Conditions: Fusion of Spine, Lumbar Region
Keywords: Acetaminophen po Acetaminophen IV Pain management minimally invasive lumbar fusions Ofirmev Analgesics Opioid Pain Postoperative Spinal
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 28
Healthy volunteers: yes

Brief summary:
Simple explanation and rationale:

Recovery after spine surgery is usually accompanied by severe pain which has traditionally been managed with opioids. It is common practice to supplement opioid treatment with different classes of analgesics which work through alternative pain pathways and receptors in order to achieve an additive or synergistic effect while reducing the amount of opioids necessary for pain control.

Acetaminophen can be a beneficial supplemental analgesic to opioids for postoperative pain relief.

Intervention:

Patients will be randomized to either the treatment with IV acetaminophen (A), PO acetaminophen (B), or hydromorphone control group (C).

Objective/Purpose:

Primary objective is to determine the impact of administering a supplemental non-opioid analgesic drug such as IV or PO acetaminophen on total opioid dose administered over the postoperative period.

Secondary objectives include investigating the impact of IV/PO acetaminophen on the level of postoperative pain, patient satisfaction, and side effects secondary to opioids such as nausea, vomiting, pruritus, sedation, respiratory depression, ileus, and urinary retention, and PACU (postoperative care unit) discharge time.

Study population:

126 patients will be enrolled in the study (42 for group A, 42 for group B, and 42 for control group C).

Follow-up and Endpoints / Outcomes:

Postoperative assessments will be done at 0, 30, and 60 minutes, 6 hours, 12 hours and 24 hours after surgery. Patients will be evaluated for pain (using a numeric rating scale), total opioid consumption, and for opioid side effects including drowsiness (using the Ramsey sedation scale and the Aldrete score at the time of arrival to and discharge from recovery room), respiratory depression, nausea, vomiting, and pruritus. Patient satisfaction will also be assessed using a numeric rating scale.

Detailed description:
Simple explanation and rationale:

Recovery after spine surgery, especially spinal fusion surgery, is usually accompanied by severe pain which has traditionally been managed with opioids. While opioids have been proven effective, they are associated with undesirable side effects including nausea, vomiting, pruritus, sedation, respiratory depression, ileus, and urinary retention leading to increased time required in recovery and a decrease in patient satisfaction. For this reason, it is common practice to supplement opioid treatment with different classes of analgesics which work through alternative pain pathways and receptors in order to achieve an additive or synergistic effect while reducing the amount of opioids necessary for pain control.

Acetaminophen is a centrally-acting cyclooxygenase inhibitor nonsteroidal anti-inflammatory medication that has minimal, if any, gastrointestinal and platelet-inhibiting side effects, and is better tolerated by patients than other cyclooxygenase inhibitors. This medication can be a beneficial supplemental analgesic to opioids for postoperative pain relief. Previously conducted studies demonstrate a rationale for the use of intravenous/PO acetaminophen in a multimodal analgesic regimen to reduce postoperative analgesia.

Intervention:

Patients will be randomized to either the treatment with IV acetaminophen (A), PO acetaminophen (B), or hydromorphone control group (C). Patients who are randomized to group A will receive 1 g of IV acetaminophen during the wound closure and every 4 to 6 hours postoperatively for a total of 4 g in 24 hours. Patients who are randomized to group B will receive 1 g of PO acetaminophen before surgery and every 4 to 6 hours postoperatively for a total of 4 g in 24 hours. Patients who are randomized to control group C will not receive acetaminophen. Post-operatively, patients in both groups will also receive IV hydromorphone PCA (patient-controlled analgesia) only for 24 hours for pain.

Objective/Purpose:

Primary objective is to determine the impact of administering a supplemental non-opioid analgesic drug such as IV or PO acetaminophen on total opioid dose administered over the postoperative period.

Secondary objectives include investigating the impact of IV/PO acetaminophen on the level of postoperative pain, patient satisfaction, and side effects secondary to opioids such as nausea, vomiting, pruritus, sedation, respiratory depression, ileus, and urinary retention, and PACU discharge time.

Study population:

126 patients will be enrolled in the study (42 for group A, 42 for group B, and 42 for control group C).

Follow-up and Endpoints / Outcomes:

Postoperative assessments will be done at 0, 30, and 60 minutes, 6 hours, 12 hours and 24 hours after surgery. Patients will be evaluated for pain (using a numeric rating scale), total opioid consumption, and for opioid side effects including drowsiness (using the Ramsey sedation scale and the Aldrete score at the time of arrival to and discharge from recovery room), respiratory depression, nausea, vomiting, and pruritus. Patient satisfaction will also be assessed using a numeric rating scale.

Statistics:

All sample size calculations with reference to:

* Specific Aim 1 reduction of opioid intake by at least 25% between the Control (Group C) and Intervention Groups A and B, and
* Specific Aim 2 improvement of Pain Score by at least 25% between the Control (Group C) and the Intervention Groups A and B,

Arms:
arm 1: Patients in group A will receive 1 g of IV acetaminophen 15 minutes prior to wound incision, and every 4 to 6 hours postoperatively for a total of 4 grams in 24 hours. arm 2: Patients in group B will receive 1 g of PO acetaminophen prior to surgery, and 1 g of oral acetaminophen every 4 to 6 hours postoperatively for a total of 4 grams in 24 hours. arm 3: Patients in the control arm (Group C) will not receive acetaminophen for 24 hours.

Interventions: intervention 1: Acetaminophen IV Soln 10 MG/ML intervention 2: Acetaminophen intervention 3: Hydromorphone
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL NUMBER: 
HS-15-00615 
 
PROTOCOL VERSION DATE: 03/28/2016 
 
TITLE:  
The effectiveness of IV/PO acetaminophen in the perioperative 
period in reducing opiate use after lumbar spine fusion: a 
prospective, randomized controlled trial 
 
STUDY ARMS: 
Acetaminophen IV + Hydromorphone hydrochloride (A) 
 
Acetaminophen  PO+ Hydromorphone hydrochloride (B) 
versus 
Hydromorphone hydrochloride (control arm) (C) 
 
IND OR IDE #: 
 
PRINCIPAL INVESTIGATOR: 
Eugenia Ayrian, MD 
LAC+USC Medical Center 
Department of Anesthesiology 
1200 N. State Street, IPT, Room C4E100 
Los Angeles, CA 90033 
TELEPONE: (818) 636-3161 
FAX: (818) 952-4027 
 
CO-INVESTIGATOR(S): 
Maxim Benbassat MD, Dimiter Arnaudov MD, Chelsia Varner 
MD, Vladimir Zelman MD, Thomas Chen MD PhD, Patrick 
Hsieh MD, John Liu MD, Frank Acosta MD, Anoosh 
Javaherian MD 
 
STUDY COORDINATOR: 
Yao-Ping Zhang MD, Anush Arakelyan 
 
SPONSOR: 
Keck Medical Center USC 
 
PARTICIPANTS/LOCATONS: 
Keck Medical Center USC 
 
 
AMENDMENTS/REVISIONS:  
1 of 12 
 


TABLE OF CONTENTS 
 
1. 
Background and Hypothesis 
3 
2. 
Objectives and Purpose 
3 
3. 
Study Design 
4 
4. 
Drug and Device Information 
4 
5. 
Selection and Withdrawal of Subjects 
5 
6. 
Descriptive Factors, Stratification, Randomization Scheme 
5 
7. 
Study Agent Administration or Intervention 
and Toxicity Management Plan 
5 
8. 
Assessment of Efficacy and Safety 
6 
9. 
Clinical and Laboratory Evaluations and Study Calendar 
6 
10. Criteria for Evaluation and Endpoint Definitions 
7 
11. Special Instructions 
7 
12. Data Collection and Monitoring 
7 
13. Statistical Considerations 
7 
14. Registration Guidelines 
9 
15. Biohazard Containment 
9 
16. Ethical and Regulatory Considerations 
9 
17. References 
9 
18. Appendix 
10 
2 of 12 
 


1.0 
BACKGROUND AND HYPOTHESES 
 
Recovery after spine surgery, especially spinal fusion surgery, is usually accompanied by severe pain.  
Traditionally, the mainstay of pain control after spinal surgery has been opioids. While opioids have been 
proven effective, they are associated with undesirable side effects including nausea, vomiting, pruritus, 
sedation, respiratory depression, ileus, and urinary retention. These effects lead to increased time 
required in PACU recovery and a decrease in patient satisfaction. For this reason, it is common practice 
to supplement opioid treatment with different classes of analgesics which work through alternative pain 
pathways and receptors in order to achieve an additive or synergistic effect while reducing the amount of 
opioids necessary for pain control. 
 
Acetaminophen is a nonsteroidal anti-inflammatory medication. Specifically, it is a centrally-acting 
cyclooxygenase inhibitor that has minimal, if any, gastrointestinal and platelet-inhibiting side effects, and 
is better tolerated by patients than other cyclooxygenase inhibitors. This medication can be a beneficial 
supplemental analgesic to opioids for postoperative pain relief. Previously conducted studies demonstrate 
a rationale for the use of intravenous acetaminophen in a multimodal analgesic regimen to reduce 
postoperative analgesia. The bibliography of these of studies is below:  
 
1. Cakan T, et al. Intravenous paracetamol improves quality of postoperative analgesia but 
does not decrease narotic requirements. J Neurosurg Anesthesiol, 2008;20:169-173 
2. Devin CJ, McGirt MJ. Best evidence in multimodal pain management in spine surgery 
and means of assessing postoperative pain and functional outcomes. J of Clin 
Neuroscience, 2015 Jun;22(6):930-8 
3. Emir E, et al. Tramadol versus low dose tramadol-paracetamol for patient controlled 
analgesia during spinal vertebral surgery. Kaohsiung J Med Sci, 2010;26(6):308-315 
4. Garcia RM, et al. A multimodal approach for postoperative pain management after 
lumbar decompression surgery: a prospective randomized study. J Spinal Disord Tech, 
26:291-297, 2013 
5. Korkmaz Dilmen O, et al. Efficacy of intravenous paracetamol, metamizol and lomoxicam 
on postoperative pain and morphine consumption after lumbar disc surgery. Eur J 
Anaesthesiol, 2010;27(5):428-432 
6. Toygar P, et al. Does IV paracetamol have preemptive analgesic effect on lumbar disc 
surgeries? Article in Turkish. Agri, 2008;20(2):14-19 
7. Uzun S, Onguc Aycan I, et al. The addition of metamizole to morphine and paracetamol 
improves early postoperative analygesia and patient satisfaction after lumbar disc 
surgery. Turk Neurosurg, 2010 Jul;20(3):341-7 
8. D. Dungy, J. Prince: When IV Acetaminophen Costs Skyrocketed, One Health System 
did Some New Math. Drug Topics. Voice of the Pharmacist, 
9. J. Van Der Westhuizen, et al. Randomised controlled trial comparing oral and 
intravenous paracetamol (acetaminophen) plasma levels when given as preoperative 
analgesia. Anaesth Intensive Care.2011 Mar;39(2):242-6 
10. Garcia, et al: A multimodal approach for Postoperative Pain Management after 
Lumbar Decompression Surgery. J Spinal Disord Tech. Volume 26(6), August 
2013. 
 
 
 
Hypotheses: 
 
1. 
Use of intravenous acetaminophen in the perioperative period will decrease TOTAL opioid intake 
after lumbar spinal fusion surgery by 30% while use of oral acetaminophen in the postoperative 
period will decrease TOTAL opioid intake by 30% as well. 
3 of 12 
 


2. 
Use of intravenous acetaminophen in the perioperative period will decrease postoperative pain by 
25% and increase patient’s satisfaction and wellbeing, while use of oral acetaminophen in the 
postoperative period will decrease postoperative pain by 25% as well. 
3. 
Use of intravenous or oral acetaminophen in the perioperative period will lead to the reduction of 
opioid side effects.  
 
 
2.0 
OBJECTIVES AND PURPOSE 
 
 
Primary objective: 
• 
Determine the impact of administering a supplemental non-opioid analgesic drug such as IV 
acetaminophen or oral acetaminophen on total opioid dose administered over the perioperative 
period. 
Secondary objectives:  
• 
Impact of IV/oral acetaminophen on the level of postoperative pain 
• 
Impact of IV/oral acetaminophen on patient satisfaction 
• 
Impact of IV/oral acetaminophen on side effects secondary to opioids such as nausea, vomiting, 
pruritus, sedation, respiratory depression, ileus, and urinary retention, and PACU discharge time. 
 
 
3.0 
STUDY DESIGN 
 
This is a prospective randomized clinical trial designed to evaluate the change in opioid intake, pain 
control, and patient satisfaction with the addition of IV/oral Acetaminophen during the postoperative 
period in patients undergoing minimally invasive spine surgery.  
 
This study will include adult patients over the age of 18 years who are classified as ASA I-III, scheduled 
for elective one or two level minimally invasive lumbar fusions. Appropriate patients will be identified in 
the surgeons’ clinic. Exclusion criteria will include patients requiring surgery for neoplastic processes, 
allergy to acetaminophen, liver dysfunction and elevated Liver Function Tests (LFTs), alcohol or drug 
dependency, mental retardation, patients with <50 kg of weight, and pregnant women. In addition, 
patients requiring long-acting opioid pain management (including fentanyl patch, oxycontin, etc) for over 3 
weeks immediately prior to surgery will also be excluded. Informed consent for participation in this study 
will be obtained by the anesthesiology staff during the pre-operative anesthesia visit. 
 
Once informed consent has been obtained, patients will either be randomized to group 1 with IV 
acetaminophen (A), group 2 with oral acetaminophen, or group 3 with Hydromorphone (control arm) (C). 
Patients in group A will receive 1 g of IV acetaminophen 15 minutes prior to wound incision, and every 4 
to 6 hours postoperatively for a total of 4 grams in 24 hours. Patients in group B will receive 1 g of PO 
acetaminophen prior to surgery, and 1 g of oral acetaminophen every 4 to 6 hours postoperatively for a 
total of 4 grams in 24 hours. Patients in the control arm (Group C) will not receive acetaminophen for 24 
hours. General anesthetic medications will be identical in each group, and will include: 
 
• 
IV Propofol and IV Remifentanil (1 mcg/kg) will be used on induction. 
• 
Local injection at the beginning of the procedure with Lidocaine 0.5% (maximum 5 mg/kg) with 
Epinephrine by the surgeon. 
• 
Remifentanil infusion (0.05-0.4 mcg/kg/hr) and Propofol infusion (75-200 mcg/kg/min) for 
maintenance of anesthesia. 
• 
Bupivacaine 0.5% (maximum 3mg/kg) injected into the wound by the surgeon before closure.  
• 
Hydromorphone PCA (0.2-0.4 mg Q10 min, up to 2 mg/hr with no basal rate) for postoperative 
pain control for 24 hours after surgery. 
 
Postoperative assessments will be done at 0, 30, and 60 minutes, 6 hours, 12 hours and 24 hours after 
surgery. Patients will be evaluated for pain (using a numeric rating scale), total opioid consumption, and 
4 of 12 
 


for opioid side effects including drowsiness (using the Ramsey sedation scale and the Aldrete score at 
the time of arrival to and discharge from recovery room), respiratory depression, nausea, vomiting, and 
pruritus. Patient satisfaction will also be assessed using a numeric rating scale. Example evaluation forms 
are in the appendix. Side effects of IV/oral acetaminophen will be monitored in the postoperative period. 
 
 
4.0 
DRUG AND DEVICE INFORMATION 
 
Acetaminophen  
IND number: 
IDE number: DB00316 (APRD00252) 
The supplier: Cadence Pharmaceuticals, Inc. 
 
OFIRMEV® (acetaminophen) Injection (1000 mg / 100 mL, 10 mg / mL) 
Acetaminophen injection, is indicated for the management of mild to moderate pain, the management of 
moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever. The FDA approval 
of OFIRMEV was based on data from clinical trials in approximately 1,020 adult and 355 pediatric 
patients. These trials included two studies evaluating the safety and effectiveness of OFIRMEV in the 
treatment of pain, and one study evaluating OFIRMEV in the treatment of fever. The effectiveness of 
OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients less than 2 
years of age. 
 
Safety Information. The maximum recommended daily dose of acetaminophen (4 g) should not be 
exceeded. Administration of acetaminophen by any route in doses higher than recommended may result 
in hepatic injury, including the risk of severe hepatotoxicity and death. OFIRMEV is contraindicated in 
patients with severe hepatic impairment, severe active liver disease or with known hypersensitivity to 
acetaminophen or to any of the excipients in the formulation. Acetaminophen should be used with caution 
in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic 
malnutrition, severe hypovolemia, or severe renal impairment. OFIRMEV should be administered only as 
a 15 minute intravenous infusion. Discontinue OFIRMEV immediately if symptoms associated with allergy 
or hypersensitivity occur. Do not use in patients with acetaminophen allergy. The most common adverse 
reactions in patients treated with OFIRMEV were nausea, vomiting, headache, and insomnia in adult 
patients and nausea, vomiting, constipation, pruritus, agitation, and atelectasis in pediatric patients. The 
antipyretic effects of OFIRMEV may mask fever in patients treated for post-surgical pain. 
 
ACETAMINOPHEN 
ID/FEI: 19 41239 8 0 
The Supplier: Physician Total Care, Inc 
 
ACETAMINOPHEN EXTRA STRENGTH- acetaminophen tablet (500 mg) 
Acetaminophen is indicated for the management of minor pain and the reduction of fever.  
Safety information: The maximum recommended daily dose of acetaminophen (4 g) should not be 
exceeded. Administration of acetaminophen by any route in doses higher than recommended may result 
in hepatic injury and severe hepatotoxicity. It cannot be use with other medications containing 
acetaminophen.  
 
 
 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
Inclusion Criteria: Patients of the age of 18 and over, ASA I-III, English or Spanish speakers, scheduled 
for elective one or two level minimally invasive lumbar fusions, selected from the neurosurgical outpatient 
clinic at the Keck Hospital of USC. 
5 of 12 
 


 
Exclusion Criteria: Patients requiring surgery for neoplastic processes, allergy to acetaminophen or 
hydromorphone, liver dysfunction, alcohol or drug dependency, mental retardation, and pregnant women. 
In addition, patients requiring long-acting opioid pain management (including fentanyl patch, oxycontin, 
etc) for over 3 weeks immediately prior to surgery will also be excluded. 
 
Withdrawal Criteria: Patients may withdraw from the study at any time during the pre-operative or data 
collection period (the first 24 hours post-operatively) or later, should they no longer wish to participate. 
Patients experiencing severe post-operative pain not controlled by the post-operative pain protocol may 
withdraw should they require alternate pain management. Any patient experiencing discomfort or adverse 
reaction to the study drug, or the hydromorphone PCA may withdraw at any time to receive alternative 
pain control. 
 
 
6.0 
DESCRIPTIVE FACTORS, STRATIFICATION, RANDOMIZATION SCHEME 
 
Once informed consent is obtained, patients will be randomized to either the treatment with IV 
acetaminophen (A), with oral acetaminophen (B), or hydromorphone only (control arm) (C) group. For 
randomization, we will have 126 opaque envelopes (42 for group A, 42 for group B, and 42 for group C) 
which will be randomly distributed and opened in the preoperative area before surgery. Patients in group 
A will receive IV acetaminophen + IV hydromorphone. Patients in group B will receive oral acetaminophen 
+ IV hydromorphone. Patients in group C will receive hydromorphone only. Patient characteristics that are 
important to stratify and control include age, ASA classification, operative level, and number of spinal 
levels fused. 
 
 
7.0 
STUDY AGENT ADMINISTRATION OR INTERVENTION AND 
TOXICITY MANAGEMENT PLAN 
 
Patients will be randomized to either the treatment with IV acetaminophen (A), PO acetaminophen (B), or 
hydromorphone (C) group. Before entering the operating room, patients may be pre-medicated with 
benzodiazepines. Patients in PO acetaminophen group (B) will receive 1000mg of PO acetaminophen 15 
minutes before entering the operating room. All Patient will be receiving propofol as the induction agent, 
remifentanil as the induction opioid, and a muscle relaxant of choice. During the case, patients will only 
receive propofol and remifentanil as continuous infusions, which can be supplemented with up to 0.5 
MAC of an inhalational anesthetic (sevoflurane or desflurane). Patients who are randomized to group A 
will receive 1 g of IV acetaminophen 15 minutes prior to wound incision. Patients who are randomized to 
group A will receive IV acetaminophen every 4 to 6 hours postoperatively for a total of 4 g in 24 hours. 
Patients who are randomized to Group B will receive PO acetaminophen every 4 to 6 hours 
postoperatively for a total of 4 g in 24 hours. Patients who are randomized to group C will not receive 
acetaminophen. Post-operatively, patients in both groups will also receive IV hydromorphone PCA only 
for 24 hours for pain. 
 
AGENT 
DOSE 
ROUTE 
DAYS 
Rx INTERVAL 
NOTES 
B (acetaminophen 
PO) 
500 mg, 2 
tablets 
PO 
1 
4-6 hours (maximum 
4 g/24 h) 
1st dose 15 min 
prior to going to the 
OR 
A (acetaminophen 
IV) 
1 g/100mL 
IV over 15 min 
1 
4-6 hours (maximum 
4 g/24 h) 
1st dose intra-op 15 
minutes prior to 
wound incision 
 
Treatment will be discontinued if a patient experiences any side effects related to the medication. A 
patient may always be removed from the treatment whenever he/she wishes for reasons including but not 
limited to inadequate pain control or adverse reactions to treatment medications. 
6 of 12 
 


 
 
8.0 
ASSESSMENT OF EFFICACY AND SAFETY 
 
Side effects and toxicities that the patient will be asked about at each evaluation during the treatment 
include: nausea, vomiting, headache, and insomnia. If symptoms associated with allergy or 
hypersensitivity occur, the medication will be discontinued immediately. Maximum recommended daily 
dose of acetaminophen will not exceed 3.75g for patients <50 kg or 4g for patients > 50 kg. 
Administration of acetaminophen in doses higher than recommended may result in hepatic injury, 
including the risk of severe hepatotoxicity and death. Patients will not receive doses higher than 
recommended. Serious adverse events will be monitored up to 2 days following the last Study Medication 
dosing and followed to resolution or stabilization. Investigators will keep all safety-related documentation 
in site files. 
 
 
9.0 
CLINICAL AND LABORATORY EVALUATIONS AND STUDY CALENDAR  
 
Study Calendar 
Parameter 
Pretreatment 
15 min 
prior to 
incision 
Arrival 
to 
PACU 
30 min 
after 
arrival to 
PACU 
60 min 
after 
arrival to 
PACU 
In 6 
hours 
In 12 
hours 
In 18 
hours 
In 24 
hours 
Comprehensive History & 
Physical Examination 
X 
 
 
 
 
 
 
 
 
IV Agent administration 
 
X 
 
 
 
X 
X 
X 
 
PO Agent administration 
X 
 
 
 
 
X 
X 
X 
 
Ramsey Sedation Scale 
 
 
X 
 
 
 
 
 
 
Numeric pain scale 
 
 
X 
X 
X 
 
X 
 
X 
Aldrete score 
 
 
X 
 
X 
 
 
 
 
Respiratory depression 
scale 
 
 
X 
X 
X 
 
X 
 
X 
PONV 
 
 
X 
X 
X 
 
X 
 
X 
Pruritus 
 
 
X 
X 
X 
 
X 
 
X 
Patient discharge time from 
PACU 
 
 
 
 
X 
 
 
 
 
Patient satisfaction scale 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
10.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
Endpoint Definitions: The primary study endpoint will be determined by the impact of IV/oral 
acetaminophen on total opioid dose administered over the perioperative period. The impact of 
IV/oral acetaminophen on the level of postoperative pain, patient satisfaction, and side effects 
from opioids such as nausea, vomiting, pruritus, sedation, respiratory depression, ileus, and 
urinary retention, and PACU discharge time of all eligible patients will also be investigated. All 
eligible patients who are enrolled will be included in the analysis of the impact of IV/oral 
acetaminophen administration over the perioperative period. 
 
 
11.0 SPECIAL INSTRUCTIONS 
7 of 12 
 


 
Only standard laboratory tests or additional laboratory results necessary for the patient will be 
obtained. No additional blood samples for study purposes will be obtained from the patient. 
 
 
12.0 DATA COLLECTION AND MONITORING 
 
• 
Case Report Forms: will be in the chart for every patient and will include all data 
collected for the patient. They will be held by the Study Coordinator and locked in the 
office after data is collected. 
• 
Source Documentation and Timeliness of CRF Completion will be completed 
immediately after data collection is complete. 
• 
Study Records: Will be locked by the Study Coordinator in the office. 
• 
Data Management: Data will be labeled with a code that the research team can link to 
personal identifying data. 
• 
Data Monitoring: The PI will monitor the study methods and procedures, and will be 
meeting with investigators for data monitoring on a bimonthly basis.  
 
 
13.0 STATISTICAL CONSIDERATIONS 
 
All sample size calculations with reference to: 
 
“Specific Aim 1”, i.e. reduction of TOTAL opioid intake by at least 30% between the Control 
(Group 3)  and Intervention Group (Group1 or Group 2), meaning Group 1 versus Group 3 and 
Group 2 versus Group 3  
and 
“Specific Aim 2”, i.e. improvement of Pain Score (within 12 hours) by at least 25% between the 
Control (Group3) and the Intervention Group (Group 1 or Group2), meaning Group 1 versus 
Group 3 and Group 2 versus Group 3, 
 
were based on data from [Garcia et al, 2013; 26:291-297, J Spinal Disord Tech]. (manuscript 
attached). Also, on the grounds of literature from Westhuizen et al (Anaesth Intensive Care 
2011; 39: 242-246) and D. Dungy, J. Prince (Voice of the Pharmacist), it is suggested that IV-
Acetaminophen and Oral-Acetaminophen should have comparable effects. Thus, in our sample 
size calculations we assumed that the comparison between Group 1 vs Group 3 and Group 2 vs 
Group 3 would be similar. We have no further information regarding the distribution of the data 
(no own pilot studies) and have no further references other than the literature. 
 
On the basis of the above assumptions and for our statistical calculations as primary endpoint is 
the reduction by 30% of the total opioid used, i.e. 53.3 ± 28.9 to 37.3 mg, thus, with 0.1 type I 
alpha error probability and 80% power we will need 42 patients per arm, meaning, 126 patients 
in total which we will use to compare IV Acetaminophen vs Control groups and Oral 
Acetaminophen vs Control groups. 
 
Regarding the secondary/pain endpoint we postulate 25% decrease within 12-hours, meaning 
7.0 ± 2.9 to 5.25, thus with 0.05 type I alpha error probability and 80% power we will need 24 
patients per arm. Due to the above, we feel comfortable that by enrolling 126 patients, in total, 
we should be able to prove our hypotheses. 
8 of 12 
 


 
Similar studies have demonstrated that the dropout rate is 0% for patients in this condition. Also, 
medical charts in our hospital have demonstrated that over 100 patients are treated in this 
condition every year. Thus, it is postulated that a final sample of 126 patients can be enrolled 
within a year and a half.  
All sample size calculations are based on assumptions from published data in the literature. 
Therefore, we would like to conduct an interim analysis once 21 patients per arm i.e. 63 total 
have been collected and if necessary to account for any potential differences (in our patient 
population descriptives and or distribution vs literature) that may be observed.  
Patients will be randomized into 2 groups, Control and Intervention as per a 1:1 ratio to satisfy 
equal enrolment at any time and until the targeted sample has been reached. 
 
 
Statistical References 
1. Ostle, B. and Malone, L.C. 1988. Statistics in Research. Iowa State University Press. 
Ames, Iowa. 
2. Zar, Jerrold H. 1984. Biostatistical Analysis (Second Edition). Prentice-Hall. Englewood 
Cliffs, New Jersey. 
3. Garcia, et al: A multimodal approach for Postoperative Pain Management after Lumbar 
Decompression Surgery. J Spinal Disord Tech. Volume 26(6), August 2013. 
 
 
14.0 REGISTRATION GUIDELINES 
 
14.1 
Specify phone number to register the patients: 213-287-0038. Also identify whether the 
patients will be randomized or stratified: Patient will be randomized at the day of the surgery. 
 
14.2 
Specify the forms and records needed for registration: Informed Consent, 
Registration/Eligibility Worksheet, Flow Sheet.  
 
 
 
Note: At the time of registration, two copies of a signed and dated patient Informed Consent 
form with Bill of Rights must be available (an original for patient’s medical chart; one copy for 
the patient; and the other for the PI’s file).  
 
 
15.0 BIOHAZARD CONTAINMENT 
 
 
N/A 
 
 
 
16.0 ETHICAL AND REGULATORY CONSIDERATIONS 
 
All institutional and Federal regulations concerning the Informed Consent form will be fulfilled. 
The study will be conducted in adherence to the ICH Good Clinical Practice Guidelines. 
 
 
 
17.0 REFERENCES 
 
1. Cakan T, et al. Intravenous paracetamol improves quality of postoperative analgesia but 
does not decrease narotic requirements. J Neurosurg Anesthesiol, 2008;20:169-173 
9 of 12 
 


2. Devin CJ, McGirt MJ. Best evidence in multimodal pain management in spine surgery 
and means of assessing postoperative pain and functional outcomes. J of Clin 
Neuroscience, 2015 Jun;22(6):930-8 
3. Emir E, et al. Tramadol versus low dose tramadol-paracetamol for patient controlled 
analgesia during spinal vertebral surgery. Kaohsiung J Med Sci, 2010;26(6):308-315 
4. Garcia RM, et al. A multimodal approach for postoperative pain management after 
lumbar decompression surgery: a prospective randomized study. J Spinal Disord Tech, 
26:291-297, 2013 
5. Korkmaz Dilmen O, et al. Efficacy of intravenous paracetamol, metamizol and lomoxicam 
on postoperative pain and morphine consumption after lumbar disc surgery. Eur J 
Anaesthesiol, 2010;27(5):428-432 
6. OFIRMEV® (acetaminophen) Injection Package Insert 
7. Ostle, B. and Malone, L.C. 1988. Statistics in Research. Iowa State University Press. 
Ames, Iowa. 
8. Toygar P, et al. Does IV paracetamol have preemptive analgesic effect on lumbar disc 
surgeries? Article in Turkish. Agri, 2008;20(2):14-19 
9. Uzun S, Onguc Aycan I, et al. The addition of metamizole to morphine and paracetamol 
improves early postoperative analygesia and patient satisfaction after lumbar disc 
surgery. Turk Neurosurg, 2010 Jul;20(3):341-7 
10. Zar, Jerrold H. 1984. Biostatistical Analysis (Second Edition). Prentice-Hall. Englewood 
Cliffs, New Jersey. 
11. D. Dungy, J. Prince: When IV Acetaminophen Costs Skyrocketed, One Health Systed did Some 
New Math. Drug Topics. Voice of the Pharmacist, 
12. J. Van Der Westhuizen, et al. Randomised controlled trial comparing oral and intravenous 
paracetamol (acetaminophen) plasma levels when given as preoperative analgesia. Anaesth 
Intensive Care.2011 Mar;39(2):242-6 
 
 
 
18.0 APPENDIX 
 
 
Appendix I: 
Toxicity Scale (if applicable) 
 
Appendix II: 
Informed Consent 
 
Appendix III: Questionnaires &/or Survey Forms 
 
 
Numerical Pain Scale (1-10) 
 
 
 
Spanish version of Numerical Pain Scale (1-10) 
 
10 of 12 
 


 
 
 
Patient Satisfaction Scale 
 
 
1 – Very poor 
2 – Poor 
3 – Okay 
4 – Good 
5 – Very good 
Pain Control 
 
 
 
 
 
Drowsiness 
 
 
 
 
 
PONV 
 
 
 
 
 
Pruritus 
 
 
 
 
 
Overall satisfaction 
 
 
 
 
 
 
Spanish version of Patient Satisfaction Scale 
 
 
1 – Muy mal 
2 – Mal 
3 – Bueno 
4 – Bien 
5 – Muy bueno 
Control del dolor 
 
 
 
 
 
Somnolencia 
 
 
 
 
 
Náusea y vómitos 
 
 
 
 
 
Prurito 
 
 
 
 
 
Satisfacción general 
 
 
 
 
 
 
Ramsay Sedation Scale* 
 
Response to verbal command 
Score 
Anxious, agitated, or restless 
1 
Cooperative, oriented, tranquil 
2 
Responds only to auditory stimulus 
3 
Brisk response to light glabellar tap or loud auditory stimulus 
4 
Sluggish response to light glabellar tap or loud auditory stimulus 
5 
Does not respond to test stimulus 
6 
 
*Performed using a series of steps: observation of behavior (score 1 or 2), followed (if 
necessary) by assessment of response to voice (score 3), followed (if necessary) by 
assessment of response to loud auditory stimulus or light glabellar tap (score 4 to 6) 
 
 
Modified Aldrete Score 
 
Parameter 
Description of Patient 
Score 
Activity level 
Moves all extremities on command/voluntarily 
2 
 
Moves 2 extremities 
1 
 
Cannot move extremities 
0 
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Respirations 
Breathes deeply and coughs freely 
2 
 
Dyspneic, shallow, limited breathing 
1 
 
Apneic 
0 
Circulation 
20 mm Hg BP ± 20% of preanesthetic level 
2 
 
20-50 mm Hg BP ± 20-50% of preanesthetic level 
1 
 
50 mm Hg BP ± 50% of preanesthetic level 
0 
Consciousness Fully awake 
2 
 
Arousable to verbal stimuli 
1 
 
Non-responsive 
0 
Pulse Oximetry Maintains >92% on room air 
2 
 
Requires supplemental oxygen to maintain >92% 
1 
 
<92% on supplemental oxygen 
0 
 
 
Respiratory depression assessment  
  
Heart rate 
 
Blood pressure 
 
Respiration rate 
 
Pulse oximetry (%) 
 
 
 
Post-operative Nausea and Vomiting (PONV scale) 
 
No N/V 
0 
Nausea Only 
1 
Both N/V 
2 
 
 
Total opioid consumption  
 
Remifentanil intra-operatively 
 
Hydromorphone postoperatively (24 hrs)                   
 
 
End of study. 
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