Total knee arthroplasty (TKA) can be associated with significant postoperative pain despite multimodal analgesic (MMA) protocols, and most patients require the use of opioids postoperatively. HTX-011 is a dual-acting local anesthetic containing bupivacaine and low-dose meloxicam in an extended-release polymer. In a prior randomized controlled trial (RCT), HTX-011 reduced pain and opioid use through 72 hours after TKA compared with bupivacaine hydrochloride. This open-label study (NCT03974932) evaluated the efficacy and safety of HTX-011 combined with an MMA regimen in patients undergoing TKA under spinal anesthesia. All patients received intraoperative HTX-011 (400 mg bupivacaine/12 mg meloxicam) in combination with an MMA regimen consisting of preoperative acetaminophen, celecoxib, and pregabalin and postoperative acetaminophen and celecoxib until discharge. Opioid rescue was allowed upon patient request for additional pain control. Pain scores, opioid consumption, discharge readiness, and adverse events were recorded. Fifty-one patients were treated. Compared with the prior RCT, HTX-011 with this MMA regimen further lowered pain scores and reduced opioid use. Mean patient-reported pain scores remained in the mild range, and 82% of patients or more did not experience severe pain at any individual time point through 72 hours after surgery. Mean total opioid consumption was low over 72 hours: 24.8 morphine milligram equivalents (1-2 tablets of oxycodone 10 mg/day). Approximately 60% of patients were ready for discharge by 12 hours, and 39% were discharged without an opioid prescription and did not call back for pain management. The treatment regimen was well tolerated, and no added risk was observed with the addition of MMA. HTX-011 with an MMA regimen reduced postoperative pain and opioid use following TKA.

Helping Opioid Prescription Elimination (HOPE) is a project designed to provide surgeons with practical, real-world solutions to effectively manage postoperative pain and eliminate the need for opioids using HTX-011 (extended-release bupivacaine/low-dose meloxicam). In phase 3 herniorrhaphy and bunionectomy studies, HTX-011 without multimodal analgesia (MMA) was superior to bupivacaine hydrochloride in reducing pain and opioid consumption. Here, we examine the HOPE Hernia-1 study, which was designed to compare alternating ibuprofen/acetaminophen with concurrent use as part of an HTX-011-based non-opioid MMA regimen in patients undergoing herniorrhaphy and to evaluate the effectiveness of a personalized opioid prescription algorithm. Patients undergoing outpatient open inguinal herniorrhaphy with intraoperative administration of HTX-011 (300 mg bupivacaine/9 mg meloxicam) were randomly assigned to receive a scheduled oral regimen of ibuprofen plus acetaminophen, either taken together every 6 hours or alternating every 3 hours, for 5 days following surgery, while awake. Based on the opioid prescription algorithm evaluated here, patients could receive an oxycodone prescription upon discharge only if they had a numeric rating scale pain score of ≥ 6 at discharge and/or had received a postoperative rescue opioid. The majority of patients did not require an opioid prescription through 2 weeks following surgery, and this was similar between cohorts (alternating MMA, 89.1%; concurrent MMA, 93.6%). Patient satisfaction was high for both regimens, and 95% of patients had an opioid-free recovery. No patient discharged without a prescription called back to request one. Treatment was well tolerated, without evidence of nonsteroidal anti-inflammatory drug-related toxicity. HTX-011, used with over-the-counter products ibuprofen/acetaminophen and personalized opioid prescription algorithm in a real-world environment, has the potential to reduce opioid use and opioid prescriptions after herniorrhaphy without compromising patient satisfaction. ClinicalTrials.gov, NCT03237481.

Aim: HTX-011 (ZYNRELEF™) is an extended-release, dual-acting local anesthetic containing bupivacaine and meloxicam. In bunionectomy and herniorrhaphy studies, HTX-011 resulted in less postoperative pain and less opioid consumption versus bupivacaine HCl. Here we evaluate HTX-011 in patients aged ≥65 years. Materials & methods: Patients received placebo, bupivacaine HCl or HTX-011 following surgery. End points included pain intensity, total opioid consumption, opioid-free patients and safety. Results: HTX-011-treated patients reported lower postoperative pain through 72 h versus bupivacaine HCl and placebo. Elderly patients administered HTX-011 used fewer opioids versus bupivacaine HCl, and a greater proportion remained opioid-free through 72 h. HTX-011 was well tolerated with a safety profile similar to bupivacaine HCl and placebo. Conclusion: HTX-011 maintained effectiveness and was well tolerated in elderly patients. Clinical Trial registration numbers: NCT03295721 and NCT03237481

BACKGROUND:Most severe pain occurs within the first 72 hours after an operation, and current local anesthetics have a limited duration of action. HTX-011 is a dual-acting, local anesthetic containing bupivacaine, and low-dose meloxicam in an extended-release polymer. In a prior phase 3 inguinal herniorrhaphy study, HTX-011 alone provided superior pain relief for 72 hours and significantly decreased opioid use compared with saline placebo and bupivacaine hydrochloride. This open-label study assessed the safety, efficacy, and opioid-sparing properties of HTX-011 as the foundation of a scheduled, nonopioid, multimodal analgesia regimen in patients undergoing open inguinal herniorrhaphy.METHODS:This study was conducted in 2 sequential cohorts. All patients received a single, intraoperative dose of HTX-011 prior to wound closure, followed by a scheduled postoperative regimen of oral ibuprofen and acetaminophen for 72 hours. Patients in cohort 2 also received a single intraoperative dose of ketorolac. Opioid analgesics were available by request only.RESULTS:More than 90% of patients remained opioid-free through 72 hours postoperatively, and 83% of patients remained opioid-free through day 28 (last study visit). Pain was well controlled, and mean intensity of the pain never increased higher than the mild range during the first 72 hours. Ketorolac did not demonstrate any additional benefit. HTX-011 with this multimodal analgesia regimen was well tolerated.CONCLUSION:HTX-011 when used as the foundation of a nonopioid, multimodal analgesia regimen, provided effective and well-tolerated analgesia without the need for opioids in the majority of patients recovering from an open inguinal herniorrhaphy.

BACKGROUND:HTX-011 is an extended-release, dual-acting local anesthetic consisting of bupivacaine and low-dose meloxicam in a novel polymer that is administered by needle-free application during surgery. The active ingredients are released from the polymer by controlled diffusion over 72 hours. METHODS:This phase 2b, double-blind, placebo-controlled and active-controlled trial enrolled patients undergoing primary unilateral total knee arthroplasty under general anesthesia. Two hundred thirty-two patients were randomized into 4 groups: HTX-011 400 mg bupivacaine/12 mg meloxicam, applied without a needle into the surgical site, the same dose of HTX-011 with a separate 50 mg ropivacaine injection into the posterior capsule, bupivacaine hydrochloride (HCl) 125 mg injection, and saline placebo injection. Only opioids were permitted for postoperative pain rescue. Primary and key secondary endpoints were mean area under the curve of pain intensity scores over 48 hours and 72 hours, respectively, for HTX-011 groups vs placebo. RESULTS:Both HTX-011 groups had significantly reduced mean pain intensity vs placebo through 48 and 72 hours (both P < .001). Ropivacaine added a small initial benefit in the first 12 hours. Both HTX-011 groups also had decreased mean pain intensity vs bupivacaine HCl alone through 48 and 72 hours (P < .05). The HTX-011 groups had significantly earlier discharge readiness along with lower opioid consumption through 72 hours. HTX-011 alone or with ropivacaine was well-tolerated with a safety profile similar to controls. CONCLUSION:Needle-free application of HTX-011 400 mg bupivacaine/12 mg meloxicam provided superior pain reduction through 72 hours after total knee arthroplasty compared with placebo and bupivacaine HCl alone.

Background and objectivesThere is a need for local anesthetics that provide consistent analgesia through 72 hours after surgery. This study evaluates the use of HTX-011 (bupivacaine and meloxicam in Biochronomerpolymer technology), an extended-release, dual-acting local anesthetic, in reducing both postoperative pain over 72 hours and postoperative opioid use when compared with bupivacaine hydrochloride (HCl) and saline placebo. Inclusion of low-dose meloxicam in HTX-011 is designed to reduce local inflammation caused by surgery, potentiating the analgesic effect of bupivacaine. Previously, significant synergy has been observed with bupivacaine and meloxicam with both given locally together.MethodsEPOCH 1 was a randomized, double-blind, placebo-controlled and active-controlled phase III study in subjects undergoing a primary unilateral, distal, first metatarsal bunionectomy in which subjects received either a single intraoperative dose of HTX-011, immediate-release bupivacaine HCl or saline placebo.ResultsA total of 412 subjects were dosed. The results for the primary and all four key secondary endpoints were statistically significant in favor of HTX-011. HTX-011 demonstrated superior, sustained pain reduction through 72 hours, significantly reduced opioid consumption and resulted in significantly more opioid-free subjects compared with saline placebo and bupivacaine HCl. Safety was similar across groups with fewer opioid-related adverse events observed in the HTX-011 group.ConclusionsHTX-011 demonstrated significant reduction in postoperative pain through 72 hours with significant reduction in opioid consumption and a significant increase in the proportion of opioid-free subjects compared with saline placebo and the most widely used local anesthetic, bupivacaine HCl.Trial registration numberNCT03295721.