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.

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.

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.

Eligibility will be based on biological sex

Care providers, and investigators will all be blinded to patient group identity.