Influence of Patient Sex on Pain Control and Multimodal Analgesia in Total Knee Arthroplasty

The purpose of this study is to examine the influence of sex on postoperative pain, following total knee arthroplasty (TKA). Patients will first be stratified by sex and then be randomized into one of two multimodal analgesic regimen (MAR), which differ in presence of pregabalin. We hypothesize that that acute postoperative pain scores are different over time between males and females and between multimodal analgesic regimens following TKA. Investigators will be blinded to which multimodal group patients are in. Patients will complete surveys in the office, during their hospital stay, and at followup intervals for up to six months.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative; Knee Osteoarthritis
• Intervention / Treatment: Other: Multimodal analgesia including pregabalin; Other: Multimodal analgesia not including pregabalin

Detailed Description

The overall goal of this study is to better understand the influence of patient-sex on postoperative pain perception in men versus women following total knee arthroplasty (TKA) utilizing two different multimodal analgesia regimens.

Pregabalin is a neuromuscular antagonist of voltage gated calcium channels at the post-synaptic dorsal horns in the spinal cord and brain. It binds to the alpha-2-delta subunit and interrupts pain signal transmission. The use of pregabalin as part of multimodal pain control has been associated with a decrease in postoperative opioid use.

This will be a randomized, single-blinded control trial in which patients either will or will not receive pregabalin as part of their multimodal analgesia regimen following TKA. It will be performed at a single institution, with multiple tertiary academic centers.

Patients will first be grouped according to their sex, then randomized into one of two arms:

1. Multimodal analgesia regimen including pregabalin;
2. Multimodal analgesia regimen not including pregabalin.

For the intervention group, patient will be provided with an oral preoperative pregabalin dose of 150mg on the day of surgery. Patient will continue pregabalin 75mg two times a day, for two weeks postoperatively. For both both groups, the operative technique and additional perioperative analgesic modalities will follow a standard protocol.

Primary Endpoint: Acute postoperative pain difference (up to 72 hours), measured by 100mm visual analogue scale (VAS) while at rest and mobilization, between males and females and between multimodal analgesic regimens in patients undergoing TKA.

Secondary Endpoints:

• Pain control measured by 100mm visual analogue scale (VAS) while at rest and mobilization.
• Pain control additionally measured by morphine equivalent units (MEq).
• Number of postoperative days to opioid cessation.
• Pain measured by Knee Injury and Osteoarthritis Outcome Score (KOOS).
• Physical function measured by KOOS, physical component summary (PCS-12) of VR-12.
• Mental health measured by mental component summary (MCS-12) of VR-12.
• Safety will be tracked by adverse reactions reported or observed by investigators. These will be collected via patient communication and review of the medical record.
• Additionally, severity of common short-term postoperative complications like nausea, vomiting, dizziness, and sedation will be assessed by 100mm VAS.

The study recruitment phase is estimated to last for 6 months. Subject followup is 6 months.

• Study Type: Interventional
• Enrollment (Actual): 250
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • New York
    • Great Neck, New York, United States, 11021
      • Northwell Health Orthopedic Institute at Great Neck

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, age 18-80
4. Undergoing primary unilateral TKA for primary osteoarthritis
5. English speaking
6. Patients whose primary residence is in a home and not a facility or rehabilitation center.

Exclusion Criteria:

1. Chronic (>6 months) use of neuromodulators pregabalin or gabapentin.
2. Pregnancy or lactation
3. Prior history of adverse reactions to pregabalin
4. Coexisting chronic pain condition rated ≥50mm on 100-mm VAS requiring narcotics.
5. Coexisting condition leading to sedation or dizziness
6. Kidney disease
7. History of angioedema
8. History of depression with suicidal ideation.
9. Extensive history of opioid/ substance use and/or abuse.
10. Receiving active or maintenance treatment for cancer or solid organ and/or marrow transplant.
11. Patient staying less than one night in the hospital.
12. Patients with a history of chronic obstructive pulmonary disease (COPD) with supplementary oxygen requirements.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Multimodal analgesia regimen including pregabalin; For the pregabalin group, patient will be provided with an oral preoperative pregabalin dose of 150mg on the day of surgery. Patient will continue pregabalin 75mg two times a day, for two weeks postoperatively. For both the intervention and control groups, the operative technique and additional perioperative analgesic modalities will follow a standard protocol	Other: Multimodal analgesia including pregabalin; Standardized protocol for our institution with multiple medications used for pain (NSAIDs, opioids, dexamethasone) and non-narcotic spinal. Patient will be provided with an preoperative pregabalin dose and will continue medication two weeks postoperatively.
Active Comparator: Multimodal analgesia regimen not including pregabalin; For the non-pregabalin group, patient will be undergo total knee arthroplasty with the same operative technique and additional perioperative analgesic modalities will follow a standard protocol	Other: Multimodal analgesia not including pregabalin; Standardized protocol for our institution with multiple medications used for pain (NSAIDs, opioids, dexamethasone) and non-narcotic spinal.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess influence of sex and multimodal analgesia regimens on acute postoperative pain scores at 48 hours postoperatively, in patients undergoing TKA.	Pain control measured by 100mm visual analogue scale (VAS) while at rest 48 hours after the procedure.	48 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess how sex differences and multimodal analgesia regimens influence physical function	-Pain measured by Knee Injury and Osteoarthritis Outcome Score (KOOS) of week 4, week 12, week 26 postoperatively, compared to baseline.	26 weeks
Assess how sex differences and multimodal analgesia regimens influence postoperative narcotic medication use	Pain control additionally measured by morphine equivalent units (MEq) for 24, 48, and 72 hours after the end of the procedure.	72 hours
Assess how sex differences and multimodal analgesia regimens influence postoperative narcotic medication cessation	-Number of postoperative days to opioid cessation.	2 weeks
Assess how sex differences and multimodal analgesia regimens influence chronic postoperative pain	-Chronic: Pain control measured by 100mm visual analogue scale (VAS) (0 corresponding to no pain and 100 corresponding to worst possible pain) while at rest and mobilization at week 1, week 2, week 4-6, week 12, week 26 postoperatively.	26 weeks
Assess how sex differences and multimodal analgesia regimens influence mental health	-Mental health measured by mental component summary (MCS-12) of VR-12 of week 2, week 4, week 12, week 26 postoperatively, compared to baseline.	week 26
Assess how sex differences and multimodal analgesia regimens influence physical function	-Physical function measured physical component summary (PCS-12) of Veterans Rand-12 (VR-12) at week 2, week 4, week 12, week 26 postoperatively, compared to baseline.	26 weeks
Assess how sex differences and multimodal analgesia regimens influence range of motion (ROM)	Range of Motion (ROM) of week 2, week 4, week 12, week 26 postoperatively, compared to baseline.	26 weeks

Collaborators and Investigators

• Sponsor: Northwell Health
• Investigators: Principal Investigator: Jonathan Danoff, MD, Northwell Health

Publications and helpful links

General Publications

• Berkley KJ. Sex differences in pain. Behav Brain Sci. 1997 Sep;20(3):371-80; discussion 435-513. doi: 10.1017/s0140525x97221485.
• Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth. 2013 Jul;111(1):52-8. doi: 10.1093/bja/aet127.
• Anderson GD. Gender differences in pharmacological response. Int Rev Neurobiol. 2008;83:1-10. doi: 10.1016/S0074-7742(08)00001-9.

Study record dates

Study Major Dates

• Study Start (Actual): December 9, 2020
• Primary Completion (Actual): June 20, 2023
• Study Completion (Actual): June 20, 2023

Study Registration Dates

• First Submitted: May 21, 2020
• First Submitted That Met QC Criteria: July 9, 2020
• First Posted (Actual): July 15, 2020

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 27, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anti-Anxiety Agents; Anticonvulsants; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Pregabalin
• Other Study ID Numbers: 20-0139

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes