Post-op Acetaminophen vs NSAID Use on Lumbar Spinal Fusion Outcomes

Given the potential for non-steroidal anti inflammatory drugs (NSAIDs) and acetaminophen to decrease opioid requirements following spine surgery, the investigators propose a prospective, randomized, double-blinded clinical trial comparing the efficacy of intravenous (IV) acetaminophen (Group A) or IV ketorolac (Group K) versus placebo (Group P). The impact of treatment on perioperative opioid use, opioid-related complications, functional outcomes and rates of pseudarthrosis following 1 or 2 level lumbar fusion surgery will be measured in each group. The specific aims of this study are as follows:

* Specific Aim 1: Determine the impact of IV ketorolac or IV acetaminophen use on immediate postoperative opioid requirements, postoperative pain levels and opiate related symptoms using the Opiate-Related Symptom Distress Scale (ORSDS)
* Specific Aim 2: Determine the impact of IV ketorolac or IV acetaminophen use on functional outcomes defined by return to work, Oswestry Disability Index (ODI) and the Veterans Rand-12 (VR-12) Health Survey

The primary outcome is to determine the total postoperative opioid dose (in oral morphine equivalents) in each group. The investigators hypothesize that patients in Group A and Group K will have lower total opioid use, suffer from fewer opiate related symptoms and have similar rates of pseudarthrosis to patients in Group P. The investigators hypothesize that patients in Group A and Group K will have a quicker return to work and improved early functional outcomes although they acknowledge that long term functional outcomes may be the same for all groups.

• Ketorolac (Drug), also known as Toradol: Age 18-64: Intravenous Ketorolac 30 milligrams (mg) every 6 hours for 48 hours in addition to patient-controlled analgesia and oral opioids as needed. Age 65-75: Intravenous Ketorolac 15 milligrams (mg) every 6 hours for 48 hours in addition to patient-controlled analgesia and oral opioids as needed.
• Acetaminophen (Drug), also known as Tylenol, Ofirmev: Intravenous Acetaminophen 1000mg every 6 hours for 48 hours in addition to patient-controlled analgesia and oral opioids as needed.
• Placebo (Drug), also known as Normal Saline: Intravenous Normal Saline every 6 hours for 48 hours in addition to patient-controlled analgesia and oral opioids as needed.

Primary outcomes

• Perioperative Opioid Use [Hospital stay (2-4 days)]: Measure the impact of treatment on total opioid use during the hospital stay

Secondary outcomes

• Opioid Use at 4-6 Weeks [4-6 weeks]: Track opioid use after discharge for the first 4-6 weeks
• Opioid Use at 3 Months [3 months]: Track opioid use after discharge for the first 3 months; assess for continued opioid use
• Opioid Use at 1 Year [1 year]: Track opioid use after discharge for the first 1 year; assess for continued opioid use
• Opioid Use at 2 Years [2 years]: Track total opioid use after discharge for the first 2 years; assess for continued opioid use
• Numerical Pain Rating Scale [1 days and 3 days]: Validated pain scale; will be completed by patient Minimum Score: 0 \& Maximum score 100 A lower score is representative of a low pain level
• Brief Pain Inventory [1 day and 3 days]: The Brief Pain Inventory (BPI) is a self-administered questionnaire for chronic pain conditions. The BPI gives two main scores: a pain severity score and a pain interference score. The pain severity score is calculated from the four items about pain intensity. Each item is rated from 0, no pain, to 10, pain as bad as you can imagine, and contributes with the same weight to the final score, ranging from 0 to 40. The pain interference score corresponds to the item on pain interference. The seven sub-items are rated from 0, does not interfere, to 10, completely interferes, and contributes with the same weight to the final score, ranging from 0 to 70. The first item, pain drawing diagrams (painful and most painful areas) and the items on pain relief treatment or medication (list of the treatments and amount of relief) do not contribute to the scoring.
• Opioid Related Side Effects [Hospital Stay (1-4 days)]: Ileus, nausea/vomiting, first bowel movement, first flatus, treated pruritis will be identified and recorded
• Perioperative Complications - Drain Output [Hospital Stay (1-4 days)]: Complications such as: excessive drain output, elevation in creatinine, and the need for transfusions will be identified and recorded
• Perioperative Complications - Transfusion Rate [Hospital Stay (1-4 days)]: Complications such as: excessive drain output, elevation in creatinine, and the need for transfusions will be identified and recorded
• Days to Walk 50 ft With PT [Hospital Stay (1-4 days)]: Days needed to be able to walk 50ft with PT
• Length of Stay [Hospital Stay (1-4 days)]: Will record date of discharge
• Veterans Rand - 12 [pre-operative]: The Veterans RAND 12 Item Health Survey (VR-12) is a brief, generic, multi-use, self-administered health survey comprised of 12 items. The instrument is primarily used to measure health related quality of life, to estimate disease burden and to evaluate disease-specific benchmarks with other populations. The 12 items in the questionnaire correspond to eight principal physical and mental health domains including general health perceptions; physical functioning; role limitations due to physical and emotional problems; bodily pain; energy-fatigue, social functioning and mental health.. The 12 items are summarized into two scores, a "Physical Health Summary Measure {PCS-physical component score}" and a "Mental Health Summary Measure {MCS-mental component score}". Score range is 0 to 100, higher score denotes a better outcome. This score range apply to both PCS and MCS.
• Oswestry Disability Index [pre-operative]: The Oswestry Disability Index (ODI) is the most commonly used outcome-measure questionnaire for low back pain in a hospital setting. It is a self-administered questionnaire divided into ten sections designed to assess limitations of various activities of daily living. Each section is scored on a 0-5 scale, 5 representing the greatest disability. The index is calculated by dividing the summed score by the total possible score, which is then multiplied by 100 and expressed as a percentage. Thus, for every question not answered, the denominator is reduced by 5. If a patient marks more than one statement in a question, the highest scoring statement is recorded as a true indication of disability.
• Veterans Rand - 12 [3 month follow up]: The Veterans RAND 12 Item Health Survey (VR-12) is a brief, generic, multi-use, self-administered health survey comprised of 12 items. The instrument is primarily used to measure health related quality of life, to estimate disease burden and to evaluate disease-specific benchmarks with other populations. The 12 items in the questionnaire correspond to eight principal physical and mental health domains including general health perceptions; physical functioning; role limitations due to physical and emotional problems; bodily pain; energy-fatigue, social functioning and mental health.. The 12 items are summarized into two scores, a "Physical Health Summary Measure {PCS-physical component score}" and a "Mental Health Summary Measure {MCS-mental component score}". Score range is 0 to 100, higher score denotes a better outcome. This score range apply to both PCS and MCS.
• Oswestry Disability Index [3 month follow up]: The Oswestry Disability Index (ODI) is the most commonly used outcome-measure questionnaire for low back pain in a hospital setting. It is a self-administered questionnaire divided into ten sections designed to assess limitations of various activities of daily living. Each section is scored on a 0-5 scale, 5 representing the greatest disability. The index is calculated by dividing the summed score by the total possible score, which is then multiplied by 100 and expressed as a percentage. Thus, for every question not answered, the denominator is reduced by 5. If a patient marks more than one statement in a question, the highest scoring statement is recorded as a true indication of disability.
• Return to Work [3 month follow up]: Record return to work
• Veterans Rand - 12 [1 year follow up]: The Veterans RAND 12 Item Health Survey (VR-12) is a brief, generic, multi-use, self-administered health survey comprised of 12 items. The instrument is primarily used to measure health related quality of life, to estimate disease burden and to evaluate disease-specific benchmarks with other populations. The 12 items in the questionnaire correspond to eight principal physical and mental health domains including general health perceptions; physical functioning; role limitations due to physical and emotional problems; bodily pain; energy-fatigue, social functioning and mental health.. The 12 items are summarized into two scores, a "Physical Health Summary Measure {PCS-physical component score}" and a "Mental Health Summary Measure {MCS-mental component score}". Score range is 0 to 100, higher score denotes a better outcome. This score range apply to both PCS and MCS.
• Oswestry Disability Index [1 year follow up]: The Oswestry Disability Index (ODI) is the most commonly used outcome-measure questionnaire for low back pain in a hospital setting. It is a self-administered questionnaire divided into ten sections designed to assess limitations of various activities of daily living. Each section is scored on a 0-5 scale, 5 representing the greatest disability. The index is calculated by dividing the summed score by the total possible score, which is then multiplied by 100 and expressed as a percentage. Thus, for every question not answered, the denominator is reduced by 5. If a patient marks more than one statement in a question, the highest scoring statement is recorded as a true indication of disability.
• Return to Work [1 year follow up]: Record return to work
• Numerical Pain Rating Scale [1 year follow up]: Validated pain scale; will be completed by patient Minimum Score: 0 \& Maximum score 100 A lower score is representative of a low pain level
• Veterans Rand - 12 [2 year follow up]: The Veterans RAND 12 Item Health Survey (VR-12) is a brief, generic, multi-use, self-administered health survey comprised of 12 items. The instrument is primarily used to measure health related quality of life, to estimate disease burden and to evaluate disease-specific benchmarks with other populations. The 12 items in the questionnaire correspond to eight principal physical and mental health domains including general health perceptions; physical functioning; role limitations due to physical and emotional problems; bodily pain; energy-fatigue, social functioning and mental health.. The 12 items are summarized into two scores, a "Physical Health Summary Measure {PCS-physical component score}" and a "Mental Health Summary Measure {MCS-mental component score}". Score range is 0 to 100, higher score denotes a better outcome. This score range apply to both PCS and MCS.
• Oswestry Disability Index [2 year follow up]: The Oswestry Disability Index (ODI) is the most commonly used outcome-measure questionnaire for low back pain in a hospital setting. It is a self-administered questionnaire divided into ten sections designed to assess limitations of various activities of daily living. Each section is scored on a 0-5 scale, 5 representing the greatest disability. The index is calculated by dividing the summed score by the total possible score, which is then multiplied by 100 and expressed as a percentage. Thus, for every question not answered, the denominator is reduced by 5. If a patient marks more than one statement in a question, the highest scoring statement is recorded as a true indication of disability.
• Return to Work [2 year follow up]: Record return to work
• Numerical Pain Rating Scale [2 year follow up]: Validated pain scale; will be completed by patient Minimum Score: 0 \& Maximum score 100 A lower score is representative of a low pain level

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Age 18-75
* Require 1 or 2 level lumbar spinal fusion through posterior or lateral approach
* No history of long term opioid use (daily or almost daily opioid use > 2 weeks) and not on opiates at time of presentation to clinic

Exclusion Criteria:

* Documented allergy to NSAIDs or Acetaminophen
* History of: Peptic Ulcer Disease, Congestive heart failure, Chronic liver disease, Elevated alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) greater than 1.5 times control, Bleeding disorder, Renal dysfunction (Serum creatinine > 1.5 mg/dL), Glucocorticoid use within 1 month of surgery
* Current smokers (quite date < 30 days ago)
* Revision for pseudarthrosis
* Patients who are unable to physically or mentally provide consent to the study procedures.

Participant flow

Outcome results

• Perioperative Opioid Use (Primary), Median, oral morphine equivalents (OME) (mmg): IV Ketorolac 86.25 (39.6 to 245.55); Intravenous (IV) Placebo 306.6 (161 to 423); IV Acetaminophen 192.4 (91.55 to 372.85) (p <0.001)
• Opioid Use at 4-6 Weeks (Secondary), Count of participants, Participants: IV Ketorolac 34; Intravenous (IV) Placebo 33; IV Acetaminophen 22 (p 0.048)
• Opioid Use at 3 Months (Secondary), Count of participants, Participants: IV Ketorolac 32; Intravenous (IV) Placebo 25; IV Acetaminophen 26 (p 0.595)
• Opioid Use at 1 Year (Secondary), Count of participants, Participants: IV Ketorolac 32; Intravenous (IV) Placebo 31; IV Acetaminophen 21
• Opioid Use at 2 Years (Secondary), Count of participants, Participants: IV Ketorolac 26; Intravenous (IV) Placebo 26; IV Acetaminophen 22
• Numerical Pain Rating Scale (Secondary), Median, units on a scale: IV Ketorolac 39 (22 to 58); Intravenous (IV) Placebo 46 (29.3 to 72); IV Acetaminophen 42 (25.5 to 67) (p 0.732)
• Brief Pain Inventory (Secondary), Median, score on a scale: IV Ketorolac 6.5 (3.25 to 10); Intravenous (IV) Placebo 9 (6 to 10); IV Acetaminophen 9 (6 to 10) (p 0.016)
• Opioid Related Side Effects (Secondary), Count of participants, Participants: IV Ketorolac 16; Intravenous (IV) Placebo 17; IV Acetaminophen 17
• Perioperative Complications - Drain Output (Secondary), Median, mL: IV Ketorolac 270 (135 to 400); Intravenous (IV) Placebo 235 (150 to 348.75); IV Acetaminophen 240 (160 to 390) (p 0.928)
• Perioperative Complications - Transfusion Rate (Secondary), Count of participants, Participants: IV Ketorolac 40; Intravenous (IV) Placebo 42; IV Acetaminophen 41 (p 0.078)
• Days to Walk 50 ft With PT (Secondary), Count of participants, Participants: IV Ketorolac 30; Intravenous (IV) Placebo 26; IV Acetaminophen 24 (p 0792)
• Length of Stay (Secondary), Mean, Hour: IV Ketorolac 49.5 (43.25 to 91.25); Intravenous (IV) Placebo 77 (67 to 100); IV Acetaminophen 70 (47 to 91.5) (p 0.034)
• Veterans Rand - 12 (Secondary), Mean, score on a scale: IV Ketorolac 34.7 +/- 10.8; Intravenous (IV) Placebo 34.2 +/- 10.7; IV Acetaminophen 34.5 +/- 9.7 (p 0.974)
• Oswestry Disability Index (Secondary), Mean, percentage: IV Ketorolac 36.3 +/- 14.3; Intravenous (IV) Placebo 35.4 +/- 11.1; IV Acetaminophen 40.6 +/- 15.9 (p 0.215)
• Veterans Rand - 12 (Secondary), Mean, score on a scale: IV Ketorolac 43.1 +/- 11.8; Intravenous (IV) Placebo 48.7 +/- 8.8; IV Acetaminophen 42.3 +/- 9.9 (p 0.044)
• Oswestry Disability Index (Secondary), Mean, percentage: IV Ketorolac 22.8 +/- 15.7; Intravenous (IV) Placebo 18.8 +/- 12.9; IV Acetaminophen 25.0 +/- 13.6 (p 0.191)
• Return to Work (Secondary), Count of participants, Participants: IV Ketorolac 9; Intravenous (IV) Placebo 7; IV Acetaminophen 7
• Veterans Rand - 12 (Secondary), Mean, score on a scale: IV Ketorolac 48.1 +/- 11.6; Intravenous (IV) Placebo 47.6 +/- 11.9; IV Acetaminophen 48.4 +/- 11.1
• Oswestry Disability Index (Secondary), Mean, percentage: IV Ketorolac 16.9 +/- 15.7; Intravenous (IV) Placebo 12.1 +/- 13.3; IV Acetaminophen 17.8 +/- 14.2
• Return to Work (Secondary), Count of participants, Participants: IV Ketorolac 9; Intravenous (IV) Placebo 7; IV Acetaminophen 3
• 5 more outcome measures not shown.

Adverse events

Time frame: 2-year

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2023-02-23)
• Informed Consent Form (PDF, 2017-10-30)

• Catherine Himo Gang, Study director, Research Manager for Spine Research
• Harvinder Sandhu, MD, Principal investigator, Associate Professor of Orthopedic Surgery