Conditions: Pain, Postoperative Spine Injuries and Disorders Narcotic Use
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 44
Healthy volunteers: no

Brief summary:
The aim of this study is to investigate the hypothesis that multimodal pain regimen (consisting of acetaminophen, celecoxib, gabapentin, and oxycodone) administered pre-operatively before elective spine surgery significantly decreases acute pain post-operatively as well as decreasing requirements of post-op opioids for pain control in PACU as compared to patients undergoing elective spine surgery without a pre-operative pain regimen.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Pre-op Multimodal analgesia (MMA) regimen + standard post-op oxycodone
Intervention descriptions: intervention 1: The study subjects will be assigned to the defined pre-op MMA regimen with standard postop oxycodone based pain control regimen given on an as needed basis. The treatment group outcomes will be compared to patients outside of the study including a historical control group (receiving only post-op pain regimen) prior to the implementation of the new regimen. The studied treatment group will receive within 3 hours before surgery an oral MMA regimen consisting of:

Acetaminophen 975 mg Celecoxib 200 mg Gabapentin 300 mg Oxycodone 10 mg Extended Release

Protocol document:
Prot_SAP_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
An Analysis of the Efficacy of a Pre- 
Emptive Multimodal Pain Regimen in 
Reducing Acute Post-Operative Pain and 
Narcotic Pain Medication Requirements 
in Spine Surgery 
385 First Street, Apt-3S 
MINEOLA, NY, 11501, United States 
 
Protocol Version 
May 12, 2020 
version 2 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement: 
NCT Number: NCT04522206 
Study Number: 20-00734 
PI: Muhammad Tariq, MD 


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Study Personnel 
Investigator 
Muhammad Tariq 
NYU Winthrop Hospital 
United States 
Tel: 6023631134 
Email: tariqm03@nyulangone.org 


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Synopsis 
 
 
Primary Objective 
Aim 1: Determine pain control post-operatively after elective spine surgery 
Secondary Objectives 
Aim 2: Determine patient variables significantly associated with post-operative pain 
control 
Aim 3: Determine operative variables significantly associated with post-operative pain 
control 
Aim 4: Determine long term outcomes and complication rates after pre-emptive MMA 
regimen implementation 
Study Duration 
Expected Duration: 2020 to 2022 
Study Design 
Prospective Cohort Study 
Study Population 
Adult patients undergoing elective spine surgery at NYU Winthrop Hospital 


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Number of Participants 
At a significance level of 5%, in order to achieve 80% power for detecting a 1 point mean 
difference in VAS pain scores[1], we would need a sample of 31 patients to assess the 
primary outcome. Adjusting by approximately 5% to account for patients that are found 
ineligible retrospectively, the total sample size required is 33 patients for the primary 
outcome. 
Furthermore, additional analyses to fulfill Aims 2-4 would require a larger sample size and 
would constitute separate studies based on final sample size achieved 
[1] Using the reported control group VAS scores by Garcia et al. of 8.4 and standard 
deviation of 2 
Number of Study Sites 
The study will be conducted out of NYU Winthrop hospital as well as in the outpatient 
office settings. 
Primary Outcome Variables 
Aim 1: Determine pain control post-operatively after elective spine surgery 
Measure acute pain using the VAS pain scale in PACU 
Measure opioid sparing and rescue time as determined by the time interval from 
patient extubation to time when pain medication is first demanded in PACU 
Determine secondary outcomes: length of stay in PACU, opioid dose, drain output, 
transfusion rates, and hospital length of stay. 
Secondary and Exploratory Outcome Variables 
Aim 2: Determine patient variables significantly associated with above outcomes 
The following variables will be considered: age, gender, race, comorbidities, pain 
medication use prior to surgery (including dose and number of years used), history of 


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seeing a pain management physician, history of psychological illnesses, demographic 
history, use of ambulatory aids and activity level at baseline 
Aim 3: Determine operative variables significantly associated with above outcomes 
The following variables will be considered: primary vs revision surgery, surgical site, 
number of spinal levels, length of surgery, use of intra-operative dexamethasone, 
blood loss, ASA score 
Aim 4: Determine long term outcomes and complication rates after pre-emptive MMA 
regimen implementation 
Determine patient reported VAS pain scores at 3 , 6, and 12 months post-operatively 
Determine long term pain medication use at 3 , 6, and 12 months post-operatively 
Determine rate of surgical complications including surgical site infection, readmission, 
pseudoarthrosis/lack of fusion rates, hardware complication, revision surgery, 
neurological deficit 
Visit Schedule Table (Optional) 
Study Flow Chart (optional) 


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Explanation 
Abbreviation 
Abbreviations 
 


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Explanation 
Glossary 
Glossary of Terms 
 


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Table Of Contents 
Synopsis ..................................................................................................................................... 3 
An Analysis of the Efficacy of a Pre-Emptive Multimodal Pain Regimen in Reducing 
Acute Post-Operative Pain and Narcotic Pain Medication Requirements in Spine Surge ry3 
Primary Objective ................................................................................................................................ 3 
Secondary Objectives ........................................................................................................................ 3 
Study Duration .................................................................................................................................... 3 
Study Design....................................................................................................................................... 3 
Study Population ................................................................................................................................ 3 
Number of Participants...................................................................................................................... 3 
Number of Study Sites ...................................................................................................................... 3 
Primary Outcome Variables ............................................................................................................. 3 
Secondary and Exploratory Outcome Variables .......................................................................... 3 
Visit Schedule Table (Optional) ....................................................................................................... 3 
Abbreviations....................................................................................................................................... 6 
Glossary of Terms .............................................................................................................................. 7 
1 - Introduction ...................................................................................................................... 11 
1.1 Introductory Statement ........................................................................................................... 11 
2 - Background ...................................................................................................................... 12 
2.1.1 Preclinical Experience ........................................................................................................... 12 
2.1.2 Clinical Experience .......................................................................................................................... 12 
2.2 Background/prevalence of research topic .......................................................................... 14 
3 - Rationale/Significance ................................................................................................. 15 
3.1 Problem Statement ................................................................................................................... 15 
3.2 Purpose of Study/Potential Impact ....................................................................................... 15 
3.3.1 Potential Risks ................................................................................................................................ 15 
3.3.2 Potential Benefits ...........................................................................................................................16 
4 - Study Objectives ........................................................................................................... 17 
4.1 Hypothesis ................................................................................................................................. 17 
4.2 Primary Objective ...................................................................................................................... 17 
4.3 Secondary Objectives .............................................................................................................. 17 
5 - Study Design .................................................................................................................. 18 
5.1 General Design Description.................................................................................................... 18 
5.1.1 Study Date Range and Duration................................................................................................. 18 
5.1.2 Number of Study Sites ..................................................................................................................18 
5.2 Outcome Variables .................................................................................................................. 18 
5.2.1 Primary Outcome Variables ..........................................................................................................19 
5.2.2 Secondary and Exploratory Outcome Variables ............................................................. 19 
5.3 Study Population ...................................................................................................................... 19 
5.3.1 Number of Participants ...................................................................................................................19 
5.3.2 Eligibility Criteria/Vulnerable Populations .................................................................................19 
6 - Methods ............................................................................................................................ 21 
6.1 Treatment - Drug ..................................................................................................................... 21 
6.1.1 Identity of Investigational Product/New Drug ......................................................................... 21 


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6.1.2 Dosage, Admin, Schedule ............................................................................................................21 
6.1.3 Method of Assignment/Randomization ............................................................................... 21 
6.1.4 Blinding and Procedures for Unblinding ........................................................................... 21 
6.1.5 Packaging/Labelling .......................................................................................................................21 
6.1.6 Storage Conditions .........................................................................................................................21 
6.1.7 Concomitant therapy .....................................................................................................................21 
6.1.8 Restrictions ......................................................................................................................................22 
6.2 Assessments .............................................................................................................................. 22 
6.2.1 Efficacy .............................................................................................................................................22 
6.2.2 Safety/Pregnancy-related policy .................................................................................................23 
6.2.2.1 Adverse Events Definition and Reporting ..............................................................................23 
6.2.3 Pharmacokinetics .................................................................................................................. 23 
6.2.4 Biomarkers ............................................................................................................................. 23 
6.3 Study Procedures ..................................................................................................................... 23 
6.3.1 Study Schedule...............................................................................................................................23 
6.3.2 Informed Consent ..........................................................................................................................23 
6.3.3 Screening .........................................................................................................................................24 
6.3.4 Recruitment, Enrollment and Retention ......................................................................... 24 
6.3.5 On Study Visits ...............................................................................................................................24 
6.3.6 End of Study and Follow-up .........................................................................................................24 
6.3.7 Removal of subjects.......................................................................................................................24 
6.4 Statistical Method.................................................................................................................... 24 
6.4.1 Statistical Design ...........................................................................................................................25 
6.4.2 Sample Size Considerations .........................................................................................................25 
6.4.3 Planned Analyses ................................................................................................................... 25 
6.4.3.1 Primary Analyses .............................................................................................................. 25 
6.4.3.2 Secondary Objectives Analyses ..................................................................................... 25 
6.4.3.3 Safety/Pregnancy-related policy .................................................................................... 25 
6.4.3.4 Analysis of Subject Characteristics ................................................................................. 25 
6.4.3.5 Interim Analysis................................................................................................................. 26 
6.4.3.6 Health economic evaluation ............................................................................................ 26 
6.4.3.7 Other .................................................................................................................................... 26 
6.4.4 Subsets and Covariates ................................................................................................................26 
6.4.5 Handling of Missing Data ..............................................................................................................26 
7 - Trial Administration ..................................................................................................... 27 
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization ............... 27 
7.2 Institutional Review Board (IRB) Review ............................................................................ 27 
7.3 Subject Confidentiality ............................................................................................................ 27 
7.4 Deviations/Unanticipated Problems .................................................................................... 27 
7.5 Data Collection ......................................................................................................................... 27 
7.6 Data Quality Assurance .......................................................................................................... 27 
7.7 Study Records ........................................................................................................................... 27 
7.8 Access to Source ...................................................................................................................... 27 
7.9 Data or Specimen Storage/Security ..................................................................................... 28 
7.10 Retention of Records ............................................................................................................ 28 


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7.11 Study Monitoring .................................................................................................................... 28 
7.12 Data Safety Monitoring Plan ............................................................................................... 28 
7.13 Study Modification ................................................................................................................. 28 
7.14 Study Discontinuation............................................................................................................ 28 
7.15 Study Completion................................................................................................................... 28 
7.16 Conflict of Interest Policy ..................................................................................................... 28 
7.17 Funding Source ...................................................................................................................... 28 
7.18 Publication Plan ...................................................................................................................... 29 
Appendices ....................................................................................................................................... 30 
References ......................................................................................................................................... 31 


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1 - Introduction 
1.1 Introductory Statement 
 
Pain following surgery of the spine is a common complaint9. In addition, pain is the second 
leading cause of readmission2. Continued research for novel and improved methods for 
post-operative pain control is vital; especially given the recent rising healthcare urgency to 
limiting opioid use amidst the opioid abuse crisis. Historically, post-operative pain control 
regimens have relied heavily on opioid medications provided at intervals in response to as 
needed protocols3. However, several limitations exist to this model of pain control including 
poor pain control and a host of opioid induced adverse effects35. 
Recently significant interest has been brought to the utilization of multimodal analgesia 
(MMA)15. MMA takes advantage of the synergistic effect of multiple pain medications that 
act through different mechanisms of actions to target pain more effectively. Several studies 
have highlighted the efficacy of such regimens and have proven that these regimens are 
safe5,6,8,12,15,24,31,37. 
Furthermore, the pre-emptive administration of pain medications has been believed to be 
more efficacious in controlling post-operative pain36. Pre-emptive control of pain is thought 
to mitigate or halt central nervous system sensitization (which includes prolonged changes) 
as a result of noxious stimuli such as surgery36. Therefore, we sought to evaluate the 
efficacy of a pre-emptive MMA pain regimen in controlling post-operative pain in a 
community hospital setting. 


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2 - Background 
2.1.1 Preclinical Experience 
 
A wide range of pharmacological options are available for the effective amelioration of post 
spine surgery pain. Each analgesic choice possesses inherent advantages and 
disadvantages to its applicability15. 
Acetaminophen, one of the most commonly used non-opioid analgesics utilized exerts its 
effects though cyclooxygenase (COX) inhibition. Multiple studies have demonstrated 
improved pain control and reduced opioid use with acetaminophen use in patients 
undergoing orthopaedic procedures29,33. As such acetaminophen remains a cornerstone in 
most multimodal pain regimens. 
Nonsteroidal anti-inflammatory (NSAID) medications are another commonly utilized 
analgesic choice. They exert their anti-inflammatory and analgesic effects via COX 
inhibition therefore blocking prostaglandin production. Although COX1 are ubiquitous 
throughout the body, COX2 enzymes are more specific to inflammatory tissues. Specific 
COX2 inhibitors were developed in order to minimize adverse effects of COX1 inhibition (ie 
gastric mucosa damage and platelet dysfunction). However, there has been controversy 
over the use of NSAIDs in spine surgery given concerns for nonunion, pseudoarthrosis, and 
bleeding/hematoma formation. A number of studies have shown higher nonunion rates in a 
dose dependent manner with the use of NSAIDs19,39. Nevertheless, recent studies highlight 
that COX2 inhibitors as well as NSAIDs used in lower doses prove to be efficacious for pain 
control and may not carry the same adverse effects as previously thought10,11,21,27. 
Gabapentin and pregabalin are neuromodulatory agents commonly used for neuropathic 
pain. They work by inhibiting calcium gated channels on presynaptic axons thereby 
reducing neuronal excitability. The efficacy of these neuromodulatory agents in post- 
operative pain control and reduction of opioid consumption is well documented in spine 
surgery with multiple level I studies presenting positive outcomes7,20,34,38. 
Oxycodone is a standard opioid pain medication that is widely accepted as part of a pain 
regimen for post-operative pain control4. The medication works by decreasing excitability of 
neurons by binding to mu, kappa, and delta receptors thereby inhibiting adenylyl cyclase 
signaling pathway23. 
Limited literature exists on the efficacy of these commonly used analgesics as part of a 
multimodal regimen especially one given pre-operatively. Therefore we sought to 
investigate the efficacy of a MMA regimen administered pre-operatively in terms of acute 
post-operative pain control and opioid pain medication requirements. 
 
 
2.1.2 Clinical Experience 
 
The use MMA regimens for controlling post-operative pain continue to gain acceptance and 
popularity6,8,12,15. The idea of MMA relies on the synergistic action of multiple agents 
working to inhibit pain through distinct mechanisms along the pain pathway. MMA prove to 


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improve pain control, reduce opioid consumption, decrease adverse effects, and facilitate 
recovery and rehabilitation. Furthermore, the use of analgesic agents prior to the insult of 
pain may prove to have further value by preventing pain and controlling pain before its 
onset thereby reducing sensitization. Limited studies have looked at MMA efficacy in spine 
surgery and very limited literature exists on its efficacy if given pre-emptively (ie pre- 
operatively)1,13,14,16,36. 
Garcia et al. report their findings of a preemptive MMA regimen with 22 patients 
undergoing lumbar laminectomy surgery8. In this randomized control trial (RCT), patients 
received either IV morphine only or MMA regimen consisting of 200 mg celecoxib pre-op 
and 100 mg post-op, 15 mg pregabalin pre-op, and 10 mg oxycodone extended-release 
given twice daily post-op. Medications were administered every 12 hours with first dose 
given pre-op. All patients were allowed to receive IV morphine post-op on an as needed 
basis. Pain levels were assessed using the VAS pain scale at 0, 4, 8, 12, 16, 24, and 48 
hours post-op. IV morphine requirements were recorded 6,12, and 24 hours post-op. They 
found that compared to the IV morphine group, the MMA group had lower VAS pain scores 
at all time points, a 58% reduction in morphine consumption and earlier oral food intake. 
No difference in intra-operative blood loss was noted. 
 
Another RCT by Kim et al. looked at preemptive MMA efficacy in single level lumbar fusion 
surgery in 80 patients14. Regimen consisted of 500 mg acetaminophen, 200 mg celecoxib, 
75 mg of pregabalin, and 10 mg extended release oxycodone given 1 hour before surgery 
and then twice daily. IV morphine was used in the control group. They found improved VAS 
pain scores at all time points and lower Oswentry Disability Index scores at all time points 
except day 1 post-op. Of note they did not find a difference in acute complications or in 
fusion rates at 1 year. No difference in intra-operative blood loss was noted. 
Lee et al. looked at a retrospective observational study of 393 patients undergoing lumbar 
spinal fusion from 17 hospitals sent a post-op questionnaire16. Only 79 of these patients 
were noted to have received preemptive analgesics; COX2 inhibitors with or without 
gabapentin/pregabalin. 363 patients received some form of MMA post-operatively. They did 
not find significant differences in outcomes with the post-op MMA protocols assessed. 
However, preemptive pain regimen group reported significantly lower self-administered 
PCA use post-op. Furthermore, EQ-5D activity, depression/anxiety, and self-care also 
improved significantly in the preemptive group at 2 weeks post-op. It is worth noting the 
retrospective and observational nature are limitations to the study as well as possibility of 
selection and recall bias. 
A recent study by Kien et al. looked at the preemptive use of pregabalin and celecoxib in 60 
lumbar spine fusion surgery patients in a prospective cohort study13. The patients were 
randomized to receive either the MMA regimen or placebo 2 hours pre-op. The MMA 
consisted of pregabalin 150 mg and celecoxib 200 mg. Post-op pain was managed with a 
morphine PCA. They noted VAS pain scores and morphine consumption to be significantly 
lower in the treatment group at 24 and 48 hours post-op. 
Finally, Mathiesen et al. and Rajpal et al. are additional retrospective studies looking at 
primarly post-op MMA after spine lumbar fusion surgery in 85 and 200 patients 
respectively22,26. They also note improved pain control and lower opioid requirements in the 
intervention groups. 


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Unfortunately, the long term outcomes including fusion rates and complications such as 
pseudarthrosis were not found in our review to be reported by any of the studies. 
 
 
 
 
2.2 Background/prevalence of research topic 


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3 - Rationale/Significance 
3.1 Problem Statement 
 
Increasing demand for elective spine surgery accentuates the importance of improving 
outcomes and lowering costs. One of the key challenges in spine surgery remains to be 
post-operative pain control. Pain leads to a number of adverse effects on physical, 
emotional, and social health as well as to short and long term outcomes32. 
 
 
3.2 Purpose of Study/Potential Impact 
 
Adequate and effective pain control leads to lower risk of complications, greater patient 
satisfaction, and earlier mobility, rehab as well as recovery from surgery 17,18,25,31. 
Traditionally pain control has focused on opioid pain medications utilized on an as pain 
occurs basis post-operatively3. However, recent advances in pain control research have 
brought up a shift in paradigm to targeting pain earlier 1,16,36. Pain leads to a cascade of 
neuronal activation as well as some changes that may be long term in the central nervous 
system36. Therefore blocking the pain pathway earlier prior to prevent is thought to prevent 
central sensitization to pain and prevent these long term changes in the central nervous 
system. Furthermore, this paradigm of targeting pain before it occurs is thought to lead to 
more effective pain control as well as reduce the opioid dependency on post-operative pain 
control1,16. 
Utilizing multiple agents to control pain is conjectured to work in a synergistic manner, 
described as multimodal analgesia(MMA)37. This allows not only a strategy to target pain 
more effectively through numerous distinct pathways but also allows the use of lower doses 
of each individual analgesic therefore mitigating adverse effects of each medication12,15,28. 
A growing body of evidence supports the utility of MMA in spine surgery30. 
Therefore significant interest exists in optimizing MMA protocols especially prior to the 
onset of pain for treating patients undergoing spine procedures12,15,16,37. 
 
 
3.3.1 Potential Risks 
 
Potential risks include any described adverse effects of the analgesic medications as well as 
undescribed effects of these medications on surgery or outcomes. However, since these 
medications are routinely used and common practice their effectiveness and safety have 
been thoroughly described previously in the literature. Furthermore, patients with health 
conditions that would put them at higher risk are excluded from the study. In addition, the 
medications to be used have been previously described to be safe in similar studies. For 
example, NSAIDs have been traditionally avoided due to risks on platelet function and 
operative blood loss. However, the use of celecoxib which has minimal effect on COX1 
associated with platelet function. Celecoxib has also been described in a number of studies 
for pain control in spine surgery without any evidence of increased blood loss. 


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3.3.2 Potential Benefits 
 
Some of the strengths of this study include its novel nature to assess pre-op MMA in all 
areas of spine, prospective nature, relatively large sample size, and the analysis of multiple 
patient and treatment parameters in the context of pain control. 
Adequate and effective pain control leads to lower risk of complications, greater patient 
satisfaction, and earlier mobility, rehab as well as recovery from surgery17,18,25,31. 
The long term implications are promising in terms of patient care and future post-op pain 
control after spine surgery. This study will significantly add to better controlling pain in the 
post-op period, improving outcomes, and facilitating recovery after elective spine surgery. 


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4 - Study Objectives 
4.1 Hypothesis 
 
Multimodal pain regimen (consisting of acetaminophen, celecoxib, gabapentin, and 
oxycodone) administered pre-operatively before elective spine surgery significantly 
decreases acute pain post-operatively as well as decreasing requirements of post-op 
opioids for pain control in PACU as compared to patients undergoing elective spine surgery 
without a pre-operative pain regimen. 
 
 
4.2 Primary Objective 
 
Aim 1: Determine pain control post-operatively after elective spine surgery 
 
 
 
 
 
 
4.3 Secondary Objectives 
 
 
Aim 2: Determine patient variables significantly associated with post-operative pain control 
 
 
Aim 3: Determine operative variables significantly associated with post-operative pain 
control 
 
 
Aim 4: Determine long term outcomes and complication rates after pre-emptive MMA 
regimen implementation 


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5 - Study Design 
5.1 General Design Description 
 
A prospective cohort study with patients undergoing elective spine surgery at NYU winthrop 
will be recruited for participation based on described inclusion and exclusion criteria. A 
prospective study allows the implementation of the new pain control protocol while 
assessing outcomes. 
The study subjects will be assigned to the defined pre-op MMA regimen with standard post- 
op oxycodone based pain control regimen given on an as needed basis. The treatment 
group outcomes will be compared to patients outside of the study including a historical 
control group (receiving only post-op pain regimen) prior to the implementation of the new 
regimen. 
The studied treatment group will receive within 3 hours before surgery an oral MMA 
regimen consisting of: 
 
Acetaminophen 975 mg 
Celecoxib 200 mg 
Gabapentin 300 mg 
Oxycodone 10 mg Extended Release 
 
Pain control post-op will be assessed by RN noted VAS pain scale scores in PACU. 
Furthermore, opioid sparing and rescue time as determined by the time interval from 
patient extubation to time when pain medication is first demanded in PACU1. In addition, 
variables and secondary outcomes noted in Aims 1-4 will be measured. 
The potential to selection and recall bias will be significantly reduced by standardizing all 
patients to the new protocol. Additionally, patients recruited from multiple spine surgeons 
in a private practice model at a community hospital will recruit a wide range of patients 
with variety of pathologies and demographics. A measurement bias may be indicated 
depending on the RN verbally assessing pain, however utilizing a validated outcome 
measure such as the VAS pain scale would minimize this. 
 
 
5.1.1 Study Date Range and Duration 
 
The study will be conducted and continue from 2020 to 2022. 
 
 
5.1.2 Number of Study Sites 
 
The study will be conducted out of NYU Winthrop hospital as well as in the outpatient office 
settings. 


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5.2 Outcome Variables 
 
5.2.1 Primary Outcome Variables 
 
Data will be collected using review of EPIC care electronic medical record (EMR) with 
notation of VAS score in RN documentation in PACU as well as EMR record of time of opioid 
administration if requested. The pre-op history and physical will be utilized for extracting 
demographic and clinical data. Finally, long term data will be requested from outpatient 
office patient records at defined time intervals. Pain medication usage will be reviewed with 
prescriptions given / noted in state (ISTOP) registries. Complication rates will be assessed 
using outpatient records as well as readmission/ER documentation in EMR. 
Measurement reliability is dependent on accuracy of data reported in EMR and by patients 
in follow up visits. The use of standardized data collection procedures will limit any 
measurement bias that may be observed. Discretionary data outside the standardized 
collection criteria will not be collected. Potential confounders and effect modifiers are 
outlined in the study aims as the patient and treatment characteristics. Their influence will 
be statistically evaluated using stratified univariate and multivariate analyses. 
 
 
5.2.2 Secondary and Exploratory Outcome Variables 
 
5.3 Study Population 
 
All genders and races will be included in the study. Children will be excluded based on 
differences in physiology and small sample size that would influence the outcome measures 
and therefore would skew the comparison of interest in the study. 
 
 
5.3.1 Number of Participants 
 
All patients undergoing elective spine surgery at NYU Winthrop hospital will be screened 
and assessed for potential inclusion into the study. Patients meeting the inclusion criteria 
and avoiding the exclusion criteria will be recruited into the study. Based on the power 
analysis atleast 31 patients would be needed for the primary outcome. However, in the 
recruitment period, the goal would be to include as many participants as possible (100-200) 
in order for the secondary and ancillary outcomes to be achieved for statistical subgroup 
analyses. 
 
 
5.3.2 Eligibility Criteria/Vulnerable Populations 
Eligibility Criteria will be assessed by the PI as well as the lead author on the study. 
Inclusion Criteria: 


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Undergoing elective spine surgery at NYU Winthrop 
Age over 18 years 
 
Exclusion Criteria: 
 
History of neuromuscular disorders 
History of inflammatory arthropathies 
History of spine metastases or active cancer in spine 
Medical History including any of the following: renal dysfunction, gastric ulcers, hepatic 
dysfunction, coagulopathic/bleeding disorders, prior adverse or allergic reactions to any 
of the medications in the study 
Age less than 18 years 


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6 - Methods 
6.1 Treatment - Drug 
 
6.1.1 Identity of Investigational Product/New Drug 
 
All drugs utilized are well established and FDA approved. They are also currently in 
common use. 
 
Acetaminophen (Tylenol) 
Celecoxib (Celebrex) 
Gabapentin (Neurontin) 
Oxycodone 10 mg Extended Release (Oxycontin) 
 
 
6.1.2 Dosage, Admin, Schedule 
 
The studied treatment group will receive within 3 hours before surgery an oral MMA 
regimen consisting of: 
 
Acetaminophen 975 mg 
Celecoxib 200 mg 
Gabapentin 300 mg 
Oxycodone 10 mg Extended Release 
 
 
6.1.3 Method of Assignment/Randomization 
 
6.1.4 Blinding and Procedures for Unblinding 
 
6.1.5 Packaging/Labelling 
 
Included in hospital inpatient pharmacy. Administration through nursing similar to all drugs 
in the inpatient setting. No special packaging or labelling will be utilized. 
 
 
6.1.6 Storage Conditions 
 
Stored by hospital pharmacy under appropriate conditions. 


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6.1.7 Concomitant therapy 
 
No restrictions to concomitant therapy outside of allowances of maximum medication doses 
and adverse effects. Concomitant use will be monitored. 
 
 
6.1.8 Restrictions 
 
No restrictions of note. 
 
 
6.2 Assessments 
 
Pain control post-op will be assessed by RN noted VAS pain scale scores in PACU. 
Furthermore, opioid sparing and rescue time as determined by the time interval from 
patient extubation to time when pain medication is first demanded in PACU1. In addition, 
variables and secondary outcomes noted in Aims 1-4 will be measured. 
Data will be collected using review of EPIC care electronic medical record (EMR) with 
notation of VAS score in RN documentation in PACU as well as EMR record of time of opioid 
administration if requested. The pre-op history and physical will be utilized for extracting 
demographic and clinical data. Finally, long term data will be requested from outpatient 
office patient records at defined time intervals. Pain medication usage will be reviewed with 
prescriptions given / noted in state (ISTOP) registries. Complication rates will be assessed 
using outpatient records as well as readmission/ER documentation in EMR. 
 
 
 
6.2.1 Efficacy 
 
Measurement reliability is dependent on accuracy of data reported in EMR and by patients 
in follow up visits. The use of standardized data collection procedures will limit any 
measurement bias that may be observed. Discretionary data outside the standardized 
collection criteria will not be collected. Potential confounders and effect modifiers are 
outlined in the study aims as the patient and treatment characteristics. Their influence will 
be statistically evaluated using stratified univariate and multivariate analyses. 
The study outcomes of VAS pain score and opioid sparing/rescue time will be calculated as 
a mean using PACU VAS pain scores noted in EMR and time from extubation to when opioid 
demanded in PACU for pain. Comparison to detect a statistical difference of these outcomes 
compared to historical control group will be done using student's t test. Furthermore, 
patient and treatment characteristics will be evaluated using univariate and multivariate 
analyses with cox proportional hazards regression modeling. Atypical associations or unmet 
assumptions will be handled by data transformation to meet assumptions or by the use of 
alternative modeling methods. The source of biostatistical expertise will come from the 
department biostatistician. 


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6.2.2 Safety/Pregnancy-related policy 
 
Pregnant patients are excluded from study. 
 
The risks of the MMA include drug hypersensitivity reactions or adverse effects of the 
medications. In order to minimize these risks a thorough pre-operative history would be 
conducted and reviewed to screen for any known allergies as well as any health conditions 
(ie liver or kidney disease) which would lead to higher risk of adverse effects of the MMA 
medications. Furthermore, since a single dose is use of the medication it limits medication 
exposure and risk of adverse effects. 
 
 
6.2.2.1 Adverse Events Definition and Reporting 
 
Adverse events will be defined as any events not considered within the realm of routine 
post-operative course. Adverse events will be monitored in the post-operative period while 
in the hospital as well as once seen outpatient in the office. Chart review from all providers 
will be screened for adverse events until last follow-up to date. 
 
 
6.2.3 Pharmacokinetics 
 
6.2.4 Biomarkers 
 
6.3 Study Procedures 
 
Administration of pain medication, including those given in this study are considered 
standard of care. However, the novel use of them in the pre-operative period rather than 
the post-operative period is the question of interest. Furthermore, the use of them in this 
particular regimen is evaluated for efficacy. The outcomes will be assessed from chart 
review in the immediate post-operative period including the PACU and hospital admission 
course. Furthermore, secondary outcomes will be assessed as chart review from office as 
part of outpatient follow-up. 
 
 
6.3.1 Study Schedule 
 
Patient visits in the office will be based on standards of care and routine follow-up practices 
without affect from this study. 


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6.3.2 Informed Consent 
 
Informed consent process will be followed per NYU policy. 
 
Informed consent will be received from all patients included in the study. The information 
obtained will be of vital importance to the progression of the field and future treatment of 
patients. Informed consent will be obtained by either the PI or the sub investigators listed 
on the study. Informed consent process will be conducted with a thorough discussion of 
risks and benefits of the study to the patients followed by permission for participation or 
declination. The consent will be obtained either in print or electronically (utilizing ipad 
resource common used for surgical consents). Consent will be obtained either at pre-op 
visit in the office or at check in to the hospital. Privacy will be protected by keeping all 
information in a safe and secure platform. Consent will be documented and recorded 
alongside the remaining patient variables in order to ensure consent is achieved for all 
participants. 
 
 
6.3.3 Screening 
 
Patient screening will be conducted by primary researcher at pre-operative visits or on the 
day of surgery. 
 
 
6.3.4 Recruitment, Enrollment and Retention 
 
6.3.5 On Study Visits 
 
No specific visits related to study 
 
 
6.3.6 End of Study and Follow-up 
 
Patient follow-up will be reviewed from outpatient records. 
 
 
6.3.7 Removal of subjects 
 
Since patients will receive routine care after the single administration of MMA pre- 
operatively. The outcomes are assessed purely from chart review and patient reported 
basis. 
 
 
6.4 Statistical Method 


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6.4.1 Statistical Design 
 
Measurement reliability is dependent on accuracy of data reported in EMR and by patients 
in follow up visits. The use of standardized data collection procedures will limit any 
measurement bias that may be observed. Discretionary data outside the standardized 
collection criteria will not be collected. Potential confounders and effect modifiers are 
outlined in the study aims as the patient and treatment characteristics. Their influence will 
be statistically evaluated using stratified univariate and multivariate analyses. 
The study outcomes of VAS pain score and opioid sparing/rescue time will be calculated as 
a mean using PACU VAS pain scores noted in EMR and time from extubation to when opioid 
demanded in PACU for pain. Comparison to detect a statistical difference of these outcomes 
compared to historical control group will be done using student's t test. Furthermore, 
patient and treatment characteristics will be evaluated using univariate and multivariate 
analyses with cox proportional hazards regression modeling. Atypical associations or unmet 
assumptions will be handled by data transformation to meet assumptions or by the use of 
alternative modeling methods. The source of biostatistical expertise will come from the 
department biostatistician. 
 
 
6.4.2 Sample Size Considerations 
 
At a significance level of 5%, in order to achieve 80% power for detecting a 1 point mean 
difference in VAS pain scores[1], we would need a sample of 31 patients to assess the 
primary outcome. Adjusting by approximately 5% to account for patients that are found 
ineligible retrospectively, the total sample size required is 33 patients. Furthermore, 
additional analyses to fulfill Aims 1-4 would require a larger sample size and would 
constitute separate studies based on final sample size achieved. 
 
[1] Using the reported control group VAS scores by Garcia et al.8 of 8.4 and standard 
deviation of 2 
 
 
6.4.3 Planned Analyses 
 
6.4.3.1 Primary Analyses 
 
6.4.3.2 Secondary Objectives Analyses 
 
6.4.3.3 Safety/Pregnancy-related policy 


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6.4.3.4 Analysis of Subject Characteristics 
 
6.4.3.5 Interim Analysis 
 
6.4.3.6 Health economic evaluation 
 
6.4.3.7 Other 
 
6.4.4 Subsets and Covariates 
 
see aims and statistical design. 
 
 
6.4.5 Handling of Missing Data 
 
Given the acute and short term nature of study's primary outcome. Missing data is 
expected to be minimal. However, if data is missing then statistically valid analyses under 
the primary missing-data assumptions would be conducted to account for it. 


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7 - Trial Administration 
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA 
Authorization 
 
In addition to IRB approval and guidelines, all patient data will be kept protected under 
HIPAA guidelines. Informed consent will be obtained from all patients. Patients will be 
treated in a professional manner consistent with standard of care. All data will be handled 
in a secure and professional manner. No financial or other incentives will be provided to 
participants. 
 
 
7.2 Institutional Review Board (IRB) Review 
 
7.3 Subject Confidentiality 
 
7.4 Deviations/Unanticipated Problems 
 
7.5 Data Collection 
 
Data will be collected using review of EPIC care electronic medical record (EMR) with 
notation of VAS score in RN documentation in PACU as well as EMR record of time of opioid 
administration if requested. The pre-op history and physical will be utilized for extracting 
demographic and clinical data. Finally, long term data will be requested from outpatient 
office patient records at defined time intervals. Pain medication usage will be reviewed with 
prescriptions given / noted in state (ISTOP) registries. Complication rates will be assessed 
using outpatient records as well as readmission/ER documentation in EMR. 
 
 
 
7.6 Data Quality Assurance 
 
Measurement reliability is dependent on accuracy of data reported in EMR and by patients 
in follow up visits. The use of standardized data collection procedures will limit any 
measurement bias that may be observed. Discretionary data outside the standardized 
collection criteria will not be collected. Potential confounders and effect modifiers are 
outlined in the study aims as the patient and treatment characteristics. Their influence will 
be statistically evaluated using stratified univariate and multivariate analyses. 
 
 
7.7 Study Records 


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7.8 Access to Source 
 
7.9 Data or Specimen Storage/Security 
 
Data will be stored in a password-protected Microsoft Excel file stored on NYU network 
drive. 
 
 
7.10 Retention of Records 
 
Records will be retained until 1 year from the conclusion of the study. 
 
 
7.11 Study Monitoring 
 
7.12 Data Safety Monitoring Plan 
 
Primary oversight of the study will be done by the PI to ensure proper evaluation, following, 
and reporting of AEs from study participants. Secondary monitoring will be done by each 
sub investigator on the review. Furthermore, systematic periodic review of data and AEs 
will be done on a monthly basis. The accumulated data will include patient pain variables 
collected in the hospital, patient clinical information in EMR, and patient follow-up data. 
Adverse events will be noted and recorded at follow-up visits and include any described 
(see drug package inserts) or undescribed events noted by patients considered by the 
clinician to be outside the realm of normal postoperative care and or recovery. These 
events will be reported to the IRB as soon as possible or at the monthly review. The study 
will be stopped if any unexpected or adverse events not previously reported for the MMA 
are noted. A summary of AEs, deviations, and report of the outcomes of these data safety 
monitoring reviews will be submitted to the IRB annually with the Continuation Submission 
 
 
7.13 Study Modification 
 
7.14 Study Discontinuation 
 
7.15 Study Completion 
 
7.16 Conflict of Interest Policy 
 
7.17 Funding Source 


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N/A 
 
 
7.18 Publication Plan 
 
The PI and lead investigator will hold responsibility for publication of data. Authorship will 
be given based on significant contributions in the project and writing process. 


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Appendices 
 
Appendix # 
Title 
Section 
Topic 
1 
Acetaminophen 
Package Insert 
6 Methods 
6.1.5 Packaging/L 
abelling 
2 
Gabapentin 
Package Insert 
6 Methods 
6.1.5 Packaging/L 
abelling 
3 
Oxycodone 
Package Insert 
6 Methods 
6.1.5 Packaging/L 
abelling 
4 
Celecoxib 
Package Insert 
6 Methods 
6.1.5 Packaging/L 
abelling 
5 
REFERENCES 
7 Trial 
Administration 
7.18 Publication 
Plan 


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References