Duloxetine RCT on Postop TKA Outcomes

Sponsor

Rush University Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT05086393

Collaborator

(none)

504

Enrollment

Location

Arms

17.9

Anticipated Duration (Months)

28.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The aim of this study is to determine if duloxetine is associated with differences in post-operative pain, patient-reported outcome measures, and opioid consumption in patients undergoing primary total knee arthroplasty compared to patients who do not receive the medication. If so, duloxetine has the potential to become widely incorporated into the multi-modal analgesic regimen given to patients following knee replacements.

Condition or Disease	Intervention/Treatment	Phase
Pain, Postoperative Total Knee Arthroplasty	Drug: Duloxetine Drug: Placebos	Phase 4

Detailed Description

Despite advances in surgical techniques and multimodal analgesia, many patients experience severe pain following total knee arthroplasty (TKA). In addition, chronic osteoarthritis, the most common reason patients undergo arthroplasty, predisposes patients to neuropathic pain with an estimated 23% of osteoarthritic patients suffering from neuropathic pain in addition to their nociceptive pain. This process is believed to lower the pain threshold and may lead to central sensitization, a condition defined as "the increase in the excitability and synaptic efficacy of neurons in the central nociceptive pathways that manifests as pain hypersensitivity." Central sensitization is present in 20% to 40% of patients with advanced knee osteoarthritis and believed to predispose them to increased preoperative and postoperative levels of pain.

In previous studies, duloxetine has been shown to reduce postoperative pain and opioid consumption. In a 2019 randomized controlled trial (RCT), Ko et al. reported that 30 milligrams (mg) of duloxetine administered one day prior to surgery and continued for 6 weeks after surgery decreased pain scores in patients with central sensitization who underwent TKA. Duloxetine administered for a shorter duration of time has also shown beneficial results. In their 2010 study, Ho et al. found that although 60 mg of duloxetine administered prior to surgery and on the first postoperative day did not significantly improve postoperative pain scores, it significantly reduced postoperative inpatient morphine requirements following TKA. Similarly, in a 2016, triple-blinded, randomized, placebo-controlled trial, YaDeau et al. found that 60 mg of duloxetine given for 15 days following surgery did not significantly impact pain scores but did significantly reduce opioid consumption in the two weeks following TKA. Although promising, these previous studies are difficult to interpret as they evaluated different patient populations, used different dosages of duloxetine, and administered for different lengths of time.

To our knowledge, all previous prospective, randomized controlled trials have examined only patients undergoing TKA, either focused only on patients with central sensitization or failed to differentiate between patients with and without central sensitization in their study population, or failed to administer duloxetine for the 4-8 week duration that has been traditionally recommended to assess the efficacy of SNRIs for other clinical indications.

The researchers propose to fill this knowledge gap by conducting a study that evaluates TKA patients, includes and differentiates patients with and without central sensitization, and administers duloxetine for the full recommended trial duration.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

504 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients randomized to the experimental arm of the study will receive 30 mg of duloxetine and will be advised to consume the medication orally daily starting one week prior to surgery and to continue until 6 weeks following surgery. The dose of 30 mg was selected as that has been used as that is the largest starting dose used in other RCTs without requiring a preceding adjustment period at a lower dosage. Patients randomized to the control arm will receive placebo tablets and advised to consume their medication similar to the treatment arm. Both groups of patients will receive their medications from the pharmacy at Rush Medical Center, which will be responsible for providing patients with the appropriate regimen. All patients will receive the same postoperative multimodal analgesic regimen that is normally administered as part of conventional care to patients undergoing THA and TKA at Rush University Medical Center.Patients randomized to the experimental arm of the study will receive 30 mg of duloxetine and will be advised to consume the medication orally daily starting one week prior to surgery and to continue until 6 weeks following surgery. The dose of 30 mg was selected as that has been used as that is the largest starting dose used in other RCTs without requiring a preceding adjustment period at a lower dosage. Patients randomized to the control arm will receive placebo tablets and advised to consume their medication similar to the treatment arm. Both groups of patients will receive their medications from the pharmacy at Rush Medical Center, which will be responsible for providing patients with the appropriate regimen. All patients will receive the same postoperative multimodal analgesic regimen that is normally administered as part of conventional care to patients undergoing THA and TKA at Rush University Medical Center.

Masking:

Triple (Participant, Care Provider, Investigator)

Masking Description:

This study will be triple-blind, thus, the patients, clinicians, and study members involved will be unaware of patient allocation during this study. After the patient completes his or her Central Sensitization Inventory, a study coordinator will grade the survey to determine if the patient should be allocated to the groups with central sensitization or without. Each patient will receive a study ID based on his or her group (detailed in Section XIV). A computer randomization system will be used to allocate patients to receive either duloxetine or a placebo based on their study ID. Only members of the Rush pharmacy staff will possess the list matching the study ID to the study group assignment, ensuring that the study remains triple-blinded and that study coordinators are unaware of a patient's assignment when he or she picks up the study medication from the pharmacy.

Primary Purpose:

Treatment

Official Title:

A Prospective, Triple-Blind, Randomized Controlled Trial Evaluating Duloxetine on Post-Operative Outcomes Following Primary Total Knee Arthroplasty in Patients With and Without Central Sensitization

Actual Study Start Date :

Nov 1, 2021

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Duloxetine Patients randomized to the experimental arm of the study will receive 30 mg of duloxetine and will be advised to consume the medication orally (per os [PO]) daily starting one week prior to surgery and to continue until 6 weeks following surgery. The dose of 30 mg was selected as that has been used as that is the largest starting dose used in other RCTs without requiring a preceding adjustment period at a lower dosage.	Drug: Duloxetine Patients will be randomized to receive Duloxetine or a placebo.
Placebo Comparator: Control Patients randomized to the control arm will receive PO-matched placebo tablets and advised to consume their medication similar to the treatment arm. Both groups of patients will receive their medications from the pharmacy at Rush Medical Center, which will be responsible for providing patients with the appropriate regimen. All patients will receive the same postoperative multimodal analgesic regimen that is normally administered as part of conventional care to patients undergoing TKA at Rush University Medical Center.	Drug: Placebos Patients will be randomized to receive Duloxetine or a placebo.

Arm

Intervention/Treatment

Experimental: Duloxetine

Patients randomized to the experimental arm of the study will receive 30 mg of duloxetine and will be advised to consume the medication orally (per os [PO]) daily starting one week prior to surgery and to continue until 6 weeks following surgery. The dose of 30 mg was selected as that has been used as that is the largest starting dose used in other RCTs without requiring a preceding adjustment period at a lower dosage.

Drug: Duloxetine

Patients will be randomized to receive Duloxetine or a placebo.

Placebo Comparator: Control

Patients randomized to the control arm will receive PO-matched placebo tablets and advised to consume their medication similar to the treatment arm. Both groups of patients will receive their medications from the pharmacy at Rush Medical Center, which will be responsible for providing patients with the appropriate regimen. All patients will receive the same postoperative multimodal analgesic regimen that is normally administered as part of conventional care to patients undergoing TKA at Rush University Medical Center.

Drug: Placebos

Patients will be randomized to receive Duloxetine or a placebo.

Outcome Measures

Primary Outcome Measures

Cumulative opioid consumption at post op day 14 (POD14) [Daily reporting of opioid consumption for 2 weeks following TKA]
Measuring in morphine equivalents, collect daily data on opioid consumption for each participant

Secondary Outcome Measures

Patient reported outcome: Visual Analogue Scale (VAS) pain score [At the 6 week postoperative mark, following TKA]
Using daily VAS pain score, scale of 1 to 10, 10 being the worst
Patient reported outcome: Knee injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS,JR) [At the 6 week postoperative mark, following TKA]
KOOS,JR outcome assessed at 6 weeks post op from TKA. This is a 0-100 score where 100 represents a perfectly functioning joint.
Patient reported outcome: Sleep duration and quality [Daily reporting of sleep duration for 2 weeks following TKA]
Post-operative sleep duration and quality assessed daily, number of hours slept
Complications [Up to 3 months following surgery]
Adverse medication effects after initiating duloxetine

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Any patient undergoing primary total knee arthroplasty for osteoarthritis
Age ≥ 18 years old
Willingness to undergo randomization and return for all scheduled visits
English speaking

Exclusion Criteria:

Age > 80 years old
American Society of Anesthesiologists (ASA) Score ≥ 4
Prior use of SSRIs or SNRIs
Use of serotonergic drugs in the past 6 months with the exception of tramadol
Known psychiatric disorder (specifically: generalized anxiety disorder, major depressive disorder, type I or type II bipolar disorder, and schizophrenia)
Heavy alcohol consumption defined as ≥ 14 drinks per week for men and ≥ 7 drinks per week for women
Opioid tolerant patients defined as ≥ 60 morphine equivalents (MEQs) per day within 90 days prior to surgery
Renal impairment defined as a glomerular filtration rate (GFR) < 30 mL/minute or creatinine >1.3 mg/dL
Non-English speaking
Non-independent (i.e. requires a caretaker to make medical decisions on their behalf)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rush University medical Center	Chicago	Illinois	United States	60612

Sponsors and Collaborators

Rush University Medical Center

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Denis Nam, M.D., M.Sc, Assistant Professor, Orthopedic Surgery, Rush University Medical Center

ClinicalTrials.gov Identifier:

NCT05086393

Other Study ID Numbers:

19081605

First Posted:

Oct 20, 2021

Last Update Posted:

Nov 18, 2021

Last Verified:

Nov 1, 2021

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Yes

Keywords provided by Denis Nam, M.D., M.Sc, Assistant Professor, Orthopedic Surgery, Rush University Medical Center

duloxetine

Additional relevant MeSH terms:

Pain, Postoperative

Duloxetine Hydrochloride

Study Results

No Results Posted as of Nov 18, 2021