Clinical trial NCT02839876
Conditions: Osteoarthritis Acetaminophen Arthroplasty, Hip Replacement
Sponsor: Duke University
Start date: 2017-03-14; Completion date: 2018-10-31
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if intravenous acetaminophen is superior to oral acetaminophen when used as part of a multimodal pathway for primary total hip arthroplasty.

Detailed description:
This is a single center, prospective, randomized controlled study. 60 subjects will be recruited (see #6 Recruitment and Compensation below). On the day of surgery, subjects will be randomized to receive either the study intervention (intravenous acetaminophen and placebo tablets) or the control intervention (intravenous saline and active acetaminophen tablets). The Investigational Drug Service will prepare each intervention package, which will include one intravenous and one oral medication dose. Only one of these routes will be active (determined by randomization). Subjects will receive doses of both an intravenous and oral study drug every 6 hours in order to maintain blinding, and will receive a total of 4 doses of each (at 0, 6, 12 and 18 hours). The dose of acetaminophen in all cases will be 1000 mg. The volume of intravenous acetaminophen (and saline) will be 100 mL. The oral dose will consist of two (2) tablets of 500 mg each (or two matching placebo tablets).

All subjects will receive a standardized anesthetic regimen for total hip arthroplasty, as follows:

A) Preoperative phase

Subjects will receive the following preoperative multimodal drugs:

* Pregabalin 75 mg PO
* Celecoxib 200 mg PO
* The interventional drugs, both IV and PO . The time that these drugs are administered will be recorded as time zero. Patients will then receive a spinal anesthetic with 12.5 mg of isobaric bupivacaine. No peripheral nerve blocks will be performed.

B) Intraoperative phase All subjects will be receive propofol infusion beginning at 50 mg/kg/min and titrated to a Richmond Agitation-Sedation Scale score of -1 to -3 (drowsy to moderate sedation). Dexamethasone 10 mg IV and ketamine 0.25 mg/kg IV up to 40 mg total will be administered as part of the standard multimodal regimen. If required, subjects may receive fentanyl 25 mcg IV as needed to treat discomfort. No joint infiltration will be performed by the surgeon.

C) Postoperative phase In the Post-Anesthesia Care Unit (PACU), subjects will have an intravenous patient-controlled analgesia (IVPCA) device connected and loading doses of hydromorphone administered by the PACU nurse as necessary (0.2 mg q 8 min prn).

On the floor, subjects will receive:

* Pregabalin 75 mg PO BID until discharge
* Celecoxib 200 mg PO BID until discharge
* Dexamethasone 10 mg IV x 1 on postoperative day 1 (24 hours after the first dose)
* Intravenous patient-controlled analgesia (IVPCA) with hydromorphone (0.2 mg q 8 min).

The remaining 3 intervention packages (IV and PO) will be administered at 6, 12 and 18 hours following the first dose. At time point 24 hours (i.e. the fifth dose of acetaminophen), all subjects will begin to receive 975 mg of oral acetaminophen, continuing every six hours until discharge.

Arms: arm 1: Subjects receive 1000 mg acetaminophen IV immediately preoperatively, as well as at 6, 12, and 18 hours postoperatively. At the same time points, subjects will receive an oral placebo. arm 2: Subjects receive 1000 mg acetaminophen PO immediately preoperatively, as well as at 6, 12, and 18 hours postoperatively. At the same time points, subjects will receive an intravenous placebo.
Interventions: intervention 1: Intravenous acetaminophen intervention 2: Oral acetaminophen
Intervention descriptions: intervention 1: Subject receives 1 g acetaminophen by the intravenous route every 6 hours for 4 doses beginning in the preoperative holding area. intervention 2: Subject receives 1 g acetaminophen by the oral route every 6 hours for 4 doses beginning in the preoperative holding area.

Protocol documents:
Prot_SAP_000.pdf: 
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1. Protocol Title 
Comparison of Multimodal Analgesic Regimen with Intravenous Acetaminophen 
to Standard Oral Multimodal Therapy in Primary Total Hip Arthroplasty: A 
Randomized Controlled Double Blind Trial 
 
2. Purpose of the study 
To determine the efficacy of intravenous versus oral acetaminophen in reducing 
opioid consumption and pain intensity when used as part of a standardized 
multimodal protocol for primary total hip arthroplasty. 
 
3. Background and Significance 
Multimodal analgesic regimens utilizing a variety of agents have become a 
standard of care for postoperative pain control following a wide variety of surgical 
procedures. With an increasingly greater emphasis on enhanced recovery and 
accelerated return to function, the opioid-sparing effect of these agents has been 
shown to result in improved patient outcomes such as mobilization, bowel 
recovery, satisfaction and hospital length of stay.1,2 Typical multimodal agents 
used for orthopedic surgery include acetaminophen, NSAIDs/COX-2 inhibitors, 
gabapentinoids, ketamine, and dexamethasone. 
 
Many of the agents that are used in these regimens are administered via the oral 
route. However, the oral route is associated with limitations: hospitalized patients 
are frequently nil per os, or unable or unwilling to swallow a large number of 
tablets. In addition, scheduling of oral medications can be difficult, especially 
when patients are asleep. Most importantly, bioavailability of orally administered 
agents that rely on absorption from the small intestine (e.g. acetaminophen) in 
the post-operative setting has been shown to be significantly reduced compared 
to preoperative levels in the same subjects.3 This is likely related to impaired 
gastric transit due to the surgical stress response as well as the effect of opioids 
and/or volatile anesthetics on gut motility. In contrast, a similar drug administered 
via the intravenous route has 100% bioavailability.  
 
While many anesthesiologists and surgeons anecdotally believe that intravenous 
acetaminophen leads to improved patient comfort and satisfaction with reduced 
opioid consumption compared to the oral route, this has not been investigated 
rigorously. This aim of this study is to compare these two routes over the first 24 
hours following total hip arthroplasty. This is a moderately painful procedure for 
which both the surgical approach and the perioperative analgesic regimen is 
highly standardized at Duke University Medical Center. This standardization 
confers an opportunity to answer this research question with minimal 
confounders. Our hypothesis is that the group receiving 4 doses of intravenous 
acetaminophen will consume at least 20% less opioid medication compared to 
the group receiving an equivalent dose of oral acetaminophen. 
 
4. Design and Procedures 


 
This is a single center, prospective, randomized controlled study. 90 
subjects will be recruited (see #6 Recruitment and Compensation below). On the 
day of surgery, subjects will be randomized to receive either the study 
intervention (intravenous acetaminophen and placebo tablets) or the control 
intervention (intravenous saline and active acetaminophen tablets). The 
Investigational Drug Service will prepare each intervention package, which will 
include one intravenous and one oral medication dose. Only one of these routes 
will be active (determined by randomization). Subjects will receive doses of both 
an intravenous and oral study drug every 6 hours in order to maintain blinding, 
and will receive a total of 4 doses of each (at 0, 6, 12 and 18 hours). The dose of 
acetaminophen in all cases will be 1000 mg. The volume of intravenous 
acetaminophen (and saline) will be 100 mL. The oral dose will consist of two (2) 
tablets of 500 mg each (or two matching placebo tablets). 
 
All subjects will receive a standardized anesthetic regimen for total hip 
arthroplasty, as follows: 
A) Preoperative phase 
Subjects will receive the following preoperative multimodal drugs: 
• Pregabalin 75 mg PO 
• Celecoxib 200 mg PO 
• The interventional drugs, both IV and PO 
. The time that these drugs are administered will be recorded as time zero. 
Patients will then receive a spinal anesthetic with 12.5 mg of isobaric 
bupivacaine. No peripheral nerve blocks will be performed. 
 
B) Intraoperative phase 
All subjects will be receiving propofol infusion beginning at 50 mcg/kg/min and 
titrated to a Richmond Agitation-Sedation Scale score of -1 to -3 (drowsy to 
moderate sedation). Dexamethasone 10 mg IV and ketamine 0.25 mg/kg IV up to 
40 mg total will be administered as part of the standard multimodal regimen. If 
required, subjects may receive fentanyl 25 mcg IV as needed to treat discomfort. 
No joint infiltration will be performed by the surgeon. 
 
C) Postoperative phase 
 
In the Post-Anesthesia Care Unit (PACU), subjects will have an intravenous 
patient-controlled analgesia (IVPCA) device connected and loading doses of 
hydromorphone administered by the PACU nurse as necessary (0.2 mg q 8 min 


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prn). 
 
On the floor, subjects will receive: 
• Pregabalin 75 mg PO BID until discharge 
• Celecoxib 200 mg PO BID until discharge 
• Dexamethasone 10 mg IV x 1 on postoperative day 1 (24 hours after the 
first dose) 
• Intravenous patient-controlled analgesia (IVPCA) with hydromorphone (0.2 
mg q 8 min).  
 
The remaining 3 intervention packages (IV and PO) will be administered at 
6, 12 and 18 hours following the first dose. At time point 24 hours (i.e. the fifth 
dose of acetaminophen), all subjects will begin to receive 975 mg of oral 
acetaminophen, continuing every six hours until discharge. 
 
Assessments 
Assessments will be performed by a blinded research assistant. 
i. Opioid consumption. Opioid consumption at 24 hours is the primary 
outcome measure. Data will be drawn from PACU records and from the 
IVPCA infusion pump on a daily basis. Related secondary outcomes will 
include PACU opioid consumption, and at time points 12 hours, 24 hours, 
36 hours and 48 hours. On discharge, patients will be provided with an 
analgesic diary in order to record their pain medications and daily worst 
pain scale out to 30 days postoperatively. 
ii. NRS-11. The 11-point Numeric Rating Scale (0-10) will be used as a 
secondary outcome measure. Two measures will be taken with each 
assessment, one at rest and one with active hip flexion. These will be 
conducted preoperatively, 1 hour after arrival to PACU, and at time points 
8 hr, 24 hr, 36 hr and 48 hr. 
iii. Satisfaction. Overall subject satisfaction will be recorded on postoperative 
day 1 and 2. 
iv. Straight leg raise. Subjects will undergo straight leg raise test in the 
presence of a physical therapist. Maximum range of motion will be 
recorded using a goniometer. (POD 1 and 2) 
v. Heel slide test. This test assesses range of motion. Subjects will be asked 
to bend their knee and hip while sliding their heel along the bed. 
vi. Self-paced walk test. This measure of overall physical performance is 
typically used in patients with osteoarthritis. Subjects are asked to walk 
quickly and safely without overexerting themselves along a hallway to a 


line marked at 20 meters, turn around, and return to the starting point. 
Time required to perform this task is recorded. 
vii. Supine to sit test. This measure of overall physical performance is typically 
used in patients with osteoarthritis. Subjects will be assessed on how easy 
it is, for them, to change from lying down to sitting on the side of the bed.  
Subjects may use assistance, if needed.  The assessment will test overall 
function and strength of hip, lower limbs, and trunk. 
 
 
Subjects will be assessed daily for opioid-related adverse events including 
the incidence of respiratory desaturation events overnight, nausea, vomiting, 
ileus, orthostasis and pruritis. 
 
Hospital costs including pharmacy-related costs, costs due to opioid-related 
adverse events, the cost associated with nursing interventions and drugs to treat 
opioid-related adverse events, and overall hospital admission costs will be 
calculated. Hospital length of stay will be measured by both raw length of stay in 
hours and by time required to achieve discharge readiness. This is defined by the 
presence of 3 criteria: a pain score of 3 or less with ambulation, no intravenous 
opioids required in the preceding 6 hours, and the ability to perform self-care (go 
to the toilet, dress, and shower).  
 
5. Selection of subjects 
Criteria for inclusion: 
• Patients scheduled for elective, primary total hip replacement for 
osteoarthritic disease 
• Age 56-85 years 
• American Society of Anesthesiologists (ASA) Physical Class I-III 
• Weight ≥50 kg 
• BMI 18-40 kg/m2 
 
Criteria for exclusion: 
• Inability to consent 
• Inability to speak English 
• Pregnancy 
• Weight <50 kg 
• Revision hip replacement 
• Emergency surgery 
• Contraindications to regional blockade: coagulopathy or bleeding 
diathesis, local infection, allergy to local anesthetics 
• Allergies/intolerances/contraindications to any of the multimodal agents 
(acetaminophen, pregabalin, celecoxib, ketamine or dexamethasone) 
• Chronic pain from a separate source other than operative hip 


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• Daily opioid equivalent use of 30 mg of morphine or greater at time of 
consent 
• History of heart failure 
• History of drug or alcohol abuse 
• Rheumatoid arthritis 
• Uncontrolled anxiety, schizophrenia or other psychiatric disorder that, in 
the opinion of the investigator, may interfere with the study assessments 
of compliance 
• History of alcoholism, chronic malnutrition, renal or liver impairment 
• Hypersensitivity to acetaminophen or any of its excipients 
 
6. Subject recruitment and compensation 
 
Potential subjects (see inclusion criteria above) will be identified and 
screened in the Pre-Anesthetic Clinic by a research assistant. Only patients 
scheduled for primary total hip arthroplasty will be eligible for this study. There 
will be no compensation for subjects for their participation.  
In the event that a potential subject is not feasible for in-person approach to 
occur, the subject will be introduced to research by a provider. The research staff 
will follow-up with a phone call using the IRB approved phone script. Subjects will 
be asked for permission for their electronic records to be viewed by research 
staff for inclusion/ exclusion criteria. If the subject qualifies and is interested in 
participating, research staff will meet the subject at the next visit to Duke for a 
formal consent. If the patient is not interested in the study, or does not meet 
inclusion/exclusion criteria, then information collected from the patient will be 
destroyed. 
 
7. Consent process 
Subjects permission to be approached for research will be obtained by the primary care 
team involved with the patient.  The consent process will be conducted by the research 
personnel or one of the physicians involved in the study. The consent process will take 
place in the pre-operative screening or the surgical clinics. Throughout the consent 
process, measures will be taken to maintain privacy, such as by conducting face-to-face 
conversations in private rooms. As much time as necessary will be spent with each 
potential subject to sufficiently explain and answer all questions, and address all concerns 
they may have in regard to the study and/or consent process.  Under HIPAA waiver, the 
study team will identify potential subjects from clinic schedules, OR schedules and 
Maestro Care. 
 
8. Subject’s Capacity to Give Legally Effective Consent 
Subjects who do not have the capacity to give legal consent will not be 
approached for participation in this study. 
 


9. Study interventions 
See #4. 
 
10. Risk/benefit assessment 
Risk to the subject 
Risks of the study intervention are minimal. Both IV and PO acetaminophen are 
FDA approved for treatment of pain in doses up to 4000 mg/day. Acetaminophen 
is a standard drug used in our multimodal pathway for total joint replacement. 
Subjects will receive an additional 400 ml of fluid (either acetaminophen or 
saline) over the first 24 hours, which may result in peripheral or pulmonary 
edema. There may be intolerances to excipients in either the IV acetaminophen 
preparation or the placebo tablets. 
 
Benefits to the subject 
There are no routine benefits to the subject for participation.  
 
11. Costs 
There will be no costs to the subject for participation in the study. Subjects will 
not be compensated for their participation. 
 
12. Data analysis and statistical considerations 
 
We will use descriptive statistics (mean (SD) or frequency (%)) and group 
comparisons via Wilcoxon rank sum or fisher exact tests to measure differences 
between groups in opioid consumption, pain scores with rest and activity, and 
other secondary outcome measures.  
 
Sample Size Justification 
 
Our typical mean opioid consumption following primary total hip arthroplasty in 
the first 24 hours is approximately 35 morphine equivalents. To address the 
primary hypothesis, that the opioid consumption in the intravenous group will be 
reduced by 20% compared to the oral group, we would need 27 subjects per 
group (80% power and alpha=0.05), or 54 total. To allow for participant drop-out, 
we will enroll a total of 90 subjects. 
 
13. Data & Safety Monitoring 
In accordance with federal regulations the PI will monitor for, review, and 
promptly report to the IRB, appropriate institutional officials, sponsor, 
coordinating center and the appropriate regulatory agency head all unanticipated 
problems involving risks to subjects or others that occur in the course of a 
subject’s participation in a research study (45 CFR 46.103(b)(5)(i) and 21 CFR 


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56.108(b)(1)), all AE reports will be reported per the DUHS IRB policies. PI will 
be monitoring all AEs and submitting reports to the IRB per DUHS IRB policy. 
 
 
Privacy, Data Storage and Confidentiality 
Potential subjects and their families will be approached in private rooms. Any 
guests not involved in the consent process will be asked to leave the room during 
any communications, unless the patient allows them to be present.  Data will be 
collected and stored in Redcap.  Efforts to maintain subject confidentiality will 
include assignment of following Federal Privacy Regulations which provide 
safeguards for privacy, security, and authorized access. Except when required by 
law, subjects will not be identified by name, social security number, address, 
telephone number, or any other direct personal identifier in study records 
disclosed outside of Duke University Health System (DUHS).  Subjects will be 
not be revealed in any reports or publications resulting from this study.  For 
records disclosed outside of DUHS, subjects will be assigned a unique code 
number. The paper/electronic data will be stored as per the RDSP. 
 
References 
1. Parvizi J, Miller AG, Gandhi K: Multimodal pain management after total joint 
arthroplasty. J Bone Joint Surg Am 2011; 93:1075–84 
2. Peters CL, Shirley B, Erickson J: The effect of a new multimodal perioperative 
anesthetic regimen on postoperative pain, side effects, rehabilitation, and 
length of hospital stay after total joint arthroplasty. J Arthroplasty 2006; 
21:132–8 
3. Petring OU, Dawson PJ, Blake DW, Jones DJ, Bjorksten AR, Libreri FC, 
Leadbeater M: Normal postoperative gastric emptying after orthopaedic 
surgery with spinal anaesthesia and i.m. ketorolac as the first postoperative 
analgesic. Br J Anaesth 1995; 74:257–60