Effect of peRiopErative duLoxetIne Administration on Opioid Consumption Following Total kneE Arthroplasty (RELIFE) (RELIFE)

December 12, 2025 updated by: Dr. Howard Meng, Sunnybrook Health Sciences Centre

Effect of Perioperative Duloxetine Administration on Opioid Consumption Following Total Knee Arthroplasty

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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). This 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 > 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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
150

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M4N 3M5
        • Recruiting
        • Sunnybrook Health Sciences Centre
        • Contact:
        • Principal Investigator:
          • Howard Meng, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age >=50
  2. Presence of knee osteoarthritis
  3. Planned for elective unilateral total knee arthroplasty
  4. ASA I - III
  5. Baseline creatinine clearance (CrCl) ≥ 30 mL/min within 60 days prior to enrolment, if available. If not available, verbal report from patient of no known renal disease.

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 (>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 > 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)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Intervention
Duloxetine 60mg OD for 2 weeks preoperatively then 60mg OD for 6 weeks post-surgery.
Drug: Duloxetine
60mg duloxetine given 2 weeks prior to total knee arthroplasty and continued for 6 weeks after surgery.
Placebo Comparator: Control
Placebo OD for 2 weeks preoperatively then OD for 6 weeks post-surgery.
Drug: Placebo
Placebo given 2 weeks prior to total knee arthroplasty and continued for 6 weeks after surgery.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Opioid consumption
Time Frame: Cumulative opioid consumption at 1 week post-operatively
Cumulative opioid consumption at 1 week post-operatively
Cumulative opioid consumption at 1 week post-operatively

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Pain at rest and with activity
Time Frame: 10-14 days preoperative; 1,6,12 weeks and 4.5 months
Maximum pain score on 0-10 Likert Scale (NRS)
10-14 days preoperative; 1,6,12 weeks and 4.5 months
Additional analgesic use
Time Frame: 8 weeks (i.e., duration of study)
Anti-neuropathic medications
8 weeks (i.e., duration of study)
Additional analgesic use: opioid prescription
Time Frame: 8 weeks (i.e., duration of study)
Family physician or orthopaedic surgeon opioid prescription
8 weeks (i.e., duration of study)
Physical function measured by BPI
Time Frame: Preoperative, 6, 12 weeks and 4.5 months
Brief Pain Inventory
Preoperative, 6, 12 weeks and 4.5 months
Physical function measured by Oxford Knee Scale
Time Frame: Preoperative, 6, 12 weeks and 4.5 months
Oxford Knee Scale
Preoperative, 6, 12 weeks and 4.5 months
Range of motion: Physical function
Time Frame: Preoperative, 6, 12 weeks and 4.5 months
Preoperative, 6, 12 weeks and 4.5 months
Emotional function measured by GAD-7
Time Frame: Preoperative, 6, 12 weeks and 4.5 months
GAD-7
Preoperative, 6, 12 weeks and 4.5 months
Emotional function measured by PHQ-9
Time Frame: Preoperative, 6, 12 weeks and 4.5 months
PHQ-9
Preoperative, 6, 12 weeks and 4.5 months
Neuropathic pain
Time Frame: 6 and 12 weeks post-surgery
Presence of neuropathic pain (S-LANSS)
6 and 12 weeks post-surgery
Chronic post-surgical pain
Time Frame: 12 weeks post-surgery
Presence of chronic post-surgical pain (based on NRS > 0)
12 weeks post-surgery
Nausea/vomiting
Time Frame: 12 weeks (i.e., duration of study)
Presence of nausea or vomiting
12 weeks (i.e., duration of study)
Patient satisfaction
Time Frame: 1 week after start of intervention; 1, 6, and 12 weeks after surgery and 4.5 months after surgery
Patient global impression of change (PGIC)
1 week after start of intervention; 1, 6, and 12 weeks after surgery and 4.5 months after surgery
Quality of recovery (QoR-15)
Time Frame: 1/6/12 weeks and and 4.5 months post-surgery
Change in Quality of Recovery-15 (QoR-15) score, a 15-item patient-reported questionnaire assessing postoperative recovery across pain, physical comfort, physical independence, psychological support, and emotional state.
1/6/12 weeks and and 4.5 months post-surgery
Adverse events
Time Frame: 1 week after starting intervention; in hospital at POD1-3, and 1, 6, and 12 weeks post-op.
Adverse events relating to study medication (dizziness, drowsiness, nausea, vomiting, insomnia)
1 week after starting intervention; in hospital at POD1-3, and 1, 6, and 12 weeks post-op.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Sunnybrook Health Sciences Centre

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2024

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 1, 2026

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2026

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 16, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 16, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 21, 2024

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 19, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 12, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • SBK 6156

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified data will be available upon request

IPD Sharing Time Frame

Upon publication, no limit on time

IPD Sharing Access Criteria

Contact study investigators

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Knee Osteoarthritis

Clinical Trials on Duloxetine

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings