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

Sponsor
Hospital for Special Surgery, New York (Other)
Overall Status
Completed
CT.gov ID
NCT03020966
Collaborator
Mallinckrodt (Industry)
154
Enrollment
1
Location
2
Arms
27.9
Actual Duration (Months)
5.5
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

  1. 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

  2. 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 Design

Study Type:
Interventional
Actual Enrollment :
154 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
IV vs. Oral Acetaminophen as a Component of Multimodal Analgesia After Total Hip Arthroplasty: a Randomized, Blinded Trial
Actual Study Start Date :
Feb 16, 2017
Actual Primary Completion Date :
Jun 16, 2019
Actual Study Completion Date :
Jun 16, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Oral Tylenol

Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo

Drug: Acetaminophen
Oral acetaminophen, intravenous placebo
Experimental: Intravenous Tylenol

Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo

Drug: Acetaminophen
Intravenous acetaminophen, oral placebo

Outcome Measures

Primary Outcome Measures

  1. Pain With Physical Therapy on Post-operative Day 1 [24 hours after the operation (post-operative day 1)]

    Numerical rating scale of pain on a scale of 0-10, with 0 representing the minimum value of no pain and 10, representing the maximum, defined as being pain as bad as imaginable.

  2. Opioid Use [Day of surgery to post-operative day 3]

    Oral morphine equivalents, cumulative, POD 0-3. Recorded in Medication Usage Database.

  3. Opioid Side Effects [24 hours after surgery (Post-operative day 1)]

    The Opioid-Related Symptom Distress Scale (ORSDS) is a Likert scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness) for 12 symptoms. Frequency is rated on a 4-point scale (1= 'Rarely', 4= 'Almost constantly'). Severity is rated on a 4-point scale (1= 'Slightly', 4= 'Very'). Bothersomeness is rated on a 5-point scale (0.8= 'Not at all', 4.0= 'Very much'). The symptom-specific ORSDS is the average of the 3 symptom distress dimensions. The composite ORSDS score is the average of 12 symptom-specific scores.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 90 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Hospital for Special Surgery New York New York United States 10021

Sponsors and Collaborators

  • Hospital for Special Surgery, New York
  • Mallinckrodt

Investigators

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

Study Documents (Full-Text)

More Information

Publications

Responsible Party:
Hospital for Special Surgery, New York
ClinicalTrials.gov Identifier:
NCT03020966
Other Study ID Numbers:
  • 2016-209
First Posted:
Jan 13, 2017
Last Update Posted:
Aug 10, 2021
Last Verified:
Aug 1, 2021
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
Additional relevant MeSH terms:
Pain, Postoperative
Acetaminophen

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Oral Tylenol Intravenous Tylenol
Arm/Group Description Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo Acetaminophen: Oral acetaminophen, intravenous placebo Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo Acetaminophen: Intravenous acetaminophen, oral placebo
Period Title: Overall Study
STARTED 77 77
COMPLETED 75 77
NOT COMPLETED 2 0

Baseline Characteristics

Arm/Group Title Oral Tylenol Intravenous Tylenol Total
Arm/Group Description Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo Acetaminophen: Oral acetaminophen, intravenous placebo Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo Acetaminophen: Intravenous acetaminophen, oral placebo Total of all reporting groups
Overall Participants 77 77 154
Age (Count of Participants)
<=18 years
0
0%
0
0%
0
0%
Between 18 and 65 years
40
51.9%
39
50.6%
79
51.3%
>=65 years
37
48.1%
38
49.4%
75
48.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
65
(10)
63
(10)
64
(10)
Sex: Female, Male (Count of Participants)
Female
42
54.5%
49
63.6%
91
59.1%
Male
35
45.5%
28
36.4%
63
40.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
3
3.9%
2
2.6%
5
3.2%
Not Hispanic or Latino
74
96.1%
75
97.4%
149
96.8%
Unknown or Not Reported
0
0%
0
0%
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
3
3.9%
3
1.9%
Asian
1
1.3%
0
0%
1
0.6%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
4
5.2%
4
5.2%
8
5.2%
White
70
90.9%
69
89.6%
139
90.3%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
2
2.6%
1
1.3%
3
1.9%
Region of Enrollment (participants) [Number]
United States
77
100%
77
100%
154
100%

Outcome Measures

1. Primary Outcome
Title Pain With Physical Therapy on Post-operative Day 1
Description Numerical rating scale of pain on a scale of 0-10, with 0 representing the minimum value of no pain and 10, representing the maximum, defined as being pain as bad as imaginable.
Time Frame 24 hours after the operation (post-operative day 1)

Outcome Measure Data

Analysis Population Description
Three patients withdrew from the protocol, but were followed using intention-to-treat principles. One patient did not wish to answer the postoperative questions, 1 could not swallow the pills, and 1 received a different anesthetic/analgesic protocol due to pre-existing expectations.
Arm/Group Title Oral Tylenol Intravenous Tylenol
Arm/Group Description Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo Acetaminophen: Oral acetaminophen, intravenous placebo Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo Acetaminophen: Intravenous acetaminophen, oral placebo
Measure Participants 75 76
Mean (Standard Deviation) [score on a scale]
3.6
(2.4)
3.9
(2.4)
2. Primary Outcome
Title Opioid Use
Description Oral morphine equivalents, cumulative, POD 0-3. Recorded in Medication Usage Database.
Time Frame Day of surgery to post-operative day 3

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Oral Tylenol Intravenous Tylenol
Arm/Group Description Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo Acetaminophen: Oral acetaminophen, intravenous placebo Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo Acetaminophen: Intravenous acetaminophen, oral placebo
Measure Participants 65 61
Mean (Standard Deviation) [Oral Morphine Equivalent (mg)]
108
(63)
121
(71)
3. Primary Outcome
Title Opioid Side Effects
Description The Opioid-Related Symptom Distress Scale (ORSDS) is a Likert scale that evaluates 3 symptom distress dimensions (frequency, severity, bothersomeness) for 12 symptoms. Frequency is rated on a 4-point scale (1= 'Rarely', 4= 'Almost constantly'). Severity is rated on a 4-point scale (1= 'Slightly', 4= 'Very'). Bothersomeness is rated on a 5-point scale (0.8= 'Not at all', 4.0= 'Very much'). The symptom-specific ORSDS is the average of the 3 symptom distress dimensions. The composite ORSDS score is the average of 12 symptom-specific scores.
Time Frame 24 hours after surgery (Post-operative day 1)

Outcome Measure Data

Analysis Population Description
Three patients withdrew from the protocol, but were followed using intention-to-treat principles. One patient did not wish to answer the postoperative questions, 1 could not swallow the pills, and 1 received a different anesthetic/analgesic protocol due to pre-existing expectations. In addition, ORSDS on POD 1 was not recorded for two patients who were lost to follow up.
Arm/Group Title Oral Tylenol Intravenous Tylenol
Arm/Group Description Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo Acetaminophen: Oral acetaminophen, intravenous placebo Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo Acetaminophen: Intravenous acetaminophen, oral placebo
Measure Participants 74 75
Mean (Standard Deviation) [score on a scale]
0.4
(0.3)
0.3
(0.3)

Adverse Events

Time Frame 3 days
Adverse Event Reporting Description Patients with a high likelihood to experience serious adverse effects, have pre-existing conditions which may put the patient at risk for adverse effects, or have contradictions to the medications in this study were not enrolled. The likelihood of serious risks occurring is low since the required doses are not high enough to cause adverse liver damage. Furthermore, the dosage of acetaminophen will be closely monitored.
Arm/Group Title Oral Tylenol Intravenous Tylenol
Arm/Group Description Patient group receiving 1000mg of oral acetaminophen and an intravenous placebo Acetaminophen: Oral acetaminophen, intravenous placebo Patient group receiving 1000mg of intravenous acetaminophen and an oral placebo Acetaminophen: Intravenous acetaminophen, oral placebo
All Cause Mortality
Oral Tylenol Intravenous Tylenol
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/75 (0%) 0/76 (0%)
Serious Adverse Events
Oral Tylenol Intravenous Tylenol
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/75 (0%) 0/76 (0%)
Other (Not Including Serious) Adverse Events
Oral Tylenol Intravenous Tylenol
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/75 (0%) 0/76 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Dr. Jacques Yadeau
Organization Hospital for Special Surgery
Phone (212) 774-2224
Email Yadeauj@hss.edu
Responsible Party:
Hospital for Special Surgery, New York
ClinicalTrials.gov Identifier:
NCT03020966
Other Study ID Numbers:
  • 2016-209
First Posted:
Jan 13, 2017
Last Update Posted:
Aug 10, 2021
Last Verified:
Aug 1, 2021