## Protocol Section
### Identification Module
**NCT ID:** NCT06423716

**Acronym:** RELIFE

**Brief Title:** Effect of peRiopErative duLoxetIne Administration on Opioid Consumption Following Total kneE Arthroplasty (RELIFE)

**Official Title:** Effect of Perioperative Duloxetine Administration on Opioid Consumption Following Total Knee Arthroplasty

#### Organization Study ID Info
**ID:** SBK 6156
#### Organization
**Class:** OTHER
**Full Name:** Sunnybrook Health Sciences Centre
### Status Module
#### Completion Date
**Date:** 2026-12-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-21

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-16

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-07-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-05-15

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-21
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-16
**Study First Submit QC Date:** 2024-05-16
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Sunnybrook Health Sciences Centre

#### Responsible Party

**Investigator Affiliation:** Sunnybrook Health Sciences Centre

**Investigator Full Name:** Dr. Colin McCartney

**Investigator Title:** Anesthesiologist, Pain Physician

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** Knee replacement surgery for osteoarthritis is a commonly performed procedure in Canada with 75,000 of these surgeries performed each year. Success rate for knee replacement surgery is high but more than 20% of patients are still dissatisfied mainly due to reports of ongoing pain. Pain control following knee surgery is important in order to allow patients to engage in recovery and rehabilitation. The current standard of pain management after surgery centers around the use of opioids which is a concerning practice as highlighted by the opioid epidemic. Duloxetine is an antidepressant that has pain relieving properties and it has been studied in patients undergoing knee replacement surgery. Studies to date have not been designed optimally to demonstrate the full effects of opioid dose reduction and the use of duloxetine as a medication following knee replacement surgery. This research study seeks to start duloxetine before surgery, at the recommended therapeutic dose, and for the duration of the early rehabilitation period. If the study is successful, this low-cost medication can improve satisfaction rates and change the standard way the pain management is typically carried out for patients undergoing the knee replacement surgery.

**Detailed Description:** The use of duloxetine around the time of total knee arthroplasty has emerged as a promising intervention to help with pain management after surgery and in particular as an opioid sparing agent. Duloxetine is an antidepressant with serotonin and norepinephrine reuptake inhibition effects that also independently exerts an analgesic effect. Duloxetine is Health Canada approved for several indications including pain arising from osteoarthritis of the knee. Pain inhibition action of duloxetine is believed to be a result of potentiation of descending inhibitory pain pathways within the central nervous system. Existing studies examining duloxetine use at the time of surgery has demonstrated statistically significant but less clinically meaningful impacts on opioid sparing and pain reduction. The deficiencies in study design of existing studies have either underdosed duloxetine (30mg instead of the recommended 60mg) and/or utilized non-standard duration of therapy (started too late, continued for only 2 weeks). Our study seeks to definitively address whether duloxetine administered 2 weeks preoperatively at 60mg once daily, in addition to standard analgesic practice, will decrease opioid consumption at 1 week postoperatively.

Prospective, randomized, blinded (investigators, clinicians, participant, data collectors/analysts) trial.

Primary Outcome

•Cumulative opioid consumption at 1 week post-operatively.

Secondary Outcomes

* Nausea/vomiting
* Discharged according to plan (ie. same day went home same day, or day 1 went home day 1) and if not, reason
* Pain at rest and with activity (NRS-11) at 1, 6, and 12 weeks and 4.5 months
* Additional analgesic use (anti-neuropathic medications, family physician or orthopaedic surgeon opioid prescription)
* Physical function (BPI, Oxford Knee Scale, range of motion
* Emotional function (GAD-7, PHQ-9 at 6 weeks and 12 weeks)
* Number of rehabilitation sessions attended (in-person or virtual)
* Patient satisfaction (PGIC) at 1, 6, and 12 weeks after medication initiation
* Presence of neuropathic pain (S-LANSS) at 6 and 12 weeks
* Presence of chronic post-surgical pain at 12 weeks (based on NRS \&gt; 0)
* Adverse events relating to study medication (dizziness, drowsiness, nausea, vomiting, insomnia)
* Intervention adherence

Interventional medication supply: Duloxetine 60mg OD for 2 weeks preoperatively then 60mg OD for 6 weeks post-surgery.

Standard of care: On the day of surgery, participants will be premedicated with acetaminophen (1000mg) and celecoxib (400mg). Per standard of care, all participants will receive an ultrasound guided adductor canal catheter (bolus ropivacaine 0.5% 10ml). This will be followed by a spinal anesthetic with mepivacaine 2% 3ml and 10mcg of fentanyl. Intraoperative sedation will consist of a propofol infusion titrated to SAS (Sedation Agitation Scale) of 3-4.

All TKAs will be performed using a standard medial parapatellar approach and the same cemented total knee system. Tourniquet will be applied and used as part of the case. Periarticular local infiltration will be used per standard practice using ropivacaine 0.2% with 1:200 000 epinephrine up to 50ml.

Post-surgery: Participants will be evaluated on POD-0, POD-1 and POD-2 while in hospital or at home through phone call and at 1, 6, and 12 weeks.

Participant satisfaction will be assessed using the Patients' Global Impression of Change (PGIC) Scale at 1, 6, and 12 weeks post-surgery.

Pain scores and opioid consumption will be recorded daily for 1 week post-operatively.

Patients will record their pain and opioid consumption on a weekly basis until week 12 post-operatively.

Physical function, emotional function, and presence of neuropathic pain will be collected at 6 and 12 weeks.

Active and passive range of motion will be assessed by orthopedic surgeon using goniometer at 6 (+/-1 week) and 12 (+/-1 week) weeks and 4.5 month (+/-2 weeks) postoperatively.

Group 1: Intervention Duloxetine 60mg OD for 2 weeks preoperatively then 60mg OD for 6 weeks post-surgery.

Group 2: Control Placebo OD for 2 weeks preoperatively then OD for 6 weeks post-surgery.

Both Groups:

On the day of surgery, standard post-anesthetic care unit (PACU) orderset will be employed and the postoperative analgesic regimen will follow standard of care including: acetaminophen 1g QID, celecoxib 200mg BID, and hydromorphone 1-3mg PO q2h PRN.

* Nurse administered IV hydromorphone push (0.3mg) followed by IV PCA hydromorphone if pain is not controlled
* ACB catheter ropivacaine 0.15% at 5cc/hr, stopped at 6:00am on POD-1

Participants will be discharged on POD-0, POD-1 or POD-2 with acetaminophen 1000mg TID, celecoxib 100mg BID, and hydromorphone (2-4mg PO q4h PRN). Patients for same-day discharge (POD-0) will have ACB catheter bolus of 10cc of 0.5% ropivacaine prior to removal.

### Conditions Module

**Conditions:**

- Knee Osteoarthritis

**Keywords:**

- total knee arthroplasty

- duloxetine

- postoperative pain

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

**Intervention Model Description:** Group 1: Intervention Duloxetine 60mg OD for 2 weeks preoperatively then 60mg OD for 6 weeks post-surgery.

Group 2: Control Placebo OD for 2 weeks preoperatively then OD for 6 weeks post-surgery.

##### Masking Info

**Masking:** QUADRUPLE

**Who Masked:**

- PARTICIPANT

- CARE_PROVIDER

- INVESTIGATOR

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 150

**Type:** ESTIMATED

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Duloxetine 60mg OD for 2 weeks preoperatively then 60mg OD for 6 weeks post-surgery.

**Intervention Names:**

- Drug: Duloxetine

**Label:** Intervention

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Placebo OD for 2 weeks preoperatively then OD for 6 weeks post-surgery.

**Intervention Names:**

- Drug: Placebo

**Label:** Control

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Intervention

**Description:** 60mg duloxetine given 2 weeks prior to total knee arthroplasty and continued for 6 weeks after surgery.

**Name:** Duloxetine

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- Control

**Description:** Placebo given 2 weeks prior to total knee arthroplasty and continued for 6 weeks after surgery.

**Name:** Placebo

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** Cumulative opioid consumption at 1 week post-operatively

**Measure:** Opioid consumption

**Time Frame:** Cumulative opioid consumption at 1 week post-operatively

#### Secondary Outcomes

**Description:** Presence of nausea or vomiting

**Measure:** Nausea/vomiting

**Time Frame:** 8 weeks (i.e., duration of study)

**Description:** Maximum pain score on 0-10 Likert Scale (NRS)

**Measure:** Pain at rest and with activity

**Time Frame:** 10-14 days preoperative; 1,6,12 weeks and 4.5 months

**Description:** Anti-neuropathic medications

**Measure:** Additional analgesic use

**Time Frame:** 8 weeks (i.e., duration of study)

**Description:** Family physician or orthopaedic surgeon opioid prescription

**Measure:** Additional analgesic use: opioid prescription

**Time Frame:** 8 weeks (i.e., duration of study)

**Description:** Brief Pain Inventory

**Measure:** Physical function measured by BPI

**Time Frame:** Preoperative, 6, 12 weeks and 4.5 months

**Description:** Oxford Knee Scale

**Measure:** Physical function measured by Oxford Knee Scale

**Time Frame:** Preoperative, 6, 12 weeks and 4.5 months

**Measure:** Range of motion: Physical function

**Time Frame:** Preoperative, 6, 12 weeks and 4.5 months

**Description:** GAD-7

**Measure:** Emotional function measured by GAD-7

**Time Frame:** Preoperative, 6, 12 weeks and 4.5 months

**Description:** PHQ-9

**Measure:** Emotional function measured by PHQ-9

**Time Frame:** Preoperative, 6, 12 weeks and 4.5 months

**Description:** Patient global impression of change (PGIC)

**Measure:** Patient satisfaction

**Time Frame:** 1, 6, and 12 weeks after surgery

**Description:** Presence of neuropathic pain (S-LANSS)

**Measure:** Neuropathic pain

**Time Frame:** 6 and 12 weeks post-surgery

**Description:** Presence of chronic post-surgical pain (based on NRS \> 0)

**Measure:** Chronic post-surgical pain

**Time Frame:** 12 weeks post-surgery

**Description:** Adverse events relating to study medication (dizziness, drowsiness, nausea, vomiting, insomnia)

**Measure:** Adverse events

**Time Frame:** in hospital at POD1-3, 1 week post-discharge

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

1. Age \>=50
2. Presence of knee osteoarthritis
3. Planned for elective unilateral total knee arthroplasty
4. ASA I - III

Exclusion Criteria:

1. Lack of patient consent; unlikely to comply with follow-up
2. Presence of contraindications to study drug use:

   * Known hypersensitivity to the drug or components of the product
   * Known liver disease - history of cirrhosis, non-alcoholic steatohepatitis
   * Uncontrolled narrow - angle glaucoma
   * Severe renal impairment (CrCl\<30mL/min)
   * Concurrent use of thioridazine
   * Concurrent use of potent CYP1A2 inhibitors (e.g. fluvoxamine) and some quinolone antibiotics (e.g. ciprofloxacin or enoxacin)
   * Concurrent use of antidepressants (e.g. MAOI, SSRI, SNRI, TCA, St. John's Wort, buspirone)
   * Concurrent use of triptan or lithium
3. Chronic and high dose opioid use (\&gt;30mg oral morphine equivalent per day)
4. Substance use disorder (cannabis and related products, alcohol use disorder, opioid used disorder, illicit drugs)
5. Uncontrolled hypertension (systolic BP \&gt; 180mmHg)
6. Untreated psychiatric illness (e.g. depression, suicidal ideation, bipolar disorder)
7. Involved in worker's compensation case/law suit (verbally declared by patient)

**Minimum Age:** 50 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** howard.meng@sunnybrook.ca

**Name:** Howard Meng, MD

**Phone:** 416-480-4864

**Role:** CONTACT

**Contact 2:**

**Email:** stephen.choi@sunnybrook.ca

**Name:** Stephen Choi

**Phone:** 416-480 -4864

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Toronto

**Contacts:**

***Contact 1:***

- **Email:** lilia.kaustov@sunnybrook.ca

- **Name:** Lilia Kaustov, PhD

- **Phone:** 416-480-6100

- **Phone Ext:** 89607

- **Role:** CONTACT

***Contact 2:***

- **Name:** Stephen Choi, MD

- **Role:** SUB_INVESTIGATOR

***Contact 3:***

- **Name:** Sebastian Tomescu, MD

- **Role:** SUB_INVESTIGATOR

***Contact 4:***

- **Name:** Howard Meng, MD

- **Role:** SUB_INVESTIGATOR

**Country:** Canada

**Facility:** Sunnybrook Health Sciences Centre

**State:** Ontario

**Zip:** M4N 3M5

### IPD Sharing Statement Module

**Access Criteria:** Contact study investigators

**Description:** De-identified data will be available upon request

**Info Types:**

- STUDY_PROTOCOL

- SAP

- ICF

**IPD Sharing:** YES

**Time Frame:** Upon publication, no limit on time

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000001168

- Term: Arthritis

- ID: D000007592

- Term: Joint Diseases

- ID: D000009140

- Term: Musculoskeletal Diseases

- ID: D000012216

- Term: Rheumatic Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC05

- Name: Musculoskeletal Diseases

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

### Condition Browse Module - Browse Leaves

- ID: M13069

- Name: Pain, Postoperative

- Relevance: LOW

- As Found: Unknown

- ID: M12926

- Name: Osteoarthritis

- Relevance: HIGH

- As Found: Osteoarthritis

- ID: M22168

- Name: Osteoarthritis, Knee

- Relevance: HIGH

- As Found: Knee Osteoarthritis

- ID: M13066

- Name: Pain

- Relevance: LOW

- As Found: Unknown

- ID: M4476

- Name: Arthritis

- Relevance: LOW

- As Found: Unknown

- ID: M10621

- Name: Joint Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M12097

- Name: Musculoskeletal Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M15045

- Name: Rheumatic Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M6323

- Name: Collagen Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000010003

- Term: Osteoarthritis

- ID: D000020370

- Term: Osteoarthritis, Knee

### Intervention Browse Module - Ancestors

- ID: D000068760

- Term: Serotonin and Noradrenaline Reuptake Inhibitors

- ID: D000014179

- Term: Neurotransmitter Uptake Inhibitors

- ID: D000049990

- Term: Membrane Transport Modulators

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000018377

- Term: Neurotransmitter Agents

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000000700

- Term: Analgesics

- ID: D000018689

- Term: Sensory System Agents

- ID: D000018373

- Term: Peripheral Nervous System Agents

- ID: D000000928

- Term: Antidepressive Agents

- ID: D000011619

- Term: Psychotropic Drugs

- ID: D000015259

- Term: Dopamine Agents

### Intervention Browse Module - Browse Branches

- Abbrev: Analg

- Name: Analgesics

- Abbrev: PsychDr

- Name: Psychotropic Drugs

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: CNSDep

- Name: Central Nervous System Depressants

- Abbrev: VaCoAg

- Name: Vasoconstrictor Agents

- Abbrev: CaAg

- Name: Cardiotonic Agents

### Intervention Browse Module - Browse Leaves

- ID: M299

- Name: Duloxetine Hydrochloride

- Relevance: HIGH

- As Found: American

- ID: M4033

- Name: Analgesics, Opioid

- Relevance: LOW

- As Found: Unknown

- ID: M12575

- Name: Norepinephrine

- Relevance: LOW

- As Found: Unknown

- ID: M15512

- Name: Serotonin

- Relevance: LOW

- As Found: Unknown

- ID: M305

- Name: Serotonin and Noradrenaline Reuptake Inhibitors

- Relevance: LOW

- As Found: Unknown

- ID: M20504

- Name: Neurotransmitter Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4032

- Name: Analgesics

- Relevance: LOW

- As Found: Unknown

- ID: M4247

- Name: Antidepressive Agents

- Relevance: LOW

- As Found: Unknown

- ID: M14474

- Name: Psychotropic Drugs

- Relevance: LOW

- As Found: Unknown

- ID: M7473

- Name: Dopamine

- Relevance: LOW

- As Found: Unknown

- ID: M17962

- Name: Dopamine Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000068736

- Term: Duloxetine Hydrochloride

### Misc Info Module

- Version Holder: 2024-05-31
