Clinical trial NCT01825655
Conditions: Pruritus
Sponsor: Virginia Commonwealth University
Start date: 2014-09-01; Completion date: 2017-11-01
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is determine if long acting antihistamine like cetirizine can help with itching induced by opioid pain medications.

Detailed description:

Arms: arm 1: zyrtec 10mg, oral, one time arm 2: Placebo, one pill, one time
Interventions: intervention 1: Cetirizine intervention 2: Placebo or sugar pill
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
Title: Effect of long acting antihistamine on opioid- induced pruritus: A double-blind placebo 
controlled study  
 
PI: Santhosh Kumar, MD 
 
NCT #: 01825655 
 
Unique Protocol ID: HM20003779 
 
Document approval date: August 26, 2015 
 
Document Type: Protocol and SAP 
 
 


 
2 
Protocol 
 
Effect of long acting antihistamine on opioid- induced pruritus: 
A double-blind placebo controlled study. 
 
Principal Investigator: Santhosh Kumar, MD 
Co-investigators: Gita Massey, MD 
                            India Sisler, MD 
                            Wei Zhao, MD 
                            Pauline Balkaransingh, MD 
                            Manar Abdalgani, MD 
                            Jennifer Newlin, PA 
                            Carrie Sitterson, NP 
                             
 
 
 
 
Correspondence: 
Santhosh Kumar, MD 
Assistant Professor of Pediatrics 
Division of Allergy & Immunology 
Virginia Commonwealth University School of Medicine 
1001 East Marshall St, P.O. Box-980225 
Telephone +804-628-1605 
Fax +804-828-5481  
 
 
 
 
 


 
3 
 
 
Background and Significance: 
Opioids are commonly used in the treatment of moderate-severe pain. Pruritus is a 
common adverse effect of this class of medications, occurring in up to 10% of subjects 
treated with oral or intravenous opioids. [1].The prevalence goes up with the dose of 
opioid being used [2]. The exact mechanism for the pruritus is unknown but there are 
two principal theories: A peripheral effect mediated by histamine released via direct mast 
cell degranulation by opioids; and a central mechanism mediated by μ opioid receptors 
in the nervous system [3, 4].  
Currently, there is no standardized treatment for opioid induced pruritus. Most studies 
conclude that opioid antagonists are the best treatment; however, they also decrease 
the analgesic effect. A recent study has compared Odansetron and diphenhydramine 
treatment for pruritus in women who received intrathecal opioids and found them equally 
effective. [5].This study was in adults receiving intrathecal opioid. There are no pediatric 
studies looking at effective treatment options for opioid-induced pruritus. As a 
consequence, the usual practice is to discontinue the opioid and use an alternate drug 
for analgesia. There are no prospective double blind studies available that have looked 
at the effect of a second-generation, non-sedating, long- acting antihistamine on opioid 
induced pruritus in children.  
 
Hypothesis: 
Histamine is the primary mediator responsible for pruritus induced by oral or intravenous 
administration of opioids. A second generation, long acting antihistamine will be effective 
at relieving the pruritus and allowing continued therapy with opioids. 
Specific aims:  
1. Our primary objective is to assess the efficacy of a long- acting antihistamine, 
Cetirizine, on opioid- induced pruritus in a double-blind, placebo controlled study. 
The primary outcome will be number of treatment failures between the treatment 
and placebo groups.  Treatment failure is defined as persistent itch score of > 3 
3hrs after receiving the intervention. 
2. Our secondary objectives are to analyze: 
- The correlation between baseline serum tryptase levels and the occurrence of 
opioid- induced pruritus.  
- The effect of age, race, sex on opioid induced pruritus and the influence of 
these parameters on antipruritic effect of the drug. 
 
 
 
 


 
4 
 
 
Methods: 
Subject recruitment: 
This study is a randomized, double blind placebo controlled study. Subjects 6-18yrs of 
age, requiring treatment with oral or intravenous opioids will be recruited from the 
pediatric inpatient units at Children's Hospital of Richmond at VCU.  
Inclusion criteria: 
- 
Children age 6-18yrs on opioids who develop pruritus and are willing to 
participate in the study 
 
Exclusion criterias: 
- 
Children with history of chronic urticaria  
- 
Children with other chronic pruritic condition like eczema, contact dermatitis, 
psoriasis 
- 
Children with known hypersensitivity to cetirizine/zyrtec 
- 
Children on second generation antihistamine 1 week prior to the study 
recruitment 
- 
Children who are unwilling or unable to swallow the capsule. 
- 
Children with chronic liver or kidney disease 
 
Study Design: 
After obtaining an informed consent from the parent or guardian, and an informed assent 
from children ages 12 years and above, serum tryptase levels will be drawn at baseline. 
For subjects whose baseline tryptase could not be drawn prior to the onset of itch 
symptom, a second attempt will be made either 24hrs after being symptom free or at a 
later date either in the inpatient or outpatient setting when they are free of symptoms.  
Subjects who develop pruritus will have a baseline itch score measured at the onset of 
the itch symptom. Subjects with itch score of > 3 will be randomized in a double blind 
fashion to the treatment group with cetirizine 10 mg once daily or to the placebo group.  
A tryptase level will be obtained 15-60 minutes after the onset of itching. Subjects will 
have itch scores measured at two time points from receiving the intervention, one at 
3hours and other at 12 hours. Subjects will be allowed to receive rescue 
Diphenhydramine (Benadryl) 3 hours post intervention at the discretion of the treating 
physician.  
Treatment failure is defined as an itch score of >3 at 3 hours post intervention and will 
result in discontinuation from the study. Successfully treated subjects will have a second 
itch score measured at 12 hours post intervention to analyze the persistence of 
antipruritic effect of the intervention. The numbers of treatment failures in each group are 
recorded. The total number of rescue Benadryl doses in each group will also be 


 
5 
recorded. The opioid dose, interval and total doses that each subject receives will be 
recorded.  Patients whose treatment has been successful in controlling the pruritus (itch 
score ≤ 2) will continue in that arm for a maximum of 12 hours or till discharge whichever 
is earlier. Patients may drop out of the study at any time. The reason for dropping out will 
be recorded.  At the conclusion of the study, patients will be reassessed by the primary 
team for further need for any anti-pruritic medications.  
 
Primary Outcome 
Number of treatment failures in the study group versus the placebo group at 3 hours 
post randomization 
 
Secondary Outcomes: 
1. Number of drop outs in the study group versus the placebo group at the end of the 
study period. 
2. Tryptase levels (Total and mature) in subjects who develop opioid-induced pruritus 
versus those who do not. 
3. Change in Tryptase levels (Total and mature) from baseline in subjects who develop 
pruritus 
4. Effect of age, race, and sex on the incidence of opioid-induced pruritus 
5. Effect of age, race, and sex on response to cetirizine in subjects with opioid-induced 
pruritus.  
6. Change in the baseline itch score between treatment and the placebo group. 
7. Number of rescue Benadryl doses between treatment and the placebo group. 
 
Preliminary Results:  
Based on our experience (n=16) over the last few months, 37% (n=6) of patients treated 
with opioids in the inpatient setting develop pruritus. Of those 6 patients, 66.6% were 
successfully treated with an antihistamine and were able to continue treatment on the 
same opioid.  
 
Statistical Method: 
Data will be analyzed using Chi square, student t-tests and Mann-Whitney U test (for 
non-parametric data) where appropriate. A p value of <0.05 will be considered 
significant. 


 
6 
Assuming a 50% reduction in the failure rate to be clinically significant, a sample size of 
66 confers a power of 0.8 at α=0.05. Assuming a 10% drop out rate in each group a total 
of 73 patients will be recruited.  
 
Time line: 
We plan to recruit at least 1 patient per week for this study. The study should be 
completed in 2years. There is a real chance of completing this study much earlier than 
the 2 year time frame.  
 
Investigator responsibilities: 
- 
The study will be approved by the Western Institutional Review Board 
- 
Conduct the study smoothly and effectively 
- 
Report any adverse effects to McNeil Pharmaceuticals.  
- 
At the completion of the study the data will be presented to McNeil before 
sending in for publication. 
 
Future research direction: 
1. To analyze the effect of antihistamine on opioid-induced itching in a much larger 
sample size. 
2. To investigate titration prick skin testing to opioid as a predictor of opioid-induced 
itching. 
 
Limitation of the study: 
1. Itch scale is subjective and hence there is no objective way to assess 
improvement in itching 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
7 
 
 
 
 
 
 
 
 
 
 
Sample size calculation 
 
Sample sizes for an α = 0.05 significance level with a two group continuity correctedχ2 
test of equal proportions – 1 sided test, equal sample sizes in each group 
 
 
Placebo 
Group 
 
Treatment 
Reduction 
 
Treatment 
Group 
Sample Size 
Per Group 
80% Power 
Sample Size 
Per Group 
90% Power 
0.3704 10% Reduction 
0.3333 
2,102 
2,890 
0.3922 15% Reduction 
0.3333 
857 
1,174 
0.4167 20% Reduction 
0.3333 
440 
599 
0.4444 25% Reduction 
0.3333 
255 
346 
0.4762 30% Reduction 
0.3333 
159 
214 
0.5556 40% Reduction 
0.3333 
70 
90 
0.6667 50% Reduction 
0.3333 
33 
43 
0.8333 60% Reduction 
0.3333 
15 
19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
8 
 
 
 
 
 
 
 
 
ITCH SCORE 
 
 
1=No 
pruritus 
2=Mild pruritus 
(no intervention 
necessary) 
3= Moderate 
pruritus 
(intervention 
necessary) 
4= Severe pruritus 
3hrs 
 
 
 
 
12hrs 
 
 
 
 
 
 
 
 
 
 
Description of the scores: 
1. No pruritus- absence of any itching 
2. Mild pruritus- presence of itching in only one location of the body (e.g. faces 
or arm). No intervention necessary as assessed by the investigator and the 
patient agreeing to the decision. Usually the itching is not relieved by the 
patient and only reported after being prompted by the investigator/ 
3. Moderate pruritus- presence of itching in more than one location, typical in 2 
locations (e.g. arms and thorax). Intervention necessary as assessed by the 
investigator and the patient. 
4. Severe pruritus- severe itching which involves almost the entire body and 
often disturbing the patient.  
Score of > 3-included in the randomization 
Improvement is a score of < 2 at 3hrs 
 
 
 
 
 
 
 
 
 
 


 
9 
 
 
 
 
 
 
 
 
 
References: 
1. Reich A, Szepietowski JC. Opioid-induced pruritus: an update. Clin Exp 
Dermatol. 2010 Jan;35(1):2-6. 
2. Bertz JM, Hermens JM, McMillan JC, Uno H, Hirshman C, Hanifin JM. Functional 
differences between human cutaneous mast cells and basophils: a comparison 
of morphine-induced histamine release. Agents Actions. 1986 Aug;18(5-6):455-
62. 
3. Fisher MM, Harle DG, Baldo BA. Anaphylactoid reactions to narcotic analgesics. 
Clin Rev Allergy. 1991 Fall-Winter;9(3-4):309-18. 
4. Swegle JM, Logemann C. Management of common opioid-induced adverse 
effects. Am Fam Physician. 2006 Oct 15;74(8):1347-54. 
5. Siddik-Sayyid SM, Yazbeck-Karam VG, Zahreddine BW, Adham AM, Dagher 
CM, Saasouh WA, Aouad MT. Ondansetron is as effective as diphenhydramine 
for treatment of morphine-induced pruritus after cesarean delivery. Acta 
Anaesthesiol Scand. 2010 Jul;54(6):764-9.