Clinical trial NCT03271151
Conditions: Joint Disease Pain, Acute Pain, Chronic
Sponsor: Hospital for Special Surgery, New York
Start date: 2017-09-28; Completion date: 2021-02-19
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Post-discharge pain after total knee arthroplasty remains problematic; many patients have excessive pain at the 2 week time point (and often thereafter). Reduction in opioid use has become a national goal, due to the 'epidemic' in opioid misuse.

In addition to enrolling non-opioid users, we will enroll up to 15 chronic opioid users.

Detailed description:

Arms: arm 1: Epidural analgesia after knee arthroplasty is not as prevalent at HSS as formerly, in large part due to the rise of local infiltration analgesia. Studies using epidural analgesia may also lack generalizability given the infrequent use of epidural analgesia at other institutions. For these reasons, we plan to use adductor canal nerve blockade + local infiltration analgesia for management of immediate postoperative pain. Patients will receive spinal anesthesia as the primary anesthetic. It is particularly important to study duloxetine ("Cymbalta") in the context of local infiltration analgesia, as patients receiving local infiltration analgesia receive increased doses of opioids, compared to patients receiving epidural analgesia. arm 2: Placebo to compare pain scores and opioid use againts Duloxetine
Interventions: intervention 1: Cymbalta intervention 2: Placebo
Intervention descriptions: intervention 1: Duloxetine ("Cymbalta") is a serotonin and norepinephrine dual reuptake inhibitor (SNRI) that is an effective treatment for painful diabetic neuropathy. It is approved for major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, and chronic musculoskeletal pain intervention 2: Placebo to compare outcomes against Duloxetine

Protocol documents:
Prot_SAP_000.pdf: 
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Effect of duloxetine on opioid use after total knee 
arthroplasty. A 
Double-blinded Randomized Control Trial 
 
FUNDER: 
Department of Anesthesiology 
PROTOCOL NO.: 
2017-0655 
VERSION & DATE: 
6/27/2021 
 
This document contains the confidential information of the Hospital for Special Surgery.  It is provided to you and your company’s personnel for 
review.  Your acceptance of this document constitutes an agreement that you will not disclose the information contained herein to others without 
the prior written consent of the Hospital for Special Surgery.  No other use or reproduction is authorized by Hospital for Special Surgery, nor does 
the Hospital for Special Surgery assume any responsibility for unauthorized use of this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ...................................................................................... 2 
PROTOCOL SYNOPSIS...................................................................................... 3 
1.0 
INTRODUCTION ................................................................................. 4 
2.0 
OBJECTIVE(S) OF CLINICAL STUDY ............................................... 5 
3.0 
STUDY HYPOTHESES ....................................................................... 5 
4.0 
STUDY DESIGN .................................................................................. 5 
4.1 
Endpoints ................................................................................................ 5 
4.1.1 
Primary Endpoint ............................................................................... 5 
4.1.2 
Secondary Endpoints ........................................................................ 5 
4.2 
Study Sites ............................................................................................. 6 
5.0 
STUDY POPULATION ........................................................................ 6 
5.1 
Number of Subjects ................................................................................ 6 
5.2 
Inclusion Criteria ..................................................................................... 6 
5.3 
Exclusion Criteria .................................................................................... 7 
6.0 
PROCEDURES ................................................................................... 7 
6.1 
Intraoperative Protocol............................................................................ 7 
6.2 
Data Collection ....................................................................................... 8 
7.0 
STATISTICAL ANALYSIS .................................................................. 9 
8.0 
ADVERSE EVENT ASSESSMENT ....................................................10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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PROTOCOL SYNOPSIS 
Protocol Title: 
Intraoperative Acupuncture for Low-Dose Opioid Total Knee 
Replacement: An Observational Prospective Cohort Study 
Protocol Number: 
2017-0655 
Protocol Date: 
06/27/2021 
Sponsor: 
Department of Anesthesiology 
Principal Investigator: 
Jacques T. YaDeau, MD, PhD 
Objective: 
We will investigate the effect of duloxetine (“Cymbalta”), a 
serotonin and norepinephrine reuptake inhibitor, on opioid use 
and pain after total knee arthroplasties (TKA). We will determine 
whether duloxetine (60 mg daily for 15 days) reduces opioid 
intake and pain scores 2 weeks after TKA. 
Study Design: 
Prospective Cohort Study 
Enrollment: 
160 
Subject Criteria: 
 
1. ASA of 1,2,3 
2. Patients with osteoarthritis scheduled for primary 
tricompartmental total knee arthroplasty with a participating 
surgeon 
3. Age 25 to 75 years 
4. Planned use of regional anesthesia 
5. Ability to follow study protocol 
6. English speaking (Primary outcome obtained via telephone 
call and secondary outcomes include questionnaires  
validated in English only) 
Data Collection: 
Sources: EPIC, Medical Records, and Patient Reported. 
Variables: Name, DOB, BMI, Race, Gender, Ethnicity, ASA, 
Procedure, Anesthesia Used, Tourniquet time and pressure, 
Opioid Use, NRS Pain Scores (movement, rest), Fibromyalgia 
SSI, Michigan Body Map, Pre-op Medication Use, 
Catastrophizing, BPI (worst, average), PROMIS, QOR9, 
ORSDS, Other side effects, Compliance with study drug, Pain 
Management Satisfaction, Blinding Assessment, WOMAC/ SF 
12/ UCLA Activity score/ Knee Society Score 
 
Statistical Analysis: 
 
Proposed analysis:  Non-inferiority and superiority tests 
(one-sided) 
 
Alpha level:  0.0042 to 0.025 
 
Beta or power level:  0.8 
 
 
 
 


 
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1.0 INTRODUCTION 
 
Duloxetine (“Cymbalta”) is a serotonin and norepinephrine dual reuptake inhibitor (SNRI) 
that is an effective treatment for painful diabetic neuropathy.  It is approved for major 
depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathy, 
fibromyalgia, and chronic musculoskeletal pain (http://pi.lilly.com/us/cymbalta-pi.pdf; 
accessed 4/18/2017).  
 
Ho et al (“Duloxetine reduces morphine requirements after knee replacement surgery” Br 
J Anaesth 2010) compared duloxetine, 60 mg, to placebo.  Duloxetine was given 2 h prior to 
surgery, as well as POD1.  Patients received general anesthesia, IV morphine PCA, and no 
peripheral nerve block.  Morphine consumption was reduced (19.5 +/- 14.5 mg; mean, SD 
vs. 30.3 +/- 18.1 mg).  Pain scores and side effects were not different. 
 
From the Cochrane review "Duloxetine for treating painful neuropathy or chronic pain", 
Lunn, Hughes, Wiffen: "The action of drugs such as duloxetine is independent of their 
effects on depression.  Onset of benefit occurs within days, earlier and at lower doses than 
in depression.  Furthermore, they have similar effects on pain in depressed and non-
depressed people.”  
 
The Anesthesia/ARJR research collaboration recently published results of a randomized, 
placebo-controlled trial of a 14-day course of duloxetine for total knee arthroplasty patients 
(YaDeau et al Anesthesiology 2016; 125).  Patients in this study received multimodal 
analgesia with epidural analgesia, adductor canal nerve blockade, meloxicam, and 
oxycodone/acetaminophen.  There was no effect of duloxetine on pain (the primary 
outcome), but there were two interesting secondary outcomes; reduced opioid intake and 
reduced nausea.  To quote from the paper; “Given the negative result for the primary 
outcome, and the paucity of studies about perioperative analgesic use of duloxetine, it is 
premature to recommend routine use of duloxetine for analgesia after TKA.  Subsequent 
studies could use multiple hypothesis testing.”  A related editorial called for ‘more research 
into this area’ (Jacobs MB and Cohen SP.  “Duloxetine for subacute pain management after 
total knee arthroplasty.  Should we write it off or reevaluate?”  Anesthesiology 2016;125:)  
 
Nationally, postoperative analgesia with combined epidural infusions and peripheral 
nerve block is uncommon, but the use of local infiltration analgesia (also termed peri-
articular injection) with adductor canal block is recommended by experts, appears to be 
gaining in popularity, and shows benefits compared to either technique alone (Sawhney 
Anesth Analg 2016; 122:2040-6; Goytizolo abstract 2017 ASRA meeting). 
 
   


 
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2.0 OBJECTIVE(S) OF CLINICAL STUDY 
 
 
There is strong justification for additional duloxetine studies with a multiple 
hypothesis testing design. As with the previous pregabalin and duloxetine studies, this 
study’s outcomes would involve following patients for pain and opioid use through POD14.  
Pain that occurs in the time period between acute and chronic pain, such as pain at 2 
weeks, can be termed subacute pain.  The previous duloxetine trial found both group had 
similar pain scores with ambulation on POD14 of 3.8 [2.3] (mean [SD]).  Excessive pain can 
cause psychological distress and impair participation in physical therapy.  The duloxetine 
group used less opioid and had less nausea.   This study will use both opioid administration 
and pain as primary outcomes.  
 
Epidural analgesia after knee arthroplasty is not as prevalent at HSS as formerly, in 
large part due to the rise of local infiltration analgesia.  Studies using epidural analgesia may 
also lack generalizability given the infrequent use of epidural analgesia at other institutions.  
For these reasons, we plan to use adductor canal nerve blockade + local infiltration 
analgesia for management of immediate postoperative pain.   Patients will receive spinal 
anesthesia as the primary anesthetic. It is particularly important to study duloxetine in the 
context of local infiltration analgesia, as patients receiving local infiltration analgesia receive 
increased doses of opioids, compared to patients receiving epidural analgesia.   
3.0  STUDY HYPOTHESES 
 
Administration of duloxetine to knee arthroplasty patients (compared to placebo) will reduce 
opioid use and pain scores during the 2 weeks after surgery. 
4.0 STUDY DESIGN 
4.1 
Endpoints 
4.1.1 Primary Outcomes 
i. 
Opioid use (cumulative oral morphine equivalents DOS- POD14) 
ii. 
Pain (NRS pain with movement on POD1, POD 2, POD14) 
 
4.1.2 Secondary Endpoints 
1. Pain Phenotype.   Some (i., ii., iii, marked POD0, are preoperative screening tools, in 
order to allow secondary, subgroup analyses).  Others will be repeated, and serve both 
as preoperative screening tools and secondary outcomes. 
i. 2011 Survey Criteria for Fibromyalgia (POD0) 
a. Fibromyalgia Symptom Severity Index 
b. Michigan Body Map 
ii. Basic demographics (POD0) 
A.  Age, BMI, gender, race/ethnicity, relationship status, education, 
disability/worker’s comp/lawsuit, occupation 
B.  Preoperative pain medication use- medication names and doses 


 
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iii. Catastrophizing (8 questions, modified) (POD0) 
iv. BPI pain intensity questions over the last week (6 questions) (POD0, POD14, 3 
months) 
a. worst, average 
v. WOMAC (test of orthopedic function) (orthopedic intake, 6 weeks, 3 months) 
vi. PROMIS depression (short form 4A: 4 items) (POD0, POD14) 
vii. PROMIS anxiety instrument (short form 4A: 4 items) (POD0, POD14) 
viii. Life satisfaction (1-10 Likert) (POD0, POD14) 
ix. Neuropathic pain (PainDETECT) (POD0, 3 months) 
x. Quality of Recovery Score (QOR9) (POD0, POD2) 
xi. PROMIS measure of sleep (Short form: 8 questions) (POD0, POD14) 
2. NRS score at rest at 2 weeks after TKA (POD0, POD1, POD2, POD14) 
3. Analgesic use (POD0-14, 6 weeks, 3 months).  A pain and analgesic diary will be 
provided for POD0-14. 
4. Side effects: Opioid-Related Symptom Distress score (POD 1, POD 14) 
5. Satisfaction with pain management (POD 14) 
6. Patient compliance with study drug administration (POD14) 
7. Blinding assessment; Bang question (POD14) 
8. Orthopedic outcomes (baseline, 6 weeks and 3 months, at routine postoperative visits) 
Knee society Knee Score (Pain and Function components),  
SF 12, WOMAC, UCLA activity score,Knee Score 
(http://www.orthopaedicscore.com/scorepages/knee_society_score.html) 
Knee Society Score Function 
(http://www.orthopaedicscore.com/scorepages/knee_society_score_function.html) 
o [the choice of orthopedic outcomes is based on standard practice for 
ARJR orthopedists) 
 
4.2 
Study Sites 
This study will take place at the main campus of the Hospital for Special Surgery (HSS). 
5.0 STUDY POPULATION 
5.1 
Number of Subjects 
160 
5.2 
Inclusion Criteria 
Subjects of either gender will be included if: 
1. ASA of 1,2,3 
2. Patients with osteoarthritis scheduled for primary tricompartmental total knee 
arthroplasty with a participating surgeon 
3. Age 25 to 75 years 
4. Planned use of regional anesthesia 
5. Ability to follow study protocol 
6. English speaking (Primary outcome obtained via telephone call and secondary 
outcomes include questionnaires validated in English only)ASA of 1 or 2 


 
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5.3 
Exclusion Criteria 
Subjects will be excluded from the study if: 
 
Use of duloxetine or other SNRIs, SSRIs,  MAOIs, Tricyclic antidepressants, triptans 
(sumatriptan, rizatriptan, naratriptan, eletriptan, almotriptan, frovatriptan), lithium, 
buspirone, St. John’s Wort 
 
Hepatic insufficiency 
o Hepatoxicity is reported as a side effect of duloxetine. “Median time to detection 
of transaminase elevation was about two months” (package insert 5.2 
 
Renal insufficiency (ESRD, HD, estimated creatinine clearance < 30 ml/min) 
o Severe CRI may impair duloxetine clearance 
o CLcr=[(140-age (years)] x weight (kg)x0.85 (for female patients)/[72xserum 
creatinine (mg/dL)] 
 
Patients younger than 25 years old and older than 80 
 
Patients intending to receive general anesthesia 
 
Allergy or intolerance to one of the study medications 
 
Patients with an ASA of IV  
 
Chronic gabapentin/pregabalin use (regular use for longer than 3 months) 
 
Chronic opioid use (taking opioids for longer than 3 months) 
 
Patients with major prior ipsilateral open knee surgery. 
6.0 PROCEDURES 
6.1 
Intraoperative Protocol 
Patients would be randomized to duloxetine (60 mg PO daily for 15 days) or placebo. 
The first dose will be given prior to surgery.  
Preferred Anesthetic/Analgesic protocol: All patients would receive a spinal epidural 
anesthetic (Mepivacaine, 45-60 mg). Epidural bolus 2% lidocaine as needed. Patients will 
be given (IV) 4mg dexamethasone, 4 mg odanestron, 20 mg famotidine, 15 mg 
ketorolac.30-50 mg Ketamine. Up to 5mg Midazolam for sedation. Propofol given as 
needed. No PCA. No intrathecal opioids. 
Adductor canal nerve block (15 cc bupivacaine, 0.25% with 2mg PF-dexamethasone). 
Periarticular injection: one deep injection prior to cementation and then a second more 
superficial injection prior to closure. The deep injection will consist of bupivacaine 0.25% 
with epinephrine, 30 cc; methylprednisolone, 40 mg/ml, 1 ml; cefazolin, 500 mg in 10 ml; 
normal saline, 22cc. The superficial injection will be 20 ml 0.25% bupivacaine. The 
methylprednisolone can be omitted at the surgeon's discretion if necessary for the patient. 
IPACK technique: 25 cc 0.25% bupivacaine 
Postoperative ketorolac (15 mg IV q 8hr, 4 doses) with subsequent oral meloxicam 
(7.5-15 mg PO daily). Oxycodone (5/10/15 mg PO q 3 hr PRN), Acetaminophen (1000 mg 
IV q 6 hr for 4 doses for one day, then 1000 mg PO q 6hr) - PO dose can be adjusted for 
weight if asked by pharmacy.  


 
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Opioid-tolerant patients (enrolled in the pilot study) may receive their customary 
analgesic medications. 
Patients in either limb of the study may have their pain medications adjusted by the 
pain management team as clinically indicated.  
 
6.2 
Data Collection 
The following data will be collected: 
1. Day of Surgery: from chart and interview 
a. Patient Demographics: name, age, race/ethnicity, gender, BMI, relationship 
status, education, disability/worker's comp/lawsuit, occupational status 
b. Preoperative phenotyping questionnaires 
i. 
Preoperative opioid/medication use 
ii. 
Fibromyalgia symptom severity index 
iii. 
Michigan body map 
iv. 
NRS pain scores (at rest and with movement) 
v. 
Catastrophizing (modified) 
vi. 
BPI pain intensity 
vii. 
PROMIS depression, and anxiety 
viii. 
QOR 9 
ix. 
Pain DETECT 
x. 
KOOS Jr, VAS/NRS (from surgeon's notes from pre-op visit) 
2. Post-Op Day 1: from chart and interview 
a. Opioid and Analgesic use 
b. Opioid related symptom distress score (ORSDS) 
c. NRS score 
3. Post-Op Day 2: from chart and interview 
a. Opioid and Analgesic use 
b. NRS score 
c. QOR9 
d. Compliance encouragement meeting: 
i. 
At time of discharge the RA will obtain the study medication from 
nurse and give it to the patient.  
ii. 
RA will review the medication diary, explain how to continue taking the 
study medication at home and/or rehab and discuss follow-up phones 
calls after discharge 
4. Post-op Day 7: via telephone 
a. Study drug compliance 
b. Opioid and analgesic use 
5. Post-op Day 14: via telephone 
a. Opioid and Analgesic use 
b. NRS score 


 
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c. BPI intensity (worst, average) 
d. PROMIS depression, and anxiety 
e. ORSDS 
f. Pain management satisfaction 
g. Study drug compliance 
h. Blinding assessment 
6. Post-op 6 weeks: via telephone interview and chart 
a. KOOS Jr, VAS/NRS (surgeon's visit) 
b. Opioid and Analgesic use 
7. Post-op Day 90: via telephone interview and chart 
a. PainDETECT 
b. BPI intensity  
c. VAS/NRS,KOOS Jr (surgeon's visit) 
 
7.0 STATISTICAL ANALYSIS 
1. Proposed analysis:  Non-inferiority and superiority tests (one-sided) 
2. Alpha level:  0.0042 to 0.025 
3. Beta or power level:  0.8 
4. Primary outcome variable estimate (mean +/- s.d. for continuous outcome, 
frequency/percentage for categorical variable):   See below 
5. Number of groups being compared (use 1 for paired analysis within the same 
subjects):  2 
6. Effect size or change expected between groups:   See below 
7. Resulting number per group: 66 
8. Total sample size required:  132 + 20% to account for attrition = 160 
 
The primary analysis will be a joint hypothesis test, where duloxetine will be 
recommended if (and only if) it is found to be (A) non-inferior to placebo in cumulative 
opioid consumption POD 0 – POD 14 and non-inferior to placebo in NRS pain score on 
POD 1, POD 2, and POD 14 and (B) superior to placebo in either cumulative opioid 
consumption or NRS pain score at at least one timepoint. Cumulative opioid use will be 
assessed for noninferiority and superiority using two-sample t-tests. NRS pain score will 
be assessed for noninferiority and superiority using linear mixed effects modeling. The 
model will be adjusted for baseline NRS score, and a group by time interaction term will 
be included in the model regardless of P value (given interest of the PI in obtaining 
estimates for each timepoint separately). 
Inequality hypothesis tests will be performed for all secondary outcomes. Continuous 
secondary outcomes measured at a single timepoint will be analyzed using two-
sample t-tests or Wilcoxon rank-sum tests, depending upon the distribution of the data. 
Categorical secondary outcomes measured at a single time point will be compared 


 
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between groups using χ2 or Fisher’s exact tests, as appropriate. Outcomes measured at 
multiple time points will be analyzed using mixed effects modeling with a group by time 
interaction term included in each model regardless of P value. 
Balance on demographics and baseline characteristics will be assessed by 
calculating standardized differences (difference in means or proportions divided by the 
pooled standard deviation) between groups.  Balance will be assessed using two 
thresholds: (1) 1.96 x (2/80)1/2 = 0.31 and (2) 0.20 (Austin 2009). 
The success of blinding in each group will be assessed using the Bang Blinding 
Index (Bang 2010). 
All analyses will be performed on an intention-to-treat basis. 
  
References: 
1. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates 
between treatment groups in propensity-score matched samples. Stat Med 2009; 28: 
3083-107. 
2. Bang H, Flaherty SP, Kolahi J, Park J. Blinding assessment in clinical trials: A review 
of statistical methods and a proposal of blinding assessment protocol. Clin Res 
Regul Aff 2010; 27:42-51 
 
8.0 ADVERSE EVENT ASSESSMENT 
All Adverse Events (AEs) will be reported in the final study report.