Randomized, Double-Blind, Placebo-Controlled Trial Comparing Opioid-Sparing and Opioid-Containing Analgesia Regimens Following Trans-sphenoidal Surgery for Pituitary Tumors
Phase: PHASE4
Conditions: Pituitary Tumor, Pain
Sponsor: St. Joseph's Hospital and Medical Center, Phoenix

 
 
 
 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED TRIAL COMPARING OPIOID-SPARING 
AND OPIOID-CONTAINING ANALGESIA REGIMENS 
FOLLOWING TRANS-SPHENOIDAL SURGERY FOR 
PITUITARY TUMORS 
 
 
 
NCT02351700 
 
 
 
 
 
 
 
 
20NOV2015 

Original July 24, 2014; Revised Jan 8, 2015; Nov 20, 2015
1
 Study Protocol Version 2.1 – Nov 20, 2015
Study Title 
Randomized, Double-Blind, Placebo-Controlled Trial Comparing Opioid-Sparing and 
Opioid-Containing Analgesia Regimens Following Trans-sphenoidal Surgery for Pituitary 
Tumors
Study Hypothesis
An opioid-sparing postoperative analgesia regimen provides superior postoperative pain 
control, limits opioid-related adverse events, and improves inpatient hospital charges 
compared to a standard opioid-containing postoperative analgesia regimen.
Objectives
Primary Objective
1) Compare postoperative pain control regimens using an opioid-sparing analgesia 
approach and a standard opioid-containing approach in patients that have 
undergone endonasal, trans-sphenoidal (ENTS) surgery. 
Secondary Objectives
1) Determine if the institution of an opioid-sparing analgesia regimen decreases the 
use of rescue narcotics in postoperative patients. 
2) Determine if the institution of an opioid-sparing analgesia regimen decreases 
opioid-related adverse events
3) Determine if the institution of an opioid-sparing analgesia regimen decreases 
hospital length of stay, pharmacy charges, and overall hospital charges. 
Background
Post-operative pain control is a common concern patients have when they consider 
undergoing a surgical procedure.  Although effective for treating acute pain, opioid 
analgesics are also associated with dose-dependent adverse effects, including constipation, 
nausea and vomiting, altered mental status, and respiratory depression, all of which have 
been shown to increase patient length of stay (1).  The use of non-opioid analgesics with 
different mechanisms of actions for acute pain control via a multi-modal approach is 
efficacious in reducing opioid consumption, decreasing the incidence of adverse effects, 
improving patient satisfaction and recovery time, and decreasing hospital costs (2,3,5). 
IRB NUMBER: PHX14BN090
IRB APPROVAL DATE: 01/12/2016

Original July 24, 2014; Revised Jan 8, 2015; Nov 20, 2015
2
Certain minimally invasive procedures may afford many patients the opportunity to 
achieve adequate post-operative pain control with minimal to no requirement of opioid 
analgesics, thereby sparing the patient known adverse effects that can increase length of 
stay and costs(3).  The ENTS approach for resection of pituitary tumors is the standard 
surgical procedure for these lesions, and is associated with pain that is more easily 
managed post-operatively,  making it an ideal procedure for an opioid-sparing post-
operative pain regimen(4).  Anecdotally, we have noted in our post-operative pituitary 
patient population that we are frequently able to adequately manage post-operative pain 
with scheduled non-opioid analgesics, often without requiring breakthrough opioid doses.  
Another safe and effective non-opioid analgesic that is widely used in multi-modal pain 
management for moderate pain is IV Caldolor (ibuprofen) (6.7.8).  After literature review, 
we were unable to find a study that had attempted to use an opioid-sparing analgesic 
regimen for post-operative pain control following ENTS approach for resection of pituitary 
tumors.
Study Design
A randomized, double-blind, placebo-controlled, intervention trial involving 100 treated 
patients undergoing ENTS resection of pituitary lesion.  Patients will be randomized into 
two groups; 50 treated patients in the opioid-sparing arm and 50 treated patients in the 
standard post-operative medication arm. 
Selection and Enrollment of Subjects
Inclusion criteria
1) Adult patient undergoing ENTS surgery for resection of pituitary tumor
2) Adults >18 and <80 years of age
3) English speaking and literate or able to understand the use of a pain scale 
4) BMI >19 and <40 kg/m²
5) Free of any physical, mental, or medical condition which, in the opinion of the 
investigator, made study participation inadvisable
Exclusion criteria
1) Renal failure (acute or chronic) or creatinine>2.0
2) Allergy or intolerance to acetaminophen, ibuprofen, or opioids
3) Pre-operative opioid tolerance, dependence, or abuse
4) Anaphylaxis to opioids
5) History of peptic ulcer disease or recent GI bleed requiring surgery
6) Cirrhosis, hepatitis, liver transplant, or liver function studies out of normal range 
(AST/ALT/bilirubin>3x upper limit of normal range)
IRB NUMBER: PHX14BN090
IRB APPROVAL DATE: 01/12/2016

Original July 24, 2014; Revised Jan 8, 2015; Nov 20, 2015
3
7) Any subject who is unwilling or unable to sign informed consent for the study
8) Pregnancy
9) Incarcerated patients
10)  Patients with chronic pain or significant medical disease whereby involvement 
in the study may, in the investigator’s opinion, impact the patient’s welfare
11) Patients with a history of TIA (transient ischemic attack) or stroke or 
myocardial infarction or a patient with risks factors for the above (such as 
hypertension, diabetes, hyperlipidemia, or smoking) that in the judgment of the 
PI places the patient at significantly elevated risk of adverse event after surgery.
Study enrollment procedures
1) Screening procedure: The outpatient clinic records of patients scheduled to 
undergo transsphenoidal surgery will be screened to determine if patients meet 
study criteria. 
2) Tracking procedure: Inpatients will be followed by the study team for 48 hours 
or until discharge, whichever is first, after surgery.  Patient data will be collected 
with a data collection sheet (Addendum B).
3) Informed consent procedure: The Investigator or a designee is responsible for 
obtaining informed consent from each patient and for obtaining the appropriate 
signatures and dates prior to the performance of any protocol procedures and 
prior to the randomizing subjects. The informed consent document will be used 
to help explain the risks and benefits in simple terms to the patient (Addendum 
C). 
4) Randomization: Eligible patients who provide consent will be randomized to 
opioid-sparing or standard pain medication regimen.  
Study Interventions
Pre-operative education and consent visit
All patients will attend a pre-operative education, consent, and pre-testing visit one 
or two days prior to the scheduled surgical date.  Prior to this session, the patient’s history 
from initial consult will be reviewed to screen for eligibility for the study; eligible patients 
will be contacted.  If consent is obtained, the patient will be randomized to either the 
opioid-sparing arm or the standard arm (Addendum A).
Randomization
IRB NUMBER: PHX14BN090
IRB APPROVAL DATE: 01/12/2016

Original July 24, 2014; Revised Jan 8, 2015; Nov 20, 2015
4
Patients will be randomized in a 1:1 ratio with blinded treatment assignment. The 
patients will be randomized using a computer generated list of random numbers from 
www.random.org. A list of 120 numbers will be randomized. Twenty extra numbers will be 
randomized to account for patients that randomize but do not undergo treatment. The 
randomized list will be placed with an ordered list of numbers from 1 to 120.  Odd numbers 
will be assigned to the treatment group and even numbers to the control group.  For 
example, the first randomized number of 61 would be assigned to the treatment group; a 
second number of 4 would be assigned to the control group. Enrollment will continue until 
at least 50 patients in each group have received treatment.
Opioid-sparing group 
Intravenous Caldolor (800mg every 8 hours) will be initiated during surgery and 
oral acetaminophen 1000 mg every 6 hours will be initiated post-operatively and 
continued until discharge or 48 hours, whichever comes first.  Breakthrough pain will be 
treated with rescue narcotics (intravenous morphine 2-4mg every 2 hours and oral 
oxycodone 5-15mg every 4 hours immediately post-operatively through discharge).  
Hydromorphone (IV 0.5-2mg every 2 hours and oral 2-4mg every 4 hours) will be used in 
patients with morphine or oxycodone allergy or intolerance. The dosing assignments in the 
study group are based on previous clinical studies of IV Caldolor (6).
Standard treatment group
Intravenous Caldolor PLACEBO will be initiated during surgery and oral 
acetaminophen 1000 mg every 6 hours will be initiated post-operatively and continued 
until discharge or 48 hours, whichever comes first.  Breakthrough pain will be treated with 
rescue narcotics (intravenous morphine 2-4mg every 2 hours and oral oxycodone 5-15mg 
every 4 hours immediately post-operatively through discharge).  Hydromorphone (IV 0.5-
2mg every 2 hours and oral 2-4mg every 4 hours) will be used in patients with morphine or 
oxycodone allergy or intolerance. 
Primary endpoints:
1) Comparison of pain scores between groups: Visual Analog Scale for Pain score at 
4hr interval x 48 hours or until discharge, whichever comes first, per hospital policy 
(Addendum C).
Secondary endpoints:
IRB NUMBER: PHX14BN090
IRB APPROVAL DATE: 01/12/2016

Original July 24, 2014; Revised Jan 8, 2015; Nov 20, 2015
5
1) Breakthrough narcotic requirement: The use of rescue narcotic in both groups 
will be recorded and compared using a standard equianalgesic oral morphine 
equivalent (OME) calculation (9).
2) Anti-emetic requirement: The total number of doses and type of any anti-emetic 
required post-operatively in both groups will be compared.
3) Constipation: The number of patients that do not have a bowel movement during 
hospitalization will be compared in both groups. Both groups will be treated with a 
standard bowel care protocol (Addendum D).
4) Opioid-related adverse events: The number of patients with opioid-associated 
adverse events, such as respiratory depression or sedation, will be documented; 
POSS sedation scale will be monitored.
5) Hospital economics:  Total hospital charges, pharmacy charges, and length of stay 
will be compared. 
6) Other adverse events: Epistaxis, potentially related to intravenous ibuprofen, will 
be compared.
Unblinding
Unblinding will occur in the case of adverse or hypersensitivity reaction to the study 
medications for the purposes of treatment and allergy documentation, or when the 
Principal Investigator and/or the Co-investigators feel that blinding is impacting patient 
care or patient safety. 
The codes for each patient will be stored with the Research Pharmacy and the Clinical 
Research nurse and documented on the study drug form.  
If it is necessary to break the blind, it will be documented, including reason for breaking the 
code, and the researchers will notify the IRB.
Data Analysis:
Frequencies will be reported for ordinal and categorical variables. Descriptive analyses 
such as minimum, maximum, mean, median, and standard deviations will be used for 
continuous variables. Demographic variables such as age, gender, and ethnicity will be 
reported. Independent samples t-tests will be used to compare mean VAS scores between 
the opioid-sparing and standard groups. 
IRB NUMBER: PHX14BN090
IRB APPROVAL DATE: 01/12/2016

Original July 24, 2014; Revised Jan 8, 2015; Nov 20, 2015
6
50 treated patients in each group are required to detect a 2 point difference on the 11 point 
(0-10) VAS with a standard deviation of 3.2 for the placebo group and 3.5 for the treatment 
group with alpha set at .05 and 90% power.
IRB NUMBER: PHX14BN090
IRB APPROVAL DATE: 01/12/2016

Original July 24, 2014; Revised Jan 8, 2015; Nov 20, 2015
7
References
1 Pizzi LT, Toner R, Foley K, Thomson E, Chow W, Kim M, Couto J, Royo M, Viscusi E. 
Relationship between potential opioid-related adverse effects and hospital length of stay in 
patients receiving opioids after orthopedic surgery. Pharmacotherapy. 2012 Jun;32(6):502-
14. Epub 2012 May 8.
2 Husted H. Fast-track hip and knee arthroplasty: clinical and organizational aspects. Acta 
Orthop Suppl. 2012 Oct;83(346):1-39. 
3 Costantini R, Affaitati G, Fabrizio A, Giamberardino MA. Controlling pain in the post-
operative setting. Int J Clin Pharmacol Ther. 2011 Feb;49(2):116-27.
4 Badie B, Nguyen P, Preston JK. Endoscopic-guided direct endonasal approach for pituitary 
surgery. Surg Neurol. 2000 Feb;53(2):168-72.
5 Dahl V, Dybvik T, Steen T, Aune AK, Rosenlund EK, Raeder JC. Ibuprofen vs. 
acetaminophen vs. ibuprofen and acetaminophen after arthroscopically assisted anterior 
cruciate ligament reconstruction. European Journal of Anaesthesiology. 2004; 21: 471-475.
6 Southworth S, Peters J, Rock A, Pavliv L. A multicenter, randomized, double-blind, 
placebo-controlled trial of intravenous ibuprofen 400 and 800mg every 6 hours in the 
management of postoperative pain. Clinical Therapeutics. 2009 Sept; 31(9):1922-1935.
7 Singla N, Rock A, and Pavliv L. A multi-center, randomized, double-blind placebo-
controlled trial of intravenous-ibuprofen for treatment of pain in post-operative orthopedic 
adult patients. Pain Medicine. 2010; 11:1284-1293.
8 Kroll PB, Meadows L, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo-
controlled trial of intravenous ibuprofen in the management of postoperative pain 
following abdominal hysterectomy. Pain Practice. 2011 Feb; 11 (1): (23-32)
9 Chung KC, Barlev A, Braun AH, Qian Y, Zagari M. Assessing analgesic use in patients with 
advanced cancer: development of a new scale--the Analgesic Quantification Algorithm. Pain 
Med. 2014 Feb;15(2):225-32. Epub 2014 Jan 8.
IRB NUMBER: PHX14BN090
IRB APPROVAL DATE: 01/12/2016

 
Original July 24, 2014; Revised Jan 8, 2015 
 
 
Eligible Patient 
Randomization 
Opioid-Sparing 
Standard Arm 
Intraoperative dose of 
800mg IV Caldolor  
Intraoperative placebo 
Scheduled Medication: 
Caldolor 800mg IV Q8hr 
Acetaminophen 1000mg  
po Q6hr 
Bowel care regimen 
Monitoring: 
Q4hr pain assessment 
with VAS as per nursing 
protocol 
Scheduled Medication: 
Caldolor PLACEBO IV Q8hr 
Acetaminophen 1000mg 
po Q6hr 
Bowel care regimen 
Monitoring: 
Q4hr pain assessment 
with VAS as per nursing 
protocol 
Nauseated? 
Yes 
Zofran 4mg IV Q6hr PRN 
Pain controlled? 
Pain controlled? 
Yes 
Yes 
No 
No 
Continue regimen 
with standard Q4hr 
pain assessment and 
documentation 
Continue regimen 
with standard Q4hr 
pain assessment 
and documentation 
Morphine 2-4mg IV Q2hr PRN pain 
(or hydromorphone 0.5-2mg IV Q2hr for morphine 
allergy) 
OR if tolerating PO,  
Oxycodone IR 5mg tabs 1-3 tabs orally every 4 hours PRN 
pain (or hydromorphone 2-4 mg orally Q4 hr for 
oxycodone allergy 
Document pre- and post-administration pain assessment 
with VAS as per nursing protocol