Clinical trial NCT04990804
Conditions: Opioid Use Spinal Diseases Surgery--Complications Surgery Postoperative Pain
Sponsor: Vanderbilt University Medical Center
Start date: 2021-08-01; Completion date: 2022-02-01
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients undergoing 1-3 level Anterior Cervical Discectomy and Fusion (ACDF) at the levels between C2 and T1 will be enrolled into this randomized prospective study. All patients enrolled in this study will undergo a trial of non-surgical treatment prior to the recommendation for surgery. After enrollment, patients will be randomized utilizing a block randomization strategy to one of two treatment groups - a standard opioid-containing postoperative pain regimen versus a non-opioid postoperative pain regimen. Postoperative outcomes will be assessed.

Detailed description:
Patients will be followed for 12 months and the following Specific Aims will be assessed:

Aim 1: Evaluate whether utilization of a non-opioid postoperative pain regimen after ACDF leads to lower rates of new chronic opioid use when compared with postoperative pain regimens utilizing opioids.

Aim 2: Evaluate whether utilization of a non-opioid postoperative pain regimen after ACDF results in equivalent postoperative pain scores in the early postoperative period.

Aim 3: Evaluate whether utilization of a non-opioid postoperative pain regimen after ACDF leads to equivalent clinical outcomes when compared with postoperative pain regimens utilizing opioids at 3 months and 12 months.

Aim 4: Evaluate whether utilization of a non-opioid postoperative pain regimen after ACDF leads to fewer postoperative complications when compared with postoperative pain regimens utilizing opioids.

Arms: arm 1: Patients will be provided a prescription for low dose opioids for 5 days postoperatively (Hydrocodone/Acetaminophen 5/325mg or Oxycodone/Acetaminophen 5/325mg) to be taken every 6 hours as needed for pain. Refills may be provided (Hydrocodone/Acetaminophen 5/325mg or Oxycodone/Acetaminophen 5/325mg) if requested by the patient at the providers discretion. In addition, patients will also be prescribed Gabapentin 300mg q8 hours or Pregabalin 75mg twice daily and a muscle relaxer (Methocarbamol 750mg BID or Flexeril 5-10 mg TID) as needed for spasms. Alternative muscle relaxers (Metaxalone 800 mg TID or Tizanidine 2-6 mg TID) may be utilized if contraindications to methocarbamol and cyclobenzaprine exist. arm 2: Patients will receive no opioids. Pain will be managed with Acetaminophen 1000mg q8 hours, Ketorolac 10mg every 6 hours (for 5 days), Gabapentin 300mg q8 hours or Pregabalin 75mg twice daily, and a muscle relaxer (Methocarbamol 750mg BID or Cyclobenzaprine 5-10 mg TID) all to be taken as scheduled for the first 2 weeks (except Ketorolac - 5 days) postoperatively as side effects permit. Other NSAIDS (Naprosyn 500 mg BID or Ibuprofen 800 mg TID) may be utilized if contraindications to Ketorolac exist. Famotidine (20mg BID) or Omeprazole (20mg daily) will be prescribed along with NSAIDS for GI prophylaxis. Alternative muscle relaxers (Metaxalone 800 mg TID or Tizanidine 2-6 mg TID) may be utilized if contraindications to methocarbamol and cyclobenzaprine exist.
Interventions: intervention 1: Opioid Analgesic intervention 2: Opioid-Free Postoperative Pain Regimen
Intervention descriptions: intervention 1: Patients will be provided a prescription for low dose opioids for 5 days postoperatively (Hydrocodone/Acetaminophen 5/325mg or Oxycodone/Acetaminophen 5/325mg) to be taken every 6 hours as needed for pain. Refills may be provided (Hydrocodone/Acetaminophen 5/325mg or Oxycodone/Acetaminophen 5/325mg) if requested by the patient at the providers discretion. In addition, patients will also be prescribed Gabapentin 300mg q8 hours or Pregabalin 75mg twice daily and a muscle relaxer (Methocarbamol 750mg BID or Flexeril 5-10 mg TID) as needed for spasms. Alternative muscle relaxers (Metaxalone 800 mg TID or Tizanidine 2-6 mg TID) may be utilized if contraindications to methocarbamol and cyclobenzaprine exist. intervention 2: Patients will receive no opioids. Pain will be managed with Acetaminophen 1000mg q8 hours, Ketorolac 10mg every 6 hours (for 5 days), Gabapentin 300mg q8 hours or Pregabalin 75mg twice daily, and a muscle relaxer (Methocarbamol 750mg BID or Cyclobenzaprine 5-10 mg TID) all to be taken as scheduled for the first 2 weeks (except Ketorolac - 5 days) postoperatively as side effects permit. Other NSAIDS (Naprosyn 500 mg BID or Ibuprofen 800 mg TID) may be utilized if contraindications to Ketorolac exist. Famotidine (20mg BID) or Omeprazole (20mg daily) will be prescribed along with NSAIDS for GI prophylaxis. Alternative muscle relaxers (Metaxalone 800 mg TID or Tizanidine 2-6 mg TID) may be utilized if contraindications to methocarbamol and cyclobenzaprine exist.

Protocol documents:
Prot_SAP_000.pdf: 
Principal Investigator: Amir M. Abtahi, MD 
Study Title: Opioid Free vs. Standard Perioperative Pain Regimen for Anterior Cervical Discectomy 
and Fusion (ACDF) Surgery 
Institution/Hospital: Vanderbilt University Medical Center 
 
Protocol Version #: 5 
 
1 
Protocol Date: 2/22/2023 
 
 
 
 
 
 
 
 
Opioid Free vs. Standard Perioperative Pain Regimen for 
Anterior Cervical Discectomy and Fusion (ACDF) Surgery 
 
 
Amir M. Abtahi, MD  
Vanderbilt University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Principal Investigator: Amir M. Abtahi, MD 
Study Title: Opioid Free vs. Standard Perioperative Pain Regimen for Anterior Cervical Discectomy 
and Fusion (ACDF) Surgery 
Institution/Hospital: Vanderbilt University Medical Center 
 
Protocol Version #: 5 
 
2 
Protocol Date: 2/22/2023 
 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 


Principal Investigator: Amir M. Abtahi, MD 
Study Title: Opioid Free vs. Standard Perioperative Pain Regimen for Anterior Cervical Discectomy 
and Fusion (ACDF) Surgery 
Institution/Hospital: Vanderbilt University Medical Center 
 
Protocol Version #: 5 
 
3 
Protocol Date: 2/22/2023 
1.0 
Background 
 
Historically, opioids have been the mainstay of pain management after spine surgery. 
Inadequately controlled postoperative pain is a common patient complains and is also a 
common reason for readmission after spine surgery (7,8). The Joint Commission 
guidelines, Hospital Consumer Assessment of Healthcare Providers and Systems 
(HCAHPS) surveys, and outcome-based and bundled payment models have placed a 
strong emphasis on adequate postoperative pain control and decreased readmission 
rates. 
 
While opioids are an effective means of short-term pain control, their use is associated 
with a number of detrimental effects including respiratory depression, altered cognition, 
urinary retention, gastrointestinal dysfunction, and chronic opioid use. Over the past two 
decades, overdoses and deaths from opioids have reached epidemic proportions in the 
United States and prescription opioids are a major cause of opioid addiction and opioid-
related overdose deaths. From 1999–2018, almost 450,000 people died from an 
overdose involving opioids in the United States (1).  
 
With increased focus on the opioid epidemic, there has been a movement away from 
traditional pain control protocols towards multimodal analgesic regimens developed to 
reduce opioid consumption and associated adverse effects. Common medications utilized 
as part of these regimens include Nonsteroidal Anti-inflammatory Medications (NSAIDS), 
steroids, neuromodulatory agents, acetaminophen, and local anesthetics. NSAIDS are an 
area of intense debate among spine surgeons. While the evidence supports their use on 
low doses, many spine surgeons have been reluctant to adopt NSAIDs for perioperative 
pain management in patients undergoing spinal fusion because of concern for 
pseudarthrosis and postoperative bleeding (9-14). In addition to decreased opioid 
related postoperative complications, the potential beneﬁts of non-opioid pain regimens 
also potentially include lower rates of chronic opioid use. Chronic opioid use has been 
shown to be associated with worse patient reported outcomes after spine surgery (15). 
The proposed study aims to directly compare opioid and non-opioid postoperative pain 
regimens in patients undergoing ACDF in a randomized clinical study. Successful 
utilization of an opioid-free postoperative pain regimen in patients undergoing ACDF 
may spur the utilization of such regimens for other types of spine surgery including 
posterior cervical and lumbar spine surgeries. 
 
2.0 
Rationale and Specific Aims 
 
Over the past two decades, overdoses and deaths from opioids have reached epidemic 
proportions in the United States. From 1999–2018, almost 450,000 people died from an 
overdose involving opioids (1). Prescription opioids are a major cause of opioid addiction 
and opioid-related overdose deaths in the United States. In 2016, more than 11.5 million 
Americans reported misusing prescription opioids in the past year (2).   
 
Despite the well-documented clinical benefits of spine surgery, recent evidence suggests 
a high incidence of new chronic opioid use following spine surgery. The incidence of 


Principal Investigator: Amir M. Abtahi, MD 
Study Title: Opioid Free vs. Standard Perioperative Pain Regimen for Anterior Cervical Discectomy 
and Fusion (ACDF) Surgery 
Institution/Hospital: Vanderbilt University Medical Center 
 
Protocol Version #: 5 
 
4 
Protocol Date: 2/22/2023 
chronic opioid use after anterior cervical discectomy and fusion (ACDF) is reported 
between 11% to 39% in patients with no-preoperative opioid-use (3-5). With increasing 
awareness of the opioid epidemic, there will be greater emphasis on developing 
strategies to ensure that spine surgery patients remain opioid-free in the long-term after 
elective spine surgery. In the present study, we aim to evaluate the use of an opioid-
free postoperative pain regimen after ACDF and its effect on new chronic opioid use, 
postoperative pain control, opioid-related postoperative complications, and postoperative 
clinical outcomes. 
 
Aim 1: Evaluate whether utilization of a non-opioid postoperative pain regimen after 
ACDF results in equivalent postoperative pain scores in the early postoperative period.  
 
We hypothesize that utilization of a non-opioid postoperative pain regimen after 
ACDF leads to equivalent postoperative pain scores in the early postoperative 
period when compared with postoperative pain regimens utilizing opioids 
 
Aim 2: Evaluate whether utilization of a non-opioid postoperative pain regimen after 
ACDF leads to equivalent clinical outcomes when compared with postoperative pain 
regimens utilizing opioids at 3 months. 
 
We hypothesize that utilization of a non-opioid postoperative pain regimen after 
ACDF leads to equivalent clinical outcomes when compared with postoperative 
pain regimens utilizing opioids 
 
Aim 3: Evaluate whether utilization of a non-opioid postoperative pain regimen after 
ACDF leads to fewer postoperative complications when compared with postoperative 
pain regimens utilizing opioids. 
 
We hypothesize that utilization of a non-opioid postoperative pain regimen after 
ACDF leads to fewer postoperative complications when compared with 
postoperative pain regimens utilizing opioids 
 
Aim 4: Evaluate whether utilization of a non-opioid postoperative pain regimen after 
ACDF leads to lower rates of new chronic opioid use when compared with postoperative 
pain regimens utilizing opioids. 
 
We hypothesize that utilization of a non-opioid postoperative pain regimen after 
ACDF leads to lower rates of new chronic opioid use when compared with 
postoperative pain regimens utilizing opioid 
 
3.0 
Animal Studies and Previous Human Studies 
 
As mentioned previously, while the evidence supports their use on low doses, many 
spine surgeons have been reluctant to adopt NSAIDs for perioperative pain management 
in patients undergoing spinal fusion because of concern for pseudarthrosis and 
postoperative bleeding (9-14). Despite the well-documented clinical benefits of spine 


Principal Investigator: Amir M. Abtahi, MD 
Study Title: Opioid Free vs. Standard Perioperative Pain Regimen for Anterior Cervical Discectomy 
and Fusion (ACDF) Surgery 
Institution/Hospital: Vanderbilt University Medical Center 
 
Protocol Version #: 5 
 
5 
Protocol Date: 2/22/2023 
surgery, recent evidence suggests a high incidence of new chronic opioid use following 
spine surgery. The incidence of chronic opioid use after anterior cervical discectomy and 
fusion (ACDF) is reported between 11% to 39% in patients with no-preoperative opioid-
use (3-5). Chronic opioid use has been shown to be associated with worse patient 
reported outcomes after spine surgery (15). Successful utilization of an opioid-free 
postoperative pain regimen in patients undergoing ACDF may spur the utilization of such 
regimens for other types of spine surgery including posterior cervical and lumbar spine 
surgeries. 
 
4.0 
Inclusion/Exclusion Criteria 
 
Inclusion Criteria:  
• 
Radiographic evidence of degenerative cervical spine disease  
• 
Failure of conservative therapy  
• 
Age ≥18 years 
• 
Skeletal maturity 
 
Exclusion Criteria: 
• 
Preoperative chronic opioid use as determined by self-report 
• 
History of chronic kidney disease 
• 
Undergoing revision cervical spine surgery or concurrent posterior cervical fusion 
• 
Spinal infection 
• 
Tumor 
• 
Traumatic fracture or dislocation 
• 
Age less than 18 years 
• 
Non-English-speaking patients 
• 
Incarceration 
• 
Intolerance to NSAIDs 
• 
Any preexisting health condition the study physician believes will be exacerbated 
by participating in this study 
 
5.0 
Enrollment/Randomization 
 
This investigation will be conducted as a multi-site trial, with patients being enrolled at 
both Vanderbilt University Medical Center and University of Pittsburgh Medical Center. 
Research personnel at each institution will screen their respective patients for eligibility 
based on the surgery schedule posted in their respective EMRs. Study personnel will 
then approach patients during a preoperative clinic visit. No flyers or brochures will be 
utilized. A phone script will be used by the study staff to recruit participants over the 
phone if we are unable to recruit in person. A VUMC department letter will be sent to 
participants that study personnel are unable to see in clinic prior to study personnel 
reaching out over the phone.  
 
The patient's doctor will approve each patient for the research study prior to the 
research personnel approaching or contacting the patient. 
 


Principal Investigator: Amir M. Abtahi, MD 
Study Title: Opioid Free vs. Standard Perioperative Pain Regimen for Anterior Cervical Discectomy 
and Fusion (ACDF) Surgery 
Institution/Hospital: Vanderbilt University Medical Center 
 
Protocol Version #: 5 
 
6 
Protocol Date: 2/22/2023 
Once the patient has been consented and completed the baseline assessment, the 
patient will be randomized electronically. The randomization scheme will frequency-
match patients in a 1:1 ratio in blocks of assignments stratified by age and number of 
levels (i.e., 1 or 2 vs. 3 levels). Block sizes will be 2 and 4 with the patient as the unit of 
randomization. 
 
6.0 
Study Procedures 
 
All patients will undergo standard preoperative evaluation prior to surgery and will be 
seen by an anesthesiologist on the morning of surgery. 
 
 
Postoperative Phase (Hospital and/or Discharge – 2 weeks) 
 
Non-Opioid Group: 
These patients will receive no opioids. Pain will be managed with Acetaminophen 
1000mg q8 hours, Ketorolac 10mg every 6 hours (for 5 days), Gabapentin 300mg q8 
hours or Pregabalin 75mg twice daily, and a muscle relaxer (Methocarbamol 750mg BID 
or Cyclobenzaprine 5-10 mg TID) all to be taken as scheduled for the first 2 weeks 
(except Ketorolac – 5 days) postoperatively as side effects permit. Other NSAIDS 
(Naprosyn 500 mg BID or Ibuprofen 800 mg TID) may be utilized if contraindications to 
Ketorolac exist. Famotidine (20mg BID)  or Omeprazole (20mg daily) will be prescribed 
along with NSAIDS for GI prophylaxis. Alternative muscle relaxers (Metaxalone 800 mg 
TID or Tizanidine 2-6 mg TID) may be utilized if contraindications to methocarbamol 
and cyclobenzaprine exist. 
 
Opioid Group: 
These patients will be provided a prescription for low dose opioids for 5 days 
postoperatively (Hydrocodone/Acetaminophen 5/325mg or Oxycodone/Acetaminophen 
5/325mg) to be taken every 6 hours as needed for pain. Refills may be provided 
(Hydrocodone/Acetaminophen 5/325mg or Oxycodone/Acetaminophen 5/325mg) if 
requested by the patient at the providers discretion. In addition, patients will also be 
prescribed Gabapentin 300mg q8 hours or Pregabalin 75mg twice daily and a muscle 
relaxer (Methocarbamol 750mg BID or Flexeril 5-10 mg TID) as needed for spasms. 
Alternative muscle relaxers (Metaxalone 800 mg TID or Tizanidine 2-6 mg TID) may be 
utilized if contraindications to methocarbamol and cyclobenzaprine exist. 
 
Both groups will receive postoperative patient questionnaires on postop day 1, postop 
day 7, and postop day 14 to assess their level of pain and medication use. 
 
Postoperative Phase (2 weeks – 6 weeks) 
 
Non-Opioid Group: 
These patients will receive no opioids. Patients will be given instructions to discontinue 
use of ketorolac at 5 days postoperatively.  
 


Principal Investigator: Amir M. Abtahi, MD 
Study Title: Opioid Free vs. Standard Perioperative Pain Regimen for Anterior Cervical Discectomy 
and Fusion (ACDF) Surgery 
Institution/Hospital: Vanderbilt University Medical Center 
 
Protocol Version #: 5 
 
7 
Protocol Date: 2/22/2023 
Acetaminophen, Gabapentin 300mg q8 hours or Pregabalin 75mg twice daily, and 
muscle relaxers (Methocarbamol 750mg BID or Cyclobenzaprine 5-10 mg TID) may be 
continued as needed between 2 and 6 weeks with instructions to discontinue use by 6 
weeks postoperatively. 
 
If pain control remains poor at 6 weeks postoperatively, patients will be referred to pain 
management at our institution. 
 
Opioid Group: 
Opioid prescriptions between 2 and 6 weeks postoperatively will not be provided unless 
requested by the patient and will be at the providers discretion. Patients will not be 
provided with any prescriptions for opioids by the treating surgeon beyond 6 weeks 
postoperatively.  
 
Acetaminophen, Gabapentin 300mg q8 hours or Pregabalin 75mg twice daily, and 
muscle relaxers (Methocarbamol 750mg BID or Cyclobenzaprine 5-10 mg TID) may be 
continued as needed between 2 and 6 weeks with instructions to discontinue use by 6 
weeks postoperatively. 
 
If pain control remains poor at 6 weeks postoperatively, patients will be referred to pain 
management at our institution. 
 
7.0 
Risks 
 
The risk to human subjects of participation in this study is minimal due to the nature of 
the interventions being compared. Both standard opioid-containing postoperative pain 
regimens and non-opioid postoperative pain regimens are acceptable standards of care, 
and both are currently utilized at our institution. The risks of opioid pain medication use 
include sedation, nausea / vomiting, constipation, respiratory depression, physical 
dependence, and overdose. The short-duration, low dose regimens proposed for use in 
this study pose minimal risk for serious adverse events. The risks of non-opioid 
postoperative pain regimens depend on the medications used. The medications 
proposed for use in the study include propofol, ketamine, lidocaine, dexmedetomidine, 
ketorolac, acetaminophen, gabapentin, pregabalin, methocarbamol, and cyclobenzaprine 
as well as other medications that may be utilized for pain control in the perioperative 
period at the discretion of the provider. These medications are all commonly used in the 
care of postoperative spine patients undergoing ACDF and therefore do not represent 
departures from the standard of care. 
 
There is a small risk of breach of confidentiality, but the data for this study will be 
secured in a password-protected database. Access to this database will be limited to the 
PI, study coordinator, and study staff at VUMC and UPMC. Data will be deidentified for 
data analysis and interpretation. 
 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 


Principal Investigator: Amir M. Abtahi, MD 
Study Title: Opioid Free vs. Standard Perioperative Pain Regimen for Anterior Cervical Discectomy 
and Fusion (ACDF) Surgery 
Institution/Hospital: Vanderbilt University Medical Center 
 
Protocol Version #: 5 
 
8 
Protocol Date: 2/22/2023 
 
AE’s, unanticipated problems and protocol deviations will be reviewed by the PI and 
study staff on a weekly basis. The principal Investigator will notify the Institutional 
Review Board (IRB) of a serious adverse event according to institutional policy. 
However, based on the nature of the intervention the investigators don’t expect any 
AE’s.   
 
9.0 
Study Withdrawal/Discontinuation 
 
Participants can withdraw from the study at any time. If any of the participants wish to 
withdraw from the study for any reason, the investigators will not use their data for 
analysis. All information will be destroyed on that participant. 
 
10.0 Statistical Considerations 
 
Data collected at VUMC and UPMC will be compiled into one dataset. Descriptive 
statistics will be used to describe participant characteristics across the two groups and to 
summarize feasibility. The acceptability analyses for outcomes will be intent-to-treat. 
Descriptive statistics will be used to summarize the outcome measures pre and post-
intervention for the two groups. Between and within group comparison will be 
conducted using 2X2 Mixed ANOVA. The effect size will also be determined using a 
partial eta square value. Missing observations due to drop-out and other reasons not 
related to the treatments will be handled with multiple imputation methodology. This 
method will allow us to use data with some missing values and avoid the information 
loss that is inherent in a complete case analysis. All the data will be explored graphically 
and numerically to observe the effects. 
 
11.0 Privacy/Confidentiality Issues 
 
The study’s data will be stored in a VUMC REDCap folder, a password protected 
database, and any paper study forms will be stored in a locked room of the admin 
offices of the Department of Orthopaedics at either VUMC or UPMC. Only the PI, study 
coordinator, and research staff from VUMC and UPMC will have access to this database. 
Participant identifiers will be removed from all study forms and the database before 
analysis. The link between the data and subjects’ identifying information will be found in 
a REDCap form that will be password protected and only accessible by the PI and 
research coordinator. Once the study is complete, the code list will be destroyed, and all 
other identifiable data or information not part of the limited data set will be destroyed at 
the expiration of the project. 
 
 
12.0 Follow-up and Record Retention 
 
Participants will be enrolled in this study for a period of 12 months. Enrollment is 
expected to last 18-24 months. The total duration of the study is expected to last 3 
years.