Clinical trial NCT03088800
Conditions: Pain Management
Sponsor: Antonios Likourezos
Start date: 2018-04-30; Completion date: 2020-07-30
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Current literature supports ibuprofen and APAP are the most commonly used analgesics in the pediatric ED for acute traumatic/non-traumatic pain. However, the analgesic benefits of combination ibuprofen and APAP in this specific setting does not exist, but instead only as it applies to pediatric patients with postoperative pain. Thus, we have designed a double-blind, randomized, controlled clinical trial to evaluate analgesic efficacy, safety and feasibility of combination therapy to potentially broaden its clinical application in the pediatric ED. The investigators' hypothesize that combination oral ibuprofen and APAP therapy is superior to either drug alone and is an excellent analgesic modality for controlling acute traumatic/non-traumatic pain in the pediatric ED.

Detailed description:
The investigators' hypothesize the combination of oral ibuprofen and acetaminophen (APAP) is superior to either analgesic alone plus placebo for pediatric emergency department patients with acute traumatic/non-traumatic pain

1. Intent to Treat, prospective, randomized, double-blind trial.
2. Primary outcome: Pain reduction via NRS/FACES pain scale at times 0 and 60 minutes from administration of medication(s).

   Secondary outcomes: Antipyretic effects, level of analgesia achieved with each patient diagnosis(es), incidence and type of adverse effect(s), and patients' and parents' satisfaction with achieved level of analgesia.
3. Population : ages 3 - 17. Sample size 90 patients (30 per arm). Group 1: oral ibuprofen at 10mg/kg dose and placebo of equal volume; Group 2: oral APAP at 15 mg/kg dose and placebo of equal volume; and, Group 3: oral ibuprofen at 10 mg/kg dose and APAP at 15mg/kg dose.
4. Location: Urban tertiary care hospital Pediatric ED with 40,000 annual departmental visits.
5. Duration of Enrollment: 1 year from commencement of the study.

6/7. Patients will be enrolled and randomized upon triage by an assigned nurse dedicated to the study into one of three groups by using a blocks-randomization scheme for every 15 patients maintained by the ED pharmacists.

8\. For patients experiencing breakthrough pain, oral morphine sulfate at 0.2mg/kg will be provided.

Group 1: oral ibuprofen at 10 mg/kg dose and placebo of equal volume;

Group 2: oral APAP at 15 mg/kg dose and placebo of equal volume; and,

Group 3: oral ibuprofen at 10 mg/kg dose and APAP at 15mg/kg dose. Medications including placebo will be given via prefilled syringes of identical volume, color and flavor. Level of analgesia will be assessed at times 0 and 60 minutes from administration of medication(s).

All enrolled patients, health care practitioners, and research associates will be blinded to the study medication(s) given and to the allocation sequence. Pharmacist(s) who are aware of the study medication(s) will not enroll patients. The allocation sequence code will only be revealed to the researchers once recruitment, data collection, and data entry are completed.

Arms: arm 1: Oral Ibuprofen at 10mg/kg dose and placebo of equal volume arm 2: Oral APAP at 15 mg/kg and placebo of equal volume arm 3: Oral Ibuprofen at 10mg/kg dose and APAP at 15mg/kg dose.
Interventions: intervention 1: Ibuprofen intervention 2: APAP
Intervention descriptions: intervention 1: Oral Ibuprofen at 10 mg/kg dose intervention 2: Oral APAP at 15mg/kg dose

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Project Title: IBUPAP – Combination of Oral Ibuprofen and Acetaminophen (APAP) is Superior 
to Either Analgesic Alone for Pediatric Emergency Department (ED) Patients with Acute Mild to 
Moderate Pain 
 
 
NCT: 03088800 
 
 
Date:  September 24, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


I. Project Title: IBUPAP – Combination of Oral Ibuprofen and Acetaminophen (APAP) 
is Superior to Either Analgesic Alone for Pediatric Emergency Department (ED) 
Patients 
with 
Acute 
Mild 
to 
Moderate 
Pain 
 
 
II. Hypothesis/Research question: The combination of oral ibuprofen and acetaminophen 
(APAP) is superior to either analgesic alone plus placebo for pediatric emergency 
department patients with acute mild to moderate traumatic/non-traumatic pain. 
  
III. Goals /Objectives: Objective #1: Assess level of analgesia with combination oral 
ibuprofen and APAP therapy on a 10-cm visual analogue (NRS) or FACES pain scale in 
comparison to either analgesic medication alone plus placebo. Objective #2: Assess 
antipyretic effects with combination oral ibuprofen and APAP versus either analgesic 
medication alone plus placebo. Objective #3: Note level of analgesia achieved with each 
diagnosis(es). Objective #4: Assess the incidence and type of adverse effect(s) of the study 
medications as well as patients’ and parents’ satisfaction with achieved level of analgesia.  
 
IV. Rationale: Current literature supports ibuprofen and APAP are the most commonly used 
analgesics in the pediatric ED for acute mild to moderate traumatic/non-traumatic pain. 
However, the analgesic benefits of combination ibuprofen and APAP in this specific setting 
does not exist, but instead only as it applies to pediatric patients with postoperative pain. 
Thus, we have designed a double-blind, randomized, controlled clinical trial to evaluate 
analgesic efficacy, safety and feasibility of combination therapy to potentially broaden its 
clinical application in the pediatric ED. We hypothesize that combination oral ibuprofen 
and APAP therapy is superior to either drug alone and is an excellent analgesic modality 
for controlling acute mild to moderate traumatic/non-traumatic pain in the pediatric ED. 
 
V. Literature review: Pierce and Voss in meta-analysis and qualitative review of 85 studies 
compared analgesic and antipyretic effects of ibuprofen and APAP (54 contained analgesic 
efficacy data and 35 contained antipyretic data) in children and adults and demonstrated 
better fever control and greater pain relief in patients receiving ibuprofen (1). Clark et al 
randomized 300 hundred pediatric ED patients (aged 6-17 years old) with acute 
musculoskeletal injuries less than 48 hours prior to admission to weight-based APAP at 15 
mg/kg dose, ibuprofen at 10 mg/kg dose or codeine at 1 mg/kg dose (100 patients in each 
group). The results demonstrated greater analgesics effect of ibuprofen at 60 minutes with 
greater percentage of patients achieving adequate analgesia based on pre-determined 
change in pain score (2). Another double-blind crossover trial comparing analgesic efficacy 
of APAP at 15 mg/kg dose versus ibuprofen at 10 mg/kg dose in pediatric patients with 
acute migraine showed that ibuprofen was twice as likely as APAP to abort migraine within 
2 hours (3). Ibuprofen at 10 mg/kg dose was also found in a randomized, double-blind, 
multicenter, controlled trial by Bertin et al to have similar analgesic efficacy as compared 
to APAP at 10 mg/kg dose in pediatric patients (aged 1-6 years old) with 
pharyngitis/tonsillitis (4) or acute unilateral/bilateral otitis media (5). The evidence 
supporting the use of combination ibuprofen and APAP in pediatric patients, however, is 
limited to those with post-operative pain. Ong et al conducted a qualitative systematic 
review of 21 studies involving 1909 patients comparing the analgesic benefit of 


combination non-steroidal anti-inflammatory drug (NSAID) (diclofenac, ketoprofen, 
ketorolac, tenoxicam, rofecoxib, apirin) and APAP for acute pediatric postoperative pain 
demonstrating better analgesic efficacy of combination therapy as compared to APAP or 
NSAID alone in 85% and 64% of studies (6). Similarly, combination NSAID (rofecoxib 
or ibuprofen) and APAP was again found to require less rescue analgesia in the pediatric 
population after teeth extraction and tonsillectomy (7, 8). 
 
VI. Methodology:  (A clear outline of to whom, what, where and by whom) 
 
a. Study Design: Prospective, randomized, double-blinded, controlled clinical trial. 
 
b. Setting: Urban tertiary care hospital pediatric ED with 40,000 annual departmental 
visits.  
 
c. Inclusion/Exclusion Criteria: Patients with acute mild to moderate traumatic/non-
traumatic pain will be screened by the triage nurse, research associate(s), 
resident(s), fellow(s) and attending physician(s) involved in the study. Enrollment 
is to be carried out for patients during the weekdays/weekends when pharmacy 
resident(s) are present in the ED. 
 
Inclusion criteria: ages 3-17 years old presenting to the pediatric ED with mild to 
moderate traumatic/non-traumatic pain (ie, NRS 1-4, FACES 2). Exclusion 
criteria: (1) documented or suspected pregnancy, (2) parental refusal, (3) allergies 
to NSAIDS or APAP, (4) inability to tolerate oral medications or contraindications 
to oral medication route, (5) received analgesics within 4 hours prior to ED 
presentation, (6) inability to use pain scales.  
 
d. Randomization: Patients will be enrolled and randomized upon triage by an 
assigned nurse dedicated to the study into one of three groups by using a blocks-
randomization scheme maintained by the ED pharmacists. Group 1: oral ibuprofen 
at 10mg/kg dose and placebo of equal volume; Group 2: oral APAP at 15 mg/kg 
dose and placebo of equal volume; and, Group 3: oral ibuprofen at 10 mg/kg dose 
and APAP at 15mg/kg dose. Medications including placebo will be given via 
prefilled syringes of identical volume, color and flavor. Level of analgesia will be 
assessed at times 0 and 60 minutes from administration of medication(s). 
 
All enrolled patients, health care practitioners, and research associates will be 
blinded to the study medication(s) given and to the allocation sequence. 
Pharmacist(s) who are aware of the study medication(s) will not enroll patients. The 
allocation sequence code will only be revealed to the researchers once recruitment, 
data collection, and data entry are completed. 
 
e. Data collection instruments: The research associates and participating residents 
will prospectively collect NRS/FACES pain scale scores, antipyretic effects, 
patient diagnosis(es), adverse effect(s), patient diagnosis(es), and vital signs at 
times 0 and 60 minutes from administration of medication(s). Patients will be 


reassessed for type of adverse effect(s) after administration of study medication(s) 
with responses noted (eg, nausea, vomiting, dizziness). The research assistants will 
additionally review the pediatric ED log sheet daily during the enrollment period 
to make note of those patients excluded from the study based on criteria. 
 
f. Primary Data Analysis: An intent-to-treat analysis will be performed using SPSS 
software. Continuous variables will be compared using analysis of using 2 tests. 
The primary analysis will utilize a test for differences in mean self-reported pain 
intensity among groups using analysis of variance. For presence of adverse events 
adjusted odds ratios will be calculated using 2 tests. Two-sided tests of significance 
will be used throughout. Baseline characteristics will be measured with descriptive 
frequencies.  
References: 
 
1. Pierce CA, Voss B. Efficacy and safety of ibuprofen and acetaminophen in children and 
adults: a meta-analysis and qualitative review. Ann Pharmacother. 2010 Mar; 44(3):489-
506. doi: 10.1345/aph.1M332. Epub 2010 Feb 11. 
2. Clark E, Plint AC, Correll R, Gabory I, Passi B. A randomized, controlled trial of 
acetaminophen, ibuprofen and codeine for acute pain relief in children with 
musculoskeletal trauma. Pediatrics. 2007 Mar; 119(3):460-7. 
3. Hamalainen ML, Hoppu K, Valkeila E, Santavuori P. Ibuprofen or acetaminophen for the 
acute treatment of migraine in children: a double-blind, randomized, placebo-controlled, 
crossover study. Neurology. 1997 Jan; 48(1):103-7. 
4. Bertin L, Pons G, d’Athis P, Lasfargues G, et al. Randomized, double-blind, multicentre, 
controlled trial of ibuprofen versus acetaminophen (paracetamol) and placebo for treatment 
of symptoms of tonsillitis and pharyngitis in children. J Pediatr. 1991 Nov; 119(5):811-4. 
5. Bertin L, Pons G, d’Athis P, Duhamel JF, et al. A randomized, double-blind, multicentre 
controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of otitis 
media in children. Fundam Clin Pharmacol. 1996; 10(4):387-92. 
6. Ong CK, Seymour RA, Lirk P, Merry AF. Combining paracetamol (acetaminophen) with 
nonsteroidal antiinflammatory drugs: a qualitative systematic review of analgesic efficacy 
for acute postoperative pain. Anesth Analg. 2010 Apr 1; 110(4):1170-9. 
7. Kraglund F. Acetaminophen plus a nonsteroidal anti-inflammatory drug decreases 
postoperative pain more than either drug alone. J Am Dent Assoc. 2014 Sep; 145(9):966-
8. 
8. Pickering AE, Bridge HS, Nolan J, Stoddart PA. Double-bind, placebo-controlled 
analgesic study of ibuprofen or rofecoxib in combination with paracetamol for 
tonsillectomy in children. Br J Anaesth. 2002 Jan; 88(1):72-7.