Conditions: Carpal Tunnel Ganglion Cyst Trigger Finger De Quervain Disease
Keywords: Adult soft-tissue hand surgery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 72
Healthy volunteers: no

Brief summary:
The purpose of this research study is to find out which combination of pain medications following surgery work the best and result in the fewest side effects.

Detailed description:
This is a prospective, randomized, double-blind study comparing the efficacy of acetaminophen/hydrocodone (AH) to acetaminophen/ibuprofen (AIBU) in providing adequate post-operative pain relief in elective, soft tissue hand surgery patients.

Arms:
arm 1: Acetaminophen 500 mg and Ibuprofen 400 mg arm 2: Acetaminophen 325 mg and Hydrocodone 5 mg

Interventions: intervention 1: Acetaminophen/Ibuprofen intervention 2: Acetaminophen/Hydrocodone
Intervention descriptions: intervention 1: Postoperatively, subjects will be given acetaminophen 500 mg / ibuprofen 400mg every 4 hours, as needed, for one week or until essentially pain-free intervention 2: Postoperatively, subjects will be given acetaminophen 325 mg / hydrocodone 5 mg every 4 hours, as needed, for one week or until essentially pain-free

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 14  
                                                         
 
 
HRP-503f - Protocol for 
Human Subject Research 
 
Protocol Title:   
Post-operative analgesia following elective soft-tissue surgery of the hand: A 
randomized, double blind comparison of Acetaminophen/Ibuprofen versus 
Acetaminophen/Hydrocodone 
 
Principal Investigator: Alexander Payatakes, MD 
 
 
 
 
 
Department of Orthopaedics 
 
 
 
 
 
(717) 531-5638 (tel) 
 
 
 
 
 
apayatakes@hmc.psu.edu (email)  
 
Version Date:  
 
November 10, 2014 
 
 
1.0 Objectives 
1.1 
Study Objectives 
 
Compare the efficacy of acetaminophen/hydrocodone (AH) to acetaminophen/ibuprofen (AIBU) in 
providing adequate post-operative pain relief in elective, soft-tissue hand surgery patients. 
 
 
Review the adverse events related to administration of AH or AIBU 
 
 
Subcategorize patients based on anatomic location, surgery performed, and perioperative variables 
1.2 
Primary Study Endpoints 
 
Compare the efficacy of acetaminophen/hydrocodone (AH) to acetaminophen/ibuprofen (AIBU) in 
providing adequate post-operative pain relief in elective, soft tissue hand surgery patients 
o VAS, Pain Catastrophizing Scale, medication pain relief [Likert pain score], mean daily pain 
values 
1.3 
Secondary Study Endpoints 
 
Incidence of adverse effects 
 
Patient satisfaction (yes/no) 
 
Time to stopping medication 
 
Incidence of medication discontinuation 
 
Need for additional analgesics 
 
Subcategorize patients  
o Surgery performed 
o Propofol dose 
o Fentanyl dose 
o Surgery time 
o Local anesthetic dose 
o Local anesthetic composition 
o Perioperative NSAIDs 
o PHQ-9 questionnaire score 


Page 2 of 14  
 
2.0 Background  
 
2.1 
Scientific Background and Gaps 
 
Currently, there are no randomized, controlled trial data to suggest a superior post-operative pain regimen 
in elective soft-tissue hand surgery.  As opioids have been associated with adverse effects such as abuse, 
overdose and dependency, we wish to determine if their use can be limited in favor of non-opioid 
analgesics such as acetaminophen and ibuprofen for elective soft tissue hand surgery. Use of non-
steroidal anti-inflammatory drugs is contraindicated in procedures where osseous healing is required.   
 
2.2 
Previous Data 
 
 
The study drugs have been studied extensively and have been shown to provide reproducible analgesia 
and a low rate of severe side effects or adverse events.  
 
2.3 
Study Rationale 
See study objectives 
 
3.0 Inclusion and Exclusion Criteria 
 
3.1 
Inclusion Criteria 
 
Age: 21 – 90 
 
Gender: male or female (non-pregnant) 
 
Elective, soft-tissue hand surgery indicated based on diagnosis made by either clinical exam or 
diagnostic studies (i.e. nerve conduction study, EMG) or a combination of the two  
o Carpal tunnel release, trigger finger release, first dorsal compartment release, ganglion cyst 
excision 
 
Subjects are capable of giving informed consent  
 
3.2 
Exclusion Criteria 
 
Allergy to study medication 
 
Any preexisting pain condition requiring analgesia 
 
Fibromyalgia 
 
Recent upper gastrointestinal bleeding 
 
Coagulopathy (primary or medication-related) 
 
Renal impairment 
 
Liver disease 
 
Pregnancy 
 
Patients who consent to the study but who require unexpected admission, including those requiring 
admission resulting from operative complications, will be excluded before randomization. 
3.3 
Early Withdrawal of Subjects 
3.3.1 Criteria for removal from study 
Patients will be withdrawn from the study for safety reasons including severe adverse 
reactions, failure of subject to adhere to protocol requirements, or subject consent withdrawal. 
3.3.2 Follow-up for withdrawn subjects 
If a patient is withdrawn from the study, data collection will be terminated from that time 
point forward.  All prior data collected will be included in the analysis.  These subjects will 
not be replaced, but instead more subjects may need to be enrolled. These new data will be 
recorded and analyzed as would any other new enrollee.  No further follow up of withdrawn 
subjects is necessary as the study follow-up terminates at two weeks following surgery. 
 


Page 3 of 14  
4.0 Recruitment Methods 
 
4.1 
Identification / Recruitment of subjects 
Subjects will be identified as part of their initial or routine evaluation by one of the study investigators in 
the Bone & Joint Institute.  These patients would normally be treated at the Penn State Hershey Medical 
Center and will be receiving the same operative care as those not enrolled in the study. 
 
4.2 
Recruitment materials – N/A 
 
4.3 
Eligibility/screening of subjects - N/A 
 
5.0 Consent Process and Documentation  
 
 
5.1 
Consent Process  
 
5.1.1 Obtaining Informed Consent 
5.1.1.1 Timing and Location of Consent 
 
 
Subjects presenting to the study investigators’ practice site as part of their initial or 
routine evaluation will be given the opportunity to participate in the research study.  
Patients will be given information about the study and asked to participate. If 
eligible, based on inclusion and exclusion criteria, informed consent will be 
obtained at the time of the screening visit and the patient will be enrolled in the 
study. 
5.1.1.2 Coercion or Undue Influence during Consent 
Subjects will be given ample time to read and review the consent form on their own.  
All questions the patient may have will be answered, and written consent will be 
obtained. A member of the research team will assist in the explanation and obtaining 
of the written consent.  A copy of the signed consent will be given to the patient and 
another copy sent to Medical Records. 
 
5.1.2 Waiver or alteration of the informed consent requirement - N/A 
 
5.2 
Consent Documentation 
 
5.2.1 Written Documentation of Consent 
A member of the research team will assist in the explanation and obtaining of the written 
consent.  A copy of the signed consent will be given to the patient and another copy sent to 
Medical Records. 
 
5.2.2 Waiver of Documentation of Consent - N/A 
 
5.3 
Consent – Other Considerations  
 
5.3.1 Non-English Speaking Subjects – N/A 
 
5.3.2 Cognitively Impaired Adults - N/A 
 
5.3.2.1 Capability of Providing Consent - N/A 
 
5.3.2.2 Adults Unable To Consent - N/A 
 
5.3.2.3 Assent - N/A 


Page 4 of 14  
 
5.3.3 Subjects who are not yet adults (infants, children, teenagers)  
 
5.3.3.1 Parental Permission - N/A 
 
5.3.3.2 Assent - N/A 
 
6.0 Study Design and Procedures 
 
6.1 
Study Design  
This will be a randomized, double-blind study in which physicians and patients are blinded to the 
treatment protocol. 
 
Recruitment  Randomization  Surgery  Treatment (AH v AIBU) 
 
AH  post-operative assessment at one week 
 
AIBU  post-operative assessment at one week 
 
Patient still having pain at one week  satisfied with medication regimen (yes/no) 
 
Yes  continue current regimen 
 
No prescription for oxycodone  
 
Final study visit  data collection  discard unused study medication 
 
6.2 
Study Procedures 
 
6.2.1 Visit 1 - Screening/Baseline Visit 
Patients will be given information about the study and asked to participate. If eligible, based 
on inclusion and exclusion criteria, informed consent will be obtained at the time of the 
screening visit and the patient will be enrolled in the study.  Baseline pain scale (VAS) 
measurements will be obtained as well as the PHQ-9 questionnaire and Pain Catastrophizing 
Scale.  Patients will be provided instructions regarding study dosage and provided a patient 
diary with instructions. 
 
Patients will be randomized to one of two recruitment groups (patient/PI blinded) 
 
AH – Acetaminophen 325 mg/Hydrocodone 5 mg 
 
AIBU – Acetaminophen 500 mg/Ibuprofen 400 mg 
 
6.2.2 Visit 2 – Surgery Day 
Instructions regarding study drug dosage will be reviewed with the patient and study drug 
provided to the patient. 
 
The dose for the AH group will be two capsules containing a total of 325 mg of 
acetaminophen and 5 mg of hydrocodone – one study tablet contained within a capsule and 
one placebo tablet (cellulose will be used as a filler within the placebo to simulate the weight 
of an ibuprofen tablet) within a separate capsule. 
 
The dose for the AIBU group will be two capsules – one study tablet containing 
acetaminophen 500 mg and the second capsule containing ibuprofen 400 mg. 
 


Page 5 of 14  
Subjects will be instructed to take one dose (two capsules) of medication every four hours 
(maximum of 6 times per day) for 7 days or until pain free, whichever comes sooner.   
 
6.2.3 Visit 3 - Phone call 1 – Post-operative day 7 (or next business day) 
Patients will be contacted by research personnel at 7 days following surgery at which point 
they will be asked if they are still having pain requiring medication (yes/no). 
If patients are still having pain, they will be asked if they are satisfied with the current pain 
regimen (yes/no). If “yes” then they will be asked to continue the current pain regimen. 
Unblinding will occur at this time.  If they were randomized to the AH group, they will 
receive a prescription for one additional week of this medication.  If they were randomized to 
the AIBU group, they will be instructed to take the Acetaminophen and Ibuprofen as directed 
on an as needed basis.  If “no” (not satisfied with current regimen), they will be prescribed 
oxycodone 5 mg and instructed to take one or two tablets every 4 hours as needed for pain. 
Patients will be asked to record the date and time that they stopped taking the analgesic 
medication and asked to bring the opioid tablets with them to their final clinic visit.  Data 
collection stops at this time.  
 
6.2.4 Visit 4 – Final visit – Post-operative day 14 
Patient will be asked to return to clinic approximately two weeks post-operatively (+/- 4 
days) for suture removal and to conclude the study.  Patient diary will be collected. Study 
medications will be counted and accuracy ensured.  All study medication will be discarded by 
study personnel. Data collection ends one week postoperatively.  Patient diaries with data will 
be collected at this final visit. 
 
6.2.5 Study Visit Flowsheet 
 
Screening visit 
Surgery 
1 week Post-operative phone call 
2-week Post-operative visit 
Enrollment; 
Randomization; 
Baseline VAS, Pain 
Catastrophizing Scale, 
PH-9 questionnaire via 
patient diary 
Dispense study drug;  
Pain assessment/continue 
medication?  Finish patient diary 
completion. 
Collect patient diary / 
dispose of study medication 
 
 
6.3 
Duration of Participation 
Subjects will be asked to participate in the study through their two-week post-operative visit. 
 
6.4 
Test Article(s) (Study Drug(s) and/or Study Device(s)) 
6.4.1  Description 
The study drugs consist of a combination of Acetaminophen 325mg / Hydrocodone 5 mg 
(AH) or Acetaminophen 500mg / Ibuprofen 400mg (AIBU).   AH has been approved by the 
FDA under the trade name Norco. The mechanism of action of acetaminophen is to inhibit the 
synthesis of prostaglandins in the central nervous system and work peripherally to block pain 
impulse generation.  The mechanism of action of hydrocodone is to block pain perception in 
the cerebral cortex by binding to specific receptor molecules (opiate receptors) within the 
neuronal membranes of synapses.  The mechanism of action of ibuprofen is to reversibly 
inhibit cyclo-oxygenase 1 and 2 (COX-1 and COX-2), which results in decreased formation of 
prostaglandin precursors that cause inflammation and pain.  
                             6.4.2  Treatment Regimen 
The dose for the AH group will be two capsules containing a total of 325 mg of 
acetaminophen and 5 mg of hydrocodone – one study tablet contained within a capsule and 
one placebo tablet within a separate capsule.  The non-opioid group (AIBU) will be given two 


Page 6 of 14  
capsules per dose – one containing acetaminophen 500mg and the other containing ibuprofen 
400mg.  Patients will be instructed to take one dose (two capsules) of medication every four 
hours, as needed, for one week (7 days) or until pain free, whichever comes sooner.  If patients 
have pain that is not controlled with the study medication, they will be given a prescription for 
oxycodone 5 mg and instructed to take one to two tablets every four hours as needed for pain.  
Anti-emetic medications will be prescribed if indicated.  These patients will be analyzed in a 
subgroup analysis. 
                             6.4.3  Method for Assigning Subject to Treatment Groups 
Patients will be randomized to receive either AH or AIBU during their pre-operative clinic 
visit.  Randomization will be conducted by the research coordinator (and not any study 
personnel who must remain blinded). 
                             6.4.4 Subject Compliance Monitoring 
Patients will be asked to record the time, in addition to a visual analog score (VAS) and Likert 
scale in their patient diary 6 times daily with every dose of medication (every 4 hours).  They 
will not continue to record these measurements after no longer taking the study medication. 
6.4.5 Blinding of the Test Article 
The opioid and non-opioid analgesic regimen will be compounded by investigational 
pharmacy.  Randomization will be performed prior to surgery and the study medication will be 
given to the patient by a member of the investigational pharmacy or clinical nursing not 
involved with the study after surgery.  Physicians and other pertinent study personnel will be 
blinded to the treatment regimen. 
6.4.6 Receiving, Storage, Dispensing and Return 
6.4.6.1  
Receipt of Test Article  
The study drugs will be obtained by the investigational pharmacy. 
6.4.6.2 
Storage 
The study drugs will be stored at room temperature monitored by investigational 
pharmacy. 
6.4.6.2 
Preparation and Dispensing 
The study drugs will be packaged and stored by investigational pharmacy.  The 
week-long supply of study drug will be dispensed to the patient after surgery.   
Patients will be given 6 doses of medication per day, in two pill bottles – one 
containing yellow capsules and the other blue capsules.  Each dose will consist of 
two capsules of acetaminophen 325 mg/hydrocodone 5 mg or acetaminophen 500 
mg/ibuprofen 400 mg.  The total number of capsules in the 2-week long pill 
bottles will be 84, or 12 per day. Patients will be instructed not to take more than 
6 doses each day.  Additional pain medication outside of the study medication 
will not be allowed.  However, patients will be able to request oxycodone 5 mg if 
the study medication does not provide adequate pain relief. 


Page 7 of 14  
6.4.6.3   Return or Destruction of the Test Article 
Patients will be instructed to bring their pill containers with them to the final 
post-operative visit at which time study personnel will be responsible for 
discarding all remaining study medications. 
6.4.6.4   Prior and Concomitant Therapy 
 
Patients will be excluded from the study if they are currently being treated for 
any pain-related condition or are taking any pain medication regularly.  All other 
concomitant medications will be allowed to continue. 
 
7.0 Data and Specimen Banking 
 
7.1 
Data and/or specimens being stored  
 
Patient Name, MRN #, Date of Birth, Phone number, Gender, Ethnicity, Race, Occupation, Right 
or Left handedness, and link to identifier code 
 
VAS Scale 
 
Likert Scale 
 
PHQ-9 questionnaire 
 
Pain Catastrophizing Scale 
 
7.2 
Location of storage 
All research data will be kept on a password-protected computer or in a locked filing cabinet and 
accessible only to the research personnel. 
 
7.3 
Duration of storage 
All research data will be stored for length of time required by federal regulations/funding source and then 
destroyed (minimum 3 years). 
 
7.4 
Access to data and/or specimens 
Only research personnel will have access to the study data. 
 
7.5 
Procedures to release data or specimens – N/A 
 
7.6 
Process for returning results - N/A 
 
8.0 Statistical Plan 
 
8.1 
Sample size determination 
Sample size was determined based on a review of prior studies that used the VAS as the main outcome 
tool.  A total sample size of 147 was determined based on the number needed to detect a difference of 5 
mm assuming a standard deviation of 10 mm in the VAS and when also considering a 15 % drop out rate.  
147 total patients initially enrolled in the study would account for 64 patients per treatment arm (AH v 
AIBU).  
 
8.2 
Statistical methods 
The daily average pain score (VAS) will be compared between AIBU and AH groups using either t-test or 
Wilcoxon test for each of the 6 days after the operation. The number of days till pain free will be 
compared between the two groups using survival techniques such as log-rank test.   Chi-square tests will 
be used to compare treatment groups for categorical variables (satisfaction, change in pain regimen, 
adverse events).  Level of significance will be set at p < 0.05. 
 


Page 8 of 14  
Secondary statistical analysis will include multivariate analyses to determine which variables such as 
anatomic location, surgery performed, and perioperative medication will impact the daily average pain 
score or modify the effect of AIBU versus AH. These can be accomplished by adding these variables and 
their interaction with treatment groups in the regression model. As these are secondary analysis, any 
interesting findings will be subject to validation in future studies.  We will also seek to determine which 
groups of patients, if any, will more frequently request to change to the hydrocodone arm during the study 
due to inadequate analgesia.   
 
Any deviations from the previously described statistical plan will be described and justified in a protocol 
amendment. 
 
9.0 Confidentiality, Privacy and Data Management  
 
9.1 
Confidentiality 
 
9.1.1 Identifiers associated with data and/or specimens 
 
9.1.1.1 Use of Codes, Master List 
Patient Name, MRN #, Date of Birth, Phone number, and link to identifier code. A 
linking code list (identifiers will be linked to a unique code) will be kept in the study 
investigator’s research office. Only research personnel will have access to the list. 
 
9.1.2 Storage of Data and/or Specimens 
All research data will be stored in the study investigator’s research office for length of time 
required by federal regulations/funding source and then destroyed (minimum 3 years). 
 
9.1.3 Access to Data and/or Specimens 
Only research personnel will have access to the study data. 
. 
9.1.4 Transferring Data and/or Specimens – N/A 
                                                                                                                                                          
9.2 
Privacy 
 
 
Only the minimum necessary information will be requested for this study. All research data will be kept 
on a password-protected computer or in a locked filing cabinet and accessible only to the research 
personnel. 
 
10.0 Data and Safety Monitoring Plan  
 
10.1 
Periodic evaluation of data 
The research coordinator will complete the appropriate report form and logs; assist the principal 
investigator to prepare reports and notify the IRB and any applicable reporting agencies of all 
unanticipated problems / adverse events. 
 
The research coordinator and principal investigator will confirm that all adverse events are correctly 
entered in the AE log; be available to answer any questions concerning AEs; notify the IRB and any 
applicable reporting agencies of unanticipated problems and AEs as appropriate.  All assessments of AEs 
will be made by a licensed medical professional who is an investigator on the research. 
 
10.2 
Data that are reviewed  
Data to be reviewed includes the patient’s diary (VAS, Likert scales, Pain Catastrophizing Scale, and 
PHQ questionnaire) as well as  incidence of adverse effects, patient satisfaction, time to stopping 
medication, incidence of medication discontinuation, need for additional analgesics, surgery performed, 
propofol dose, fentanyl dose, surgery time, local anesthetic dose, local anesthetic composition, and 
perioperative NSAIDs.  . 


Page 9 of 14  
 
10.3 
Method of collection of safety information 
Data will be collected beginning after informed consent at time of enrollment through one –week 
postoperatively.  All data will be collected at the patient’s final visit (approximately two weeks post-
operatively).  Data will be collected via the patient’s diary, phone script, and review of the medical 
record. 
 
10.4 
Frequency of data collection 
Data collection begins immediately following informed consent through one-week post-operatively, with 
collection of all data completed at the patient’s final visit (approximately 2 weeks post-operatively). 
  
10.5 
Individual’s reviewing the data 
All data will be reviewed by members of the research team at completion of study.  Reporting of any 
adverse events will be reviewed as they occur. 
 
10.6 
Frequency of review of cumulative data 
There will be no interim analysis in this study.  The entire study period will be one week post-operatively 
where patients will be recording pain scores in their patient diaries.  Adverse events will be reviewed as 
they occur. 
 
10.7 
Statistical tests 
The daily average pain (VAS) will be compared between AIBU and AH groups using either t-test or 
Wilcoxon test for each of the 6 days after the operation.  The number of days till pain free will be 
compared between the two groups using survival techniques such as log-rank test.  Chi-square tests will 
be used to compare treatment groups for categorical variables (satisfaction, change in pain regimen, 
adverse events).  Level of significant will be set at p < 0.05. 
 
Secondary statistical analysis will include multivariate analyses to determine which variables such as 
anatomic location, surgery performed, and perioperative medication will impact the daily average pain 
score or modify the effect of AIBU versus AH.  These can be accomplished by adding these variables and 
their interaction with treatment groups in the regression model.  As these are secondary analysis, any 
interesting findings will be subject to validation in future studies.  We w ill also seek to determine which 
groups of patients, if any, will more frequently request to change to the hydrocodone arm during the study 
due to inadequate analgesia. 
 
Any deviation from the previously described statistical plan will be described and justified in a protocol 
amendment. 
 
All analyses comparing the treatment groups will be conducted on an intention-to-treat basis.  Two-tailed 
tests will be used at all times. 
 
10.8 
Suspension of research 
There will be no stopping rules in this study, as all medications are FDA approved and safe for patient 
use.   
 
If a patient, at any point in the post-operative course, demonstrates a significant adverse event related to 
the study medication (i.e. intractable nausea/vomiting), then they will have an opportunity to switch to the 
non-opioid pain regimen.  If they are having pain that is not relieved with the AIBU regimen, they will 
have the opportunity to contact the study physician and obtain a prescription for oxycodone  Anti-nausea 
medication will be prescribed as indicated.  These patients will not be removed from the study, but will be 
included in a subgroup analysis.  Study primary and secondary endpoints will continue to be monitored in 
a similar fashion. 
 
 


Page 10 of 14  
11.0 Risks 
 
The most common side effects associated with acetaminophen/hydrocodone include:  
 
Nausea, vomiting, constipation, lightheadedness, dizziness, or drowsiness 
 
Rare side effects/adverse events associated with acetaminophen/hydrocodone include but are not limited to:  
 
Cardiovascular: Bradycardia, cardiac arrest, circulatory collapse, coma, hypotension  
 
Central nervous system: Anxiety, dysphoria, euphoria, fear, lethargy, lightheadedness, malaise, mental clouding, 
mental impairment, mood changes, physiological dependence, sedation, somnolence, stupor  
 
Dermatologic: Pruritus, rash  
 
Endocrine & metabolic: Hypoglycemic coma  
 
Gastrointestinal: Abdominal pain, constipation, gastric distress, heartburn, peptic ulcer, xerostomia  
 
Genitourinary: Ureteral spasm, urinary retention, vesical sphincter spasm  
 
Hematologic: Agranulocytosis, bleeding time prolonged, hemolytic anemia, iron deficiency anemia, occult blood 
loss, thrombocytopenia  
 
Hepatic: Hepatic necrosis, hepatitis  
 
Neuromuscular & skeletal: Skeletal muscle rigidity  
 
Otic: Hearing impairment or loss (chronic overdose)  
 
Renal: Renal toxicity, renal tubular necrosis  
 
Respiratory: Acute airway obstruction, apnea, dyspnea, respiratory depression (dose related)  
 
Miscellaneous: Allergic reactions, clamminess, diaphoresis 
 
The most common side effects associated with ibuprofen include: 
Dyspepsia, nausea, vomiting, diarrhea, abdominal pain, and flatulence 
 
1% to 10% of patients may be at risk for these side effects:  
Cardiovascular: Edema (1% to 3%)  
Central nervous system: Dizziness (3% to 9%), headache (1% to 3%), nervousness (1% to 3%)  
Dermatologic: Rash (3% to 9%), itching (1% to 3%)  
Endocrine & metabolic: Fluid retention (1% to 3%)  
Gastrointestinal: Epigastric pain (3% to 9%), heartburn (3% to 9%), nausea (3% to 9%), abdominal 
pain/cramps/distress (1% to 3%), appetite decreased (1% to 3%), constipation (1% to 3%), diarrhea (1% to 3%), 
dyspepsia (1% to 3%), flatulence (1% to 3%), vomiting (1% to 3%)  
Otic: Tinnitus (3% to 9%)  


Page 11 of 14  
<1% of patients may be at risk for these side effects: 
(Limited to important or life-threatening): Acute renal failure, agranulocytosis, anaphylaxis, aplastic anemia, 
azotemia, blurred vision, bone marrow suppression, confusion, creatinine clearance decreased, duodenal ulcer, 
edema, eosinophilia, epistaxis, erythema multiforme, gastric ulcer, GI bleed, GI hemorrhage, GI ulceration, 
hallucinations, hearing decreased, hematuria, hematocrit decreased, hemoglobin decreased, hemolytic anemia, 
hepatitis, hypertension, inhibition of platelet aggregation, jaundice, liver function tests abnormal, leukopenia, 
melena, neutropenia, pancreatitis, photosensitivity, Stevens-Johnson syndrome, thrombocytopenia, toxic 
amblyopia, toxic epidermal necrolysis, urticaria, vesiculobullous eruptions, vision changes 
The most common side effects associated with acetaminophen include: 
 
Liver damage due to large doses, chronic use or concomitant use with alcohol or other drugs that also damage the 
liver. Chronic alcohol use may also increase the risk of stomach bleeding. 
 
Rare side effects/adverse events associated with acetaminophen include but are not limited to: 
Oral, Rectal: Frequency not defined: 
Dermatologic: Skin rash 
Endocrine & metabolic: Decreased serum bicarbonate, decreased serum calcium, decreased serum sodium, 
hyperchloremia, hyperuricemia, increased serum glucose 
Genitourinary: Nephrotoxicity (with chronic overdose) 
Hematologic & oncologic: Anemia, leukopenia, neutropenia, pancytopenia 
Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin 
Hypersensitivity: Hypersensitivity reaction (rare) 
Renal: Hyperammonemia, renal disease (analgesic) 
I.V.:  
 
>10%: Gastrointestinal: Nausea (adults 34%; children ≥5%), vomiting (adults 15%; children ≥5%) 
1% to 10%: 
Cardiovascular: Hypertension, hypotension, peripheral edema, tachycardia 
Central nervous system: Headache (adults 10%; children ≥1%), insomnia (adults 7%; children ≥1%), agitation 
(children ≥5%), anxiety, fatigue, trismus 
Dermatologic: Pruritus (children ≥5%), skin rash 
Endocrine & metabolic: Hypervolemia, hypoalbuminemia, hypokalemia, hypomagnesemia, hypophosphatemia 
Gastrointestinal: Constipation (children ≥5%), abdominal pain, diarrhea 
Genitourinary: Oliguria (children ≥1%) 
Hematologic & oncologic: Anemia 
Hepatic: Increased serum transaminases 
Local: Infusion site reaction (pain) 
Neuromuscular & skeletal: Limb pain, muscle spasm 
Ophthalmic: Periorbital edema 
Respiratory: Atelectasis (children ≥5%), abnormal breath sounds, dyspnea, hypoxia, pleural effusion, pulmonary 
edema, stridor, wheezing 
 
 
There is a risk of loss of confidentiality, but precautions will be taken to prevent this from happening.   
 
Subjects will be assigned to a treatment program by chance. The treatment received may prove to be less effective 
or to have more side effects than the other research treatment(s) or other available treatments. 
 


Page 12 of 14  
 
12.0 Potential Benefits to Subjects and Others 
 
12.1 
Potential Benefits to Subjects 
There is no benefit to individual subjects.  Subjects will play an important role in identifying a superior post-
operative pain regimen in patients who will undergo similar surgical procedures following the study period.   
 
12.2 
Potential Benefits to Others 
 
The results of this study will guide future treatment decisions.  We seek to reduce unnecessary prescribing 
of opioid pain medications, if feasible, in order to prevent patients from having unwanted side effects and 
limit the overuse or abuse of these medications. 
 
13.0 Sharing Results with Subjects - N/A 
 
14.0 Economic Burden to Subjects 
 
14.1 
Costs  
The acetaminophen/hydrocodone or acetaminophen/ibuprofen will be provided by the investigational 
drug pharmacy at no cost to subjects for the first week following surgery.  A prescription will be provided 
for subjects that continue to need pain relief thereafter. 
 
14.2 
Compensation for research-related injury 
It is the policy of the institution to provide neither financial compensation nor free medical treatment for 
research-related injury. In the event of injury resulting from this research, medical treatment is available 
but will be provided at the usual charge. Costs for the treatment of research-related injuries will be 
charged to subjects or their insurance carriers.  
 
15.0 Number of Subjects 
Approximately 150 people will take place in this research study at the Hershey Medical Center. 
 
16.0 Resources Available 
 
16.1 
Facilities and locations 
 
Penn State Milton S. Hershey Medical Center, Bone & Joint Institute 
 
Hershey Outpatient Surgery Center 
 
16.2 
Feasibility of recruiting the required number of subjects – N/A 
 
16.3 
PI Time devoted to conducting the research - N/A 
 
16.4 
Availability of medical or psychological resources - N/A 
 
16.5 
Process for informing Study Team - N/A 
 
 
17.0 Other Approvals 
  
17.1 
This study was approved by the PSHMC Scientific Review Committee on March 10, 2014, prior to IRB 
submission. 
 
 


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18.0 Subject Stipend and/or Travel Reimbursements - N/A 
 
19.0 Multi-Site Research - N/A 
 
20.0 Adverse Event Reporting 
20.1 
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB 
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) experienced 
by a subject or other individual, which in the opinion of the investigator is determined to be (1) 
unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures. 
20.2 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the Penn State quality 
assurance program office(s), IRB, the sponsor, and government regulatory bodies, of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
20.3     Unblinding Procedures 
In most cases, the unblinding will be part of managing a serious adverse reaction, and will be reported 
with the serious adverse event.  However, in cases were unblinding is not associated with a serious 
adverse event, such actions will be reported in a timely manner according to the timeline requirements for 
investigator reporting of adverse events to the IRB.   
 
21.0 Study Monitoring, Auditing and Inspecting 
21.1 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the Penn State quality 
assurance program office(s), IRB, the sponsor, and government regulatory bodies, of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
           21.2  Safety Monitoring 
The Principal Investigator will confirm that all adverse events (AE) are correctly entered into the AE 
case report forms by the coordinator; be available to answer any questions that the coordinators may have 
concerning AEs; and will notify the IRB, FDA, sponsor and/or DSMB of all applicable AEs as 
appropriate. All assessments of AEs will be made by a licensed medical professional who is an 
investigator on the research.  
 
The research coordinator will complete the appropriate report form and logs; assist the PI to prepare 
reports and notify the IRB, FDA, and/or DSMB of all Unanticipated Problems/SAE’s. 
 
22.0 References 
 
1. Opioid consumption following outpatient upper extremity surgery.  Rodgers J, Cunningham K, Fitzgerald K, 
Finnerty E.  J Hand Surg Am. 2012 Apr; 37(4):645-50. 
 
2. Opioid prescriptions soar: increase in legitimate use as well as abuse. Kuehn BM. JAMA 2007; 297:249 –
251. 


Page 14 of 14  
 
3. A flood of opioids, a rising tide of deaths. Oakie S. N Engl J Med 2010;363:1981–1985. 
 
4. Emergency department visits involving nonmedical use of selected prescription drugs—United States, 2004–
2008. Cai R, Crane E, Poneleit K, Paulozzi L. MMWR Morb Mortal Wkly Rep 2010:59:705–709. 
 
5. A randomized, controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine 
plus caffeine (Tylenol 3) after outpatient breast surgery.  Mitchell A, McCrea P, Inglis K, Porter G. Ann Surg 
Oncol. 2012 Nov;19(12):3792-800. 
 
6. The effects of oral ibuprofen and celecoxib in preventing pain, improving recovery outcomes and patient 
satisfaction after ambulatory surgery. White PF, Tang J, Wender RH, Zhao M, Time M, Zaentz A, Yumul R, 
Sloninsky A, Naruse R, Kariger R, Webb T, Fermelia DE, Tsushima GK.  Anesth Analg. 2011 Feb; 
112(2):323-9. 
 
7. Severity and impact of pain after day-surgery. Beauregard L, Pomp A, Choiniere M. Can J Anaesth. 1998 
Apr; 45(4): 304-11. 
 
8. Analysis of statistical tests to compare visual analog scale measurements among groups.   Dexter F, Chestnut 
DH.   Anesthesiology 1995; 82:896-902.  
 
 
23.0 Appendix – N/A