The purpose of the study is to compare magnitude of postsurgical analgesic effect in different groups following a single dose of study drug when administered via adductor canal block in subjects undergoing primary unilateral total knee arthroplasty.

This is a Phase 3, multicenter, randomized, double-blind, active-controlled study in approximately 160 subjects undergoing primary unilateral TKA under spinal anesthesia. The study will have 2 cohorts, enrolling in parallel.

Cohort 1 -Pharmacokinetics (PK), pharmacodynamics (PD), Efficacy, and Safety, Cohort 2 -Efficacy and Safety

An adaptive study design will be used in this study. An interim analysis to evaluate the sample size assumptions and evaluate futility will occur when a total of approximately 80 subjects (40 subjects in each arm) combined from either Cohort 1 or Cohort 2 have enrolled and provided complete assessment data for the primary efficacy outcome.

The time from study drug administration until the end of participation is Post-operative day (POD) 14 (±3 days). Therefore, subjects may participate in the study for up to 62 days.

Inclusion Criteria:

1. Male or female, ages 18 or older at screening.
2. Indicated to undergo primary unilateral total knee arthroplasty under spinal anesthesia.
3. Primary indication for TKA is degenerative osteoarthritis of the knee.
4. American Society of Anesthesiologists (ASA) physical status 1, 2, or 3.
5. Able to provide informed consent, adhere to the study schedule, and complete all study assessments.
6. Body Mass Index (BMI) ≥18 and <40 kg/m2.

Exclusion Criteria:

1. Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications for which an alternative is not named in the protocol (e.g., amide-type local anesthetics, opioids, bupivacaine HCl, NSAIDs).
2. Planned concurrent surgical procedure (e.g., bilateral TKA).
3. Undergoing unicompartmental TKA or revision TKA.
4. Concurrent painful physical condition (e.g., arthritis, fibromyalgia, cancer) that may require analgesic treatment with NSAIDs or opioids in the post dosing period for pain that is not strictly related to the knee surgery and which, in the Investigator's opinion, may confound the post dosing assessments.
5. Inadequate sensory function below the knee as assessed by the Investigator.
6. History of contralateral TKA within 1 year.
7. Previous open knee surgery on the knee being considered for TKA. Prior arthroscopy is permitted.
8. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within the past 2 years.
9. Administration of an investigational drug within 30 days or 5 elimination half-lives of such investigational drug, whichever is longer, prior to study drug administration, or planned administration of another investigational product or procedure during the subject's participation in this study.
10. Previous participation in an EXPAREL study.
11. Uncontrolled anxiety, schizophrenia, or other psychiatric disorder that, in the opinion of the Investigator, could interfere with study assessments or compliance.
12. Currently pregnant, nursing, or planning to become pregnant during the study.
13. Clinically significant medical disease that, in the opinion of the Investigator, would make participation in a clinical study inappropriate. This includes diabetic neuropathy, coagulation or bleeding disorders, severe peripheral vascular disease, renal insufficiency, hepatic dysfunction, or other conditions that would constitute a contraindication to participation in the study.
14. Currently on a neuromodulating agent (e.g., gabapentin, pregabalin [Lyrica], duloxetine [Cymbalta], etc.)].
15. Current use of systemic glucocorticoids within 30 days of randomization in this study.
16. Use of dexmedetomidine HCl (Precedex®) or clonidine within 3 days of study drug administration.
17. Any use of marijuana [including Tetrahydrocannabinol (THC) and Cannabidiol (CBD)] within 30 days prior to randomization, or planned use during the course of the study.
18. Chronic opioid use (average ≥30 oral morphine equivalents/day) within 30 days prior to randomization.

Given the coronavirus disease 2019 (COVID-19) pandemic, if there is a concern about a subject's recent or potential exposure to COVID-19, or if the subject is not medically fit/cleared for surgery due to suspected COVID-19 illness/symptoms, the subject must be excluded per Exclusion criterion #13.

Only study drug administrators (anesthesiologists) will be unblinded to perform the block procedures