg Diphenhydramine IV
Arm/Group Description	.9 normal saline IV		25 mg diphenhydramine IV administered before surgery		50 mg diphenhydramine IV administered before surgery
All Cause Mortality
	Placebo		25 mg Diphenhydramine IV		50 mg Diphenhydramine IV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		25 mg Diphenhydramine IV		50 mg Diphenhydramine IV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/27 (0%)		0/24 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		25 mg Diphenhydramine IV		50 mg Diphenhydramine IV
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/27 (44.4%)		9/24 (37.5%)		3/24 (12.5%)
Gastrointestinal disorders
Nausea	12/27 (44.4%)	12	9/24 (37.5%)	9	3/24 (12.5%)	3

Limitations/Caveats

We did not obtain preoperative quality of recovery scores of patients therefore we could not examine whether the effect of diphenhydramine was dependent upon patient's baseline characteristics.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.