IV vs. Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty (IV Tylenol)

• ClinicalTrials.gov Identifier: NCT03020966
• Recruitment Status: Completed
• First Posted: January 13, 2017
• Last Update Posted: August 7, 2020
• Sponsor: Hospital for Special Surgery, New York
• Collaborator: Mallinckrodt
• Information provided by (Responsible Party): Hospital for Special Surgery, New York

Tracking Information

• First Submitted Date: December 6, 2016
• First Posted Date: January 13, 2017
• Last Update Posted Date: August 7, 2020
• Actual Study Start Date: February 16, 2017
• Actual Primary Completion Date: June 16, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 27, 2017)

• Pain With Physical Therapy on Post-operative Day 1 [ Time Frame: Post operative day 1 ]
  NRS questionnaire
• Opioid Use [ Time Frame: Day of surgery to post-operative day 3 ]
  oral morphine equivalents, cumulative, POD 0-3. Recorded in Medication Usage Database
• Opioid Side Effects [ Time Frame: Post-operative day 1 ]
  Opioid related symptom distress scale, ORSDS, composite score POD1

Original Primary Outcome Measures (submitted: January 11, 2017)

• Postoperative pain after THR [ Time Frame: Post operative day 0 ]
  Questionnaire
• Postoperative pain after THR [ Time Frame: Post operative day 1 ]
  Questionnaire
• Postoperative pain after THR [ Time Frame: Postoperative day 2 ]
  Questionnaire
• Postoperative pain after THR [ Time Frame: Postoperative day 3 ]
  Questionnaire

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: IV vs. Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty
• Official Title: IV vs. Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty: a Randomized, Blinded Trial
• Brief Summary: The purpose of this study is to determine how well two different methods of administrating Tylenol reduce pain and improve patient satisfaction after total hip replacement (THR) surgery. The methods of administration are orally, via a pill that is to be swallowed, and intravenously. Our aim is to determine whether oral or intravenous administration of Tylenol will reduce opioid consumption and opioid-related side effects after THR.

Detailed Description

A) Opioid use after THA. Opioid use after THA can be 90 mg (+/-79) in morphine equivalents when using epidural bupivacaine / hydromorphone and multimodal analgesia. Less than 1/3 of this was via the epidural (26/90 mg). Patients reported ORSDS composite scores of 0.58

B) IV vs oral acetaminophen. The therapeutic blood concentration of acetaminophen for pain relief is 10 mcg/ml.

After an oral, single dose: In 24 fasting adult subjects, the maximal blood concentration (Cmax) of 7.7 to 17.6 mcg/mL occurred within 1 hour following a single 1000-mg dose of oral acetaminophen (liquid or caplet). Acetaminophen crosses the blood-brain barrier. Central diffusion to the brain and spinal fluid occurs within 15 to 45 minutes with maximum cerebrospinal fluid concentrations occurring at 2 to 4 hours. [Product Information: TYLENOL(R) oral, acetaminophen oral. McNeil Consumer Healthcare, Skillman, NJ, 2010].

In a randomized, double-blind, placebo-controlled, single-dose study, acetaminophen 1,000 mg provided significantly greater efficacy in treating postsurgical dental pain compared with acetaminophen 650 mg and placebo.

Oral, multiple-dose, immediate-release, elderly patients: In 12 very elderly patients (mean age, 89 years), the Cmax was 23.9 mcg/mL following the administration of acetaminophen 1000 mg orally 3 times daily for 5 days.

In adult subjects, the mean Cmax was 28 +/- 21 mcg/mL at the end of a 15-minute IV infusion of acetaminophen 1000 mg. [Product Information: OFIRMEV(TM) intravenous infusion, acetaminophen intravenous infusion. Cadence Pharmaceuticals Inc., San Diego, CA, 2010].

The oral medication has an excellent absorption and at least 85% bioavailability, but peak concentration occurs later than the IV, and the therapeutic blood concentration for pain relief (10mcg/ml) may not be achieved after one oral dose (7-17mcg/ml).A full stomach delays the absorption. With multiple doses, in elderly patients, or with renal/ liver failure, the blood concentration is higher.

Epidural bupivacaine / clonidine (Liu). Pain scores (NRS) after THA with activity on POD1 can be 3.4 mean (2.6 SD) when using epidural bupivacaine / clonidine and multimodal analgesia.

Low-opioid protocol (oxycodone may be too strong for some; cannot use Vicodin due to acetaminophen) Choice of instruments (CAM, ORSDS, Pain OUT). The ORSDS is a 4-point scale that evaluates 12 symptoms (nausea, vomiting, constipation, difficulty passing urine, difficulty concentrating, drowsiness or difficulty staying awake, feeling lightheaded or dizzy, feeling confused, feelings of general fatigue or weakness, itchiness, dry mouth and headache) via 3 symptom distress dimensions (frequency, severity, bothersomeness). It is validated for use after orthopaedic surgery, specifically including TKA patients receiving epidural analgesia and femoral nerve blockade.

Patients can meet criteria for delirium by CAM by having acute onset of inattention as well as either disorganized thinking or altered level of consciousness.Patients without acute onset can also meet criteria for delirium if inattention, disorganized thinking and altered level of consciousness are all present, with at least one factor judged to be fluctuating. CAM has been widely applied and has been specifically used to evaluate elderly TKA patients receiving epidural analgesia and femoral nerve blockade.

The Patient Outcome Questionnaire by the American Pain society is used for quality improvement, and measures 6 aspects of quality, including (1) pain severity and relief; (2) impact of pain on activity, sleep, and negative emotions; (3) side effects of treatment; (4) helpfulness of information about pain treatment; (5) ability to participate in pain treatment decisions; and (6) use of nonpharmacological strategies.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Pain, Postoperative
• Opioid Use

Intervention

• Drug: Acetaminophen
  Oral acetaminophen, intravenous placebo
• Drug: Acetaminophen
  Intravenous acetaminophen, oral placebo

Study Arms

• Experimental: Oral Tylenol
  Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo
  Intervention: Drug: Acetaminophen
• Experimental: Intravenous Tylenol
  Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo
  Intervention: Drug: Acetaminophen

Publications *

• Jules-Elysee KM, Goon AK, Westrich GH, Padgett DE, Mayman DJ, Ranawat AS, Ranawat CS, Lin Y, Kahn RL, Bhagat DD, Goytizolo EA, Ma Y, Reid SC, Curren J, YaDeau JT. Patient-controlled epidural analgesia or multimodal pain regimen with periarticular injection after total hip arthroplasty: a randomized, double-blind, placebo-controlled study. J Bone Joint Surg Am. 2015 May 20;97(10):789-98. doi: 10.2106/JBJS.N.00698.
• Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults. Clin Pharmacol Ther. 2007 Jun;81(6):840-8. Epub 2007 Mar 21.
• Singla NK, Parulan C, Samson R, Hutchinson J, Bushnell R, Beja EG, Ang R, Royal MA. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012 Sep;12(7):523-32. doi: 10.1111/j.1533-2500.2012.00556.x. Epub 2012 Apr 24.
• Qi DS, May LG, Zimmerman B, Peng P, Atillasoy E, Brown JD, Cooper SA. A randomized, double-blind, placebo-controlled study of acetaminophen 1000 mg versus acetaminophen 650 mg for the treatment of postsurgical dental pain. Clin Ther. 2012 Dec;34(12):2247-2258.e3. doi: 10.1016/j.clinthera.2012.11.003. Epub 2012 Nov 28.
• Liu SS, Bae JJ, Bieltz M, Wukovits B, Ma Y. A prospective survey of patient-controlled epidural analgesia with bupivacaine and clonidine after total hip replacement: a pre- and postchange comparison with bupivacaine and hydromorphone in 1,000 patients. Anesth Analg. 2011 Nov;113(5):1213-7. doi: 10.1213/ANE.0b013e318228fc8b. Epub 2011 Aug 4.
• Yadeau JT, Liu SS, Rade MC, Marcello D, Liguori GA. Performance characteristics and validation of the Opioid-Related Symptom Distress Scale for evaluation of analgesic side effects after orthopedic surgery. Anesth Analg. 2011 Aug;113(2):369-77. doi: 10.1213/ANE.0b013e31821ae3f7. Epub 2011 Apr 27.
• Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, Horwitz RI. Clarifying confusion: the confusion assessment method. A new method for detection of delirium. Ann Intern Med. 1990 Dec 15;113(12):941-8.
• Rade MC, Yadeau JT, Ford C, Reid MC. Postoperative delirium in elderly patients after elective hip or knee arthroplasty performed under regional anesthesia. HSS J. 2011 Jul;7(2):151-6. doi: 10.1007/s11420-011-9195-2. Epub 2011 Feb 11.
• Gordon DB, Polomano RC, Pellino TA, Turk DC, McCracken LM, Sherwood G, Paice JA, Wallace MS, Strassels SA, Farrar JT. Revised American Pain Society Patient Outcome Questionnaire (APS-POQ-R) for quality improvement of pain management in hospitalized adults: preliminary psychometric evaluation. J Pain. 2010 Nov;11(11):1172-86. doi: 10.1016/j.jpain.2010.02.012. Epub 2010 Apr 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 11, 2017): 154
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: June 16, 2019
• Actual Primary Completion Date: June 16, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

• Adult
• Scheduled for an elective primary THA with a participating surgeon,
• Planned for Combined Spinal Epidural anesthesia (CSE) and Patient Controlled Epidural Analgesia (PCEA)
• English-speaking
• Patients that did not receive pre-operative opioids

Exclusion criteria:

• Hepatic or renal insufficiency, as defined by abnormal readings on liver and kidney functioning tests.
• Hypersensitivity or contraindication to protocol medication
• Contraindication for CSE and PCEA
• Incapable to provide consent/answer questions in English
• Revision or urgent surgery
• Receiving Periarticular Injections
• History of opioid use
• Patients on disability or worker's compensation

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03020966
• Other Study ID Numbers: 2016-209
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Hospital for Special Surgery, New York
• Study Sponsor: Hospital for Special Surgery, New York
• Collaborators: Mallinckrodt

Investigators

• Principal Investigator: Jacques Ya Deau, MD, PhD; Hospital for Special Surgery, New York

• PRS Account: Hospital for Special Surgery, New York
• Verification Date: August 2020