This is a Phase 2, open-label, multi-cohort study to evaluate the analgesic efficacy, safety, and pharmacokinetics (PK) of a single, individualized dose of HTX-011 administered into the surgical site as a monotherapy or with other medications to enhance analgesia in subjects undergoing unilateral simple bunionectomy.

Inclusion Criteria:

• Is scheduled to undergo a primary unilateral, distal, first metatarsal bunionectomy with osteotomy and internal fixation under regional anesthesia.
• Has an American Society of Anesthesiologists Physical Status of I, II, or III.
• Female subjects are eligible only if not pregnant, not lactating, not planning to become pregnant during the study, sterile; or using acceptable contraceptives. For cohort 2, acceptable contraceptives excludes hormonal contraceptives.

Exclusion Criteria:

• Has had a contralateral foot bunionectomy in the past 3 months prior to the scheduled surgery.
• Has a planned concurrent surgical procedure (eg, bilateral bunionectomy or collateral procedures on the surgical foot).
• Has a pre-existing concurrent acute or chronic painful physical/restrictive condition expected to require analgesic treatment in the postoperative period for pain.
• Has a contraindication or a known or suspected history of hypersensitivity or clinically significant idiosyncratic reaction to required study medications.
• Has known or suspected daily use of opioids for 7 or more consecutive days within the previous 6 months.
• Has taken any NSAIDs within at least 10 days prior to the scheduled surgery.
• Has taken long-acting opioids within 3 days prior to the scheduled surgery.
• Has taken any opioids within 24 hours prior to the scheduled surgery.
• Has been administered bupivacaine within 5 days prior to the scheduled surgery.
• For Cohort 2 only, has been administered aprepitant or another NK1 receptor antagonist within 5 days prior to the scheduled surgery.
• Has been administered any local anesthetic within 72 hours prior to the scheduled surgery.
• Has initiated treatment with study medications within 1 month prior to study drug administration that can impact pain control.
• Has been administered systemic steroids within 5 half-lives or 10 days prior to administration of study drug.
• Has a medical condition such that, in the opinion of the Investigator, participating in the study would pose a health risk to the subject or confound the postoperative assessments.
• As per subject history and/or medical records, has active infection or is currently undergoing treatment for Hepatitis B, Hepatitis C, or human immunodeficiency virus (HIV).
• Has uncontrolled anxiety, psychiatric, or neurological disorder.
• For Cohort 2 only, is receiving pimozide, a strong or moderate CYP3A4 inhibitor, or a strong CYP3A4 inducer.
• Had a malignancy in the last year, with the exception of nonmetastatic basal cell or squamous cell carcinoma of the skin or localized carcinoma in situ of the cervix.
• Has a known or suspected history of drug abuse, a positive drug screen on the day of surgery, or a recent history of alcohol abuse. Note: Subjects with a positive drug screen who are taking an allowed, prescribed medication that is known to result in a positive drug test (eg, amphetamine and dextroamphetamine for attention-deficit/hyperactivity disorder, benzodiazepine for anxiety disorder) may be eligible for participation in the study at the discretion of the Sponsor. Subjects taking any marijuana (medical or recreational) are not allowed to participate in the study.
• Previously participated in an HTX-011 study.
• Received an investigational product or device in a clinical trial within 30 days or within 5 elimination half-lives.
• Has undergone 3 or more surgeries within 12 months.
• Has a body mass index (BMI) >39 kg/m2.

42 Days.

For each PT, subjects are included only once, even if they experienced multiple events in that PT.