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A randomized, double-blind, placebo-controlled intervention trial involving 100 treated subjects undergoing endonasal trans-sphenoidal (ENTS) resection of pituitary lesion. Subjects will be randomized into two groups: 50 treated in the opioid-sparing arm and 50 treated in the standard post-operative medication arm.
Post-operative pain control is a common concern patients have when they consider undergoing a surgical procedure. Although effective for treating acute pain, opioid analgesics are also associated with dose-dependent adverse effects, including constipation, nausea and vomiting, altered mental status, and respiratory depression, all of which have been shown to increase patient length of stay. The use of non-opioid analgesics with different mechanisms of actions for acute pain control via a multi-modal approach is efficacious in reducing opioid consumption, decreasing the incidence of adverse effects, improving patient satisfaction and recovery time, and decreasing hospital costs.Certain minimally invasive procedures may afford many patients the opportunity to achieve adequate post-operative pain control with minimal to no requirement of opioid analgesics, thereby sparing the patient known adverse effects that can increase length of stay and costs. The ENTS approach for resection of pituitary tumors is the standard surgical procedure for these lesions, and is associated with pain that is more easily managed post-operatively, making it an ideal procedure for an opioid-sparing post-operative pain regimen. Anecdotally, the investigators note that in the investigator's post-operative pituitary patient population that post-operative pain can frequently be adequately managed with scheduled non-opioid analgesics, often without requiring breakthrough opioid doses. Another safe and effective non-opioid analgesic that is widely used in multi-modal pain management for moderate pain is IV Caldolor (ibuprofen). After literature review, the investigators were unable to find a study that had attempted to use an opioid-sparing analgesic regimen for post-operative pain control following ENTS approach for resection of pituitary tumors.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IV Caldolor (ibuprofen) | Active Comparator | Intravenous (IV) Caldolor (ibuprofen) (800mg every 8 hours) initiated during surgery and oral acetaminophen 1000mg every 6 hours initiated post-operatively and continued for the duration of the hospital stay (an expected average stay of 2 days) or 48 hours, whichever comes first. Breakthrough pain will be treated with rescue narcotics (IV morphine 2-4mg every 2 hours and oral oxycodone 5-15mg every 4 hours immediately post-operatively through discharge, an expected average stay of 2 days). Hydromorphone (IV 0.5-2mg every 2 hours and oral 2-4mg every 4 hours) will be used in patients with morphine or oxycodone allergy or intolerance. |
|
| standard treatment group | Placebo Comparator | IV placebo will be initiated during surgery and oral acetaminophen 1000mg every 6 hours will be initiated post-operatively and continued for the duration of the hospital stay (an expected average stay of 2 days) or 48 hours, whichever comes first. Breakthrough pain will be treated with rescue narcotics (IV morphine 2-4mg every 2 hours and oral oxycodone 5-15mg every 4 hours immediately post-operatively through discharge, an expected average stay of 2 days). Hydromorphone (IV 0.5-2mg every 2 hours and oral 2-4mg every 4 hours) will be used in patients with morphine or oxycodone allergy or intolerance. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IV Caldolor | Drug | IV Caldolor (IV ibuprofen) intraoperatively and postoperatively |
|
| Measure | Description | Time Frame |
|---|---|---|
| Comparison of Mean Pain Scores Between Two Arms (Measured Every 4 Hours Over 48 Hour) | Comparison of pain scores between two arms using Visual Analog Scale (VAS) for Pain. Units of measure are 0=No Pain, 1=Annoying, 2=Mild Pain, 3=Troublesome, 4=Nagging Pain, Uncomfortable, 5=Distressing, 6=Miserable, 7=Horrible, 8=Intense, Dreadful, 9=Unbearable, 10=Worst Possible Pain. Higher values represent a worse outcome. There are no subscales. | mean pain score over 48 hours |
| Measure | Description | Time Frame |
|---|---|---|
| Breakthrough Narcotic Requirement | Rescue narcotic in both groups will be recorded and compared using a standard equianalgesic oral morphine equivalent (OME) calculation | until discharge from hospital, an expected stay of 2 days |
| Other Adverse Events |
| Measure | Description | Time Frame |
|---|---|---|
| Total Cost of Hospital Charges Compared Between Two Arms | Total hospital costs for patients in IV ibuprofen arm compared to IV placebo arm | until discharge from hospital, an expected stay of 2 days |
| The Number of Participants Who Have a Bowel Movement During Hospitalization in Both Groups |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Andrew S Little, MD | Barrow Neurosurgical Associates physician with SJHMC privileges | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St. Joseph's Hospital and Medical Center | Phoenix | Arizona | 85013 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22570188 | Background | Pizzi LT, Toner R, Foley K, Thomson E, Chow W, Kim M, Couto J, Royo M, Viscusi E. Relationship between potential opioid-related adverse effects and hospital length of stay in patients receiving opioids after orthopedic surgery. Pharmacotherapy. 2012 Jun;32(6):502-14. doi: 10.1002/j.1875-9114.2012.01101.x. Epub 2012 May 8. | |
| 23205862 |
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Randomized 1:1 ratio with blinded treatment assignment. Used a computer-generated list from random.org.
Adult patients undergoing endonasal transsphenoidal surgery for pituitary adenoma. Potential patients were identified in the Pituitary Clinic at Barrow Neurological Institute.
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| ID | Title | Description |
|---|---|---|
| FG000 | Opioid-sparing Group | Intravenous (IV) Caldolor (ibuprofen) (800mg every 8 hours) initiated during surgery and oral acetaminophen 1000mg every 6 hours initiated post-operatively and continued for the duration of the hospital stay (an expected average stay of 2 days) or 48 hours, whichever comes first. Breakthrough pain will be treated with rescue narcotics (IV morphine 2-4mg every 2 hours and oral oxycodone 5-15mg every 4 hours immediately post-operatively through discharge, an expected average stay of 2 days). Hydromorphone (IV 0.5-2mg every 2 hours and oral 2-4mg every 4 hours) will be used in patients with morphine or oxycodone allergy or intolerance. IV Caldolor (IV Ibuprofen): Compare addition of IV Caldolor (IV ibuprofen) intraoperatively and postoperatively against IV ibuprofen placebo added intraoperatively and postoperatively. |
| FG001 | Standard Treatment Group | IV Caldolor placebo will be initiated during surgery and oral acetaminophen 1000mg every 6 hours will be initiated post-operatively and continued for the duration of the hospital stay (an expected average stay of 2 days) or 48 hours, whichever comes first. Breakthrough pain will be treated with rescue narcotics (IV morphine 2-4mg every 2 hours and oral oxycodone 5-15mg every 4 hours immediately post-operatively through discharge, an expected average stay of 2 days). Hydromorphone (IV 0.5-2mg every 2 hours and oral 2-4mg every 4 hours) will be used in patients with morphine or oxycodone allergy or intolerance. IV Ibuprofen placebo: Compare addition of IV ibuprofen placebo intraoperatively and postoperatively against IV Caldolor (IV ibuprofen) added intraoperatively and postoperatively. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Patients age >18 years and <80 years undergoing endonasal transsphenoidal surgery for pituitary adenoma.
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| ID | Title | Description |
|---|---|---|
| BG000 | Opioid-sparing Group | Intravenous (IV) Caldolor (ibuprofen) (800mg every 8 hours) initiated during surgery and oral acetaminophen 1000mg every 6 hours initiated post-operatively and continued for the duration of the hospital stay (an expected average stay of 2 days) or 48 hours, whichever comes first. Breakthrough pain will be treated with rescue narcotics (IV morphine 2-4mg every 2 hours and oral oxycodone 5-15mg every 4 hours immediately post-operatively through discharge, an expected average stay of 2 days). Hydromorphone (IV 0.5-2mg every 2 hours and oral 2-4mg every 4 hours) will be used in patients with morphine or oxycodone allergy or intolerance. IV Caldolor (IV Ibuprofen): Compare addition of IV Caldolor (IV ibuprofen) intraoperatively and postoperatively against IV ibuprofen placebo added intraoperatively and postoperatively. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Comparison of Mean Pain Scores Between Two Arms (Measured Every 4 Hours Over 48 Hour) | Comparison of pain scores between two arms using Visual Analog Scale (VAS) for Pain. Units of measure are 0=No Pain, 1=Annoying, 2=Mild Pain, 3=Troublesome, 4=Nagging Pain, Uncomfortable, 5=Distressing, 6=Miserable, 7=Horrible, 8=Intense, Dreadful, 9=Unbearable, 10=Worst Possible Pain. Higher values represent a worse outcome. There are no subscales. | All participants enrolled with the intent to treat. | Posted | Mean | Standard Deviation | 0-10 units on a scale | mean pain score over 48 hours |
|
surgery date until hospital discharge (average of 2 days)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Opioid-sparing Group | Intravenous (IV) Caldolor (ibuprofen) (800mg every 8 hours) initiated during surgery and oral acetaminophen 1000mg every 6 hours initiated post-operatively and continued for the duration of the hospital stay (an expected average stay of 2 days) or 48 hours, whichever comes first. Breakthrough pain will be treated with rescue narcotics (IV morphine 2-4 mg every 2 hours and oral oxycodone 5-15mg every 4 hours immediately post-operatively through discharge, an expected average stay of 2 days). Hydromorphone (IV 0.5-2 mg every 2 hours and oral 2-4 mg every 4 hours) will be used in patients with morphine or oxycodone allergy or intolerance. IV Caldolor (Ibuprofen): Compare addition of IV Caldolor (ibuprofen) intraoperatively and postoperatively against IV placebo added intraoperatively and postoperatively. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Epistaxis | Respiratory, thoracic and mediastinal disorders | CTCAE | Systematic Assessment | A disorder characterized by bleeding from the nose. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| hyperkalemia | Blood and lymphatic system disorders | CTCAE | Systematic Assessment | elevated level of potassium (K+) in the blood serum. Normal potassium levels are between 3.5 and 5.0 mmol/L (3.5 and 5.0 mEq/L) with levels above 5.5 mmol/L defined as hyperkalemia. |
Groups were not balanced re:patient age, so pain scores were analyzed, including age as a covariate, to account for this difference. A second limitation is that analysis was not powered to detect rare bleeding complications or sellar hematoma.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Andrew S. Little, MD | Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center | 602-406-3181 | neuropub@dignityhealth.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 20, 2015 | Sep 28, 2021 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D010911 | Pituitary Neoplasms |
| D010146 | Pain |
| ID | Term |
|---|---|
| D004701 | Endocrine Gland Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D007029 | Hypothalamic Neoplasms |
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| ID | Term |
|---|---|
| D007052 | Ibuprofen |
| ID | Term |
|---|---|
| D010666 | Phenylpropionates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
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| IV Placebo | Drug | IV Placebo intraoperatively and postoperatively |
|
|
Epistaxis, potentially related to IV ibuprofen, will be compared between two groups
| until discharge from hospital, an expected stay of 2 days |
patients with one or more bowel movement(s) in the first 48 hours after surgery |
| until discharge from hospital, an expected stay of 2 days |
| Length of Stay in Hospital Compared Between Two Arms | Length of hospital stay from time of surgery to time of discharge. | until discharge from hospital, an expected stay of 2 days |
| Total Number of Doses of Any Anti-emetic Required Post-operatively in Both Groups | Use of antiemetics in first 48 hours after surgery | until discharge from hospital, an expected stay of 2 days |
| Husted H. Fast-track hip and knee arthroplasty: clinical and organizational aspects. Acta Orthop Suppl. 2012 Oct;83(346):1-39. doi: 10.3109/17453674.2012.700593. |
| 21255528 | Background | Costantini R, Affaitati G, Fabrizio A, Giamberardino MA. Controlling pain in the post-operative setting. Int J Clin Pharmacol Ther. 2011 Feb;49(2):116-27. doi: 10.5414/cp201401. |
| 10713196 | Background | Badie B, Nguyen P, Preston JK. Endoscopic-guided direct endonasal approach for pituitary surgery. Surg Neurol. 2000 Feb;53(2):168-72; discussion 172-3. doi: 10.1016/s0090-3019(99)00195-0. |
| 15248627 | Background | Dahl V, Dybvik T, Steen T, Aune AK, Rosenlund EK, Raeder JC. Ibuprofen vs. acetaminophen vs. ibuprofen and acetaminophen after arthroscopically assisted anterior cruciate ligament reconstruction. Eur J Anaesthesiol. 2004 Jun;21(6):471-5. doi: 10.1017/s026502150400609x. |
| 19843482 | Background | Southworth S, Peters J, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen 400 and 800 mg every 6 hours in the management of postoperative pain. Clin Ther. 2009 Sep;31(9):1922-35. doi: 10.1016/j.clinthera.2009.08.026. |
| 20609131 | Background | Singla N, Rock A, Pavliv L. A multi-center, randomized, double-blind placebo-controlled trial of intravenous-ibuprofen (IV-ibuprofen) for treatment of pain in post-operative orthopedic adult patients. Pain Med. 2010 Aug;11(8):1284-93. doi: 10.1111/j.1526-4637.2010.00896.x. Epub 2010 Jun 30. |
| 20642488 | Background | Kroll PB, Meadows L, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (i.v.-ibuprofen) in the management of postoperative pain following abdominal hysterectomy. Pain Pract. 2011 Jan-Feb;11(1):23-32. doi: 10.1111/j.1533-2500.2010.00402.x. |
| 24400921 | Background | Chung KC, Barlev A, Braun AH, Qian Y, Zagari M. Assessing analgesic use in patients with advanced cancer: development of a new scale--the Analgesic Quantification Algorithm. Pain Med. 2014 Feb;15(2):225-32. doi: 10.1111/pme.12299. Epub 2014 Jan 8. |
| 28298041 | Result | Shepherd DM, Jahnke H, White WL, Little AS. Randomized, double-blinded, placebo-controlled trial comparing two multimodal opioid-minimizing pain management regimens following transsphenoidal surgery. J Neurosurg. 2018 Feb;128(2):444-451. doi: 10.3171/2016.10.JNS161355. Epub 2017 Mar 3. |
| BG001 | Standard Treatment Group | IV Caldolor placebo will be initiated during surgery and oral acetaminophen 1000mg every 6 hours will be initiated post-operatively and continued for the duration of the hospital stay (an expected average stay of 2 days) or 48 hours, whichever comes first. Breakthrough pain will be treated with rescue narcotics (IV morphine 2-4mg every 2 hours and oral oxycodone 5-15mg every 4 hours immediately post-operatively through discharge, an expected average stay of 2 days). Hydromorphone (IV 0.5-2mg every 2 hours and oral 2-4mg every 4 hours) will be used in patients with morphine or oxycodone allergy or intolerance. IV Ibuprofen placebo: Compare addition of IV ibuprofen placebo intraoperatively and postoperatively against IV Caldolor (IV ibuprofen) added intraoperatively and postoperatively. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Standard Treatment Group | IV Caldolor placebo will be initiated during surgery and oral acetaminophen 1000mg every 6 hours will be initiated post-operatively and continued for the duration of the hospital stay (an expected average stay of 2 days) or 48 hours, whichever comes first. Breakthrough pain will be treated with rescue narcotics (IV morphine 2-4mg every 2 hours and oral oxycodone 5-15mg every 4 hours immediately post-operatively through discharge, an expected average stay of 2 days). Hydromorphone (IV 0.5-2mg every 2 hours and oral 2-4mg every 4 hours) will be used in patients with morphine or oxycodone allergy or intolerance. IV Ibuprofen placebo: Compare addition of IV ibuprofen placebo intraoperatively and postoperatively against IV Caldolor (IV ibuprofen) added intraoperatively and postoperatively. |
|
|
| Secondary | Breakthrough Narcotic Requirement | Rescue narcotic in both groups will be recorded and compared using a standard equianalgesic oral morphine equivalent (OME) calculation | All participants enrolled with the intent to treat. | Posted | Mean | Standard Deviation | mg | until discharge from hospital, an expected stay of 2 days |
|
|
|
| Secondary | Other Adverse Events | Epistaxis, potentially related to IV ibuprofen, will be compared between two groups | Posted | Number | participants | until discharge from hospital, an expected stay of 2 days |
|
|
|
| Other Pre-specified | Total Cost of Hospital Charges Compared Between Two Arms | Total hospital costs for patients in IV ibuprofen arm compared to IV placebo arm | Not Posted | until discharge from hospital, an expected stay of 2 days | Participants |
| Other Pre-specified | The Number of Participants Who Have a Bowel Movement During Hospitalization in Both Groups | patients with one or more bowel movement(s) in the first 48 hours after surgery | all patients enrolled with intent to treat | Posted | Number | participants | until discharge from hospital, an expected stay of 2 days |
|
|
|
| Other Pre-specified | Length of Stay in Hospital Compared Between Two Arms | Length of hospital stay from time of surgery to time of discharge. | all participants enrolled with the intent to treat | Posted | Mean | Standard Deviation | hours | until discharge from hospital, an expected stay of 2 days |
|
|
|
| Other Pre-specified | Total Number of Doses of Any Anti-emetic Required Post-operatively in Both Groups | Use of antiemetics in first 48 hours after surgery | all participants enrolled with the intent to treat | Posted | Mean | Standard Deviation | dose | until discharge from hospital, an expected stay of 2 days |
|
|
|
| 0 |
| 28 |
| 0 |
| 28 |
| 2 |
| 28 |
| EG001 | Standard Treatment Group | IV placebo will be initiated during surgery and oral acetaminophen 1000mg every 6 hours will be initiated post-operatively and continued for the duration of the hospital stay (an expected average stay of 2 days) or 48 hours, whichever comes first. Breakthrough pain will be treated with rescue narcotics (IV morphine 2-4mg every 2 hours and oral oxycodone 5-15mg every 4 hours immediately post-operatively through discharge, an expected average stay of 2 days). Hydromorphone (IV 0.5-2 mg every 2 hours and oral 2-4mg every 4 hours) will be used in patients with morphine or oxycodone allergy or intolerance. IV placebo: Compare addition of IV placebo intraoperatively and postoperatively against IV Caldolor (ibuprofen) added intraoperatively and postoperatively. | 0 | 34 | 2 | 34 | 0 | 34 |
|
|
| burning at IV site | Skin and subcutaneous tissue disorders | CTCAE | Systematic Assessment | I.V. fluid or medications leak into the surrounding tissue. |
|
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| D015173 |
| Supratentorial Neoplasms |
| D001932 | Brain Neoplasms |
| D016543 | Central Nervous System Neoplasms |
| D009423 | Nervous System Neoplasms |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D007027 | Hypothalamic Diseases |
| D010900 | Pituitary Diseases |
| D004700 | Endocrine System Diseases |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |