Study 3: Interscalene Brachial Plexus Nerve Block for Total Shoulder Arthroplasty or Rotator Cuff Repair in Adults

A multicenter, randomized, double-blind, placebo-controlled study (NCT02713230) (Study 3) was conducted in 156 adult patients undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair with general anesthesia. The mean age was 61 years (range 33 to 80). Prior to the surgical procedure, patients received 133 mg (10 mL) of EXPAREL expanded with normal saline to 20 mL or placebo as a brachial plexus nerve block (perineural use) via interscalene or supraclavicular approach with ultrasound guidance. Only two patients received nerve block with EXPAREL by supraclavicular approach. Postsurgically, patients were administered acetaminophen/paracetamol up to 1,000 mg orally or intravenously every 8 hours unless contraindicated. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5-10 mg every 4 hours or as needed). If a patient could not tolerate oral medication, intravenous morphine (2.5-5 mg) or hydromorphone (0.5-1 mg) could be administered every 4 hours or as needed.

In Study 3, there was a statistically significant treatment effect for EXPAREL compared to placebo in cumulative pain scores through 48 hours as measured by the AUC of the visual analog scale (VAS) pain intensity scores. There were statistically significant, but small differences in the amount of opioid consumption through 48 hours, the clinical benefit of which has not been demonstrated. For those patients who required rescue medication, the mean amount of morphine-equivalent opioid rescue used over 48 hours was 12 mg for EXPAREL-treated patients and 54 mg for placebo-treated patients and 23 mg with EXPAREL-treated patients vs. 70 mg for placebo-treated patients over 72 hours.

Although at 48 hours, 9 patients (13%) in the EXPAREL group remained opioid-free compared to 1 patient (1%) in the placebo group, a difference which was statistically significant, at 72 hours, there were 4 (6%) patients in the EXPAREL group who remained opioid-free compared to 1 (1%) patient in the placebo group, a difference that is not statistically significant. 

Study 4: Sciatic Nerve Block in the Popliteal Fossa for Bunionectomy in Adults

A multicenter, randomized, double-blind, active controlled study (NCT05157841) (Study 4) was conducted in 185 adult patients undergoing bunionectomy. The mean age was 49 years (range 18 to 76). 

Prior to the surgical procedure, patients received 133 mg of EXPAREL mixed with 20 mL saline OR 50 mg (20 mL) of 0.25% bupivacaine HCl mixed with 10 mL saline via sciatic nerve block (perineural use) in the popliteal fossa. All patients received 100 mg (20 mL) of 0.5% immediate-release bupivacaine HCl as a Mayo field block after study drug administration (i.e., in the operating room immediately prior to surgical incision). All patients also received a dose of 1,000 mg of intravenous (IV) acetaminophen at the time of surgical incision. IV fentanyl was allowed for intraoperative pain control (not exceeding 1 mcg/kg unless deemed medically necessary).

Postsurgically, all patients received one post-operative dose of 1,000 mg IV acetaminophen, administered approximately 8 hours after the first dose (approximately 8 hours after incision). Patients were administered pain medications on an as needed basis; opioids were not given on a pre-determined schedule. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5 mg and increasing the dose to 10 mg if initial opioid dose was insufficient). If a patient could not tolerate oral medication or the oral oxycodone pain relief was insufficient, IV morphine (initiated at 2 mg) or hydromorphone (initiated at 0.2 mg) could be administered. No NSAIDs or other opioids including tramadol were allowed for the breakthrough pain management and no acetaminophen (other than the scheduled IV acetaminophen) was used for breakthrough pain.

In Study 4, there was a statistically significant treatment effect for EXPAREL (with 0.5% immediate-release bupivacaine HCl as a Mayo field block) compared to bupivacaine HCl (with 0.5% immediate-release bupivacaine HCl as a Mayo field block) in cumulative pain scores through 96 hours as measured by AUC of the NRS pain intensity scores. There were statistically significant differences in the total amount of postsurgical opioid medication used through 96 hours, the clinical benefit of which has not been demonstrated. For those patients who required postsurgical opioid medication, the mean amount of morphine-equivalent opioid rescue used over 96 hours was 18 mg for patients treated with EXPAREL + Mayo field block and 45 mg for patients treated with bupivacaine HCl + Mayo field block. There was also a statistically significant difference in the percentage of opioid-free patients through 96 hours compared with bupivacaine HCl (24% in the EXPAREL + Mayo field block vs. 6% in the bupivacaine HCl + Mayo field block). 

See Figure 2 for the LS mean pain intensity scores after administration of either 133 mg of EXPAREL or 50 mg of 0.25% bupivacaine HCl.

Figure 2. NRS Pain Intensity After Administration of Study Drug by Sciatic Nerve Block in the Popliteal Fossa.

Study 5: Adductor Canal Block for Total Knee Arthroplasty in Adults

A multicenter, randomized, double-blind, active controlled study (NCT05139030) (Study 5) was conducted in 166 adult patients undergoing primary unilateral total knee arthroplasty. The mean age was 62 years (range 37 to 83). 

Prior to the surgical procedure, patients received (via adductor canal block) (perineural use):

  * 133 mg (10 mL) of 1.3% EXPAREL admixed with 50 mg (10 mL) of 0.5% bupivacaine HCl or
  * 50 mg (10 mL) of 0.5% bupivacaine HCl mixed with 10 mL normal saline.



All patients also received 37.5 mg (15 mL) of 0.25% immediate-release bupivacaine HCl as an infiltration between the popliteal artery and capsule of the knee (IPACK) block immediately following study drug administration. All patients received spinal anesthesia immediately prior to surgery with 0.5% bupivacaine HCl (up to 15 mg). All patients also received a dose of 1,000 mg of intravenous (IV) acetaminophen at the time of surgical incision. IV fentanyl was allowed for intraoperative pain control (not exceeding 1 ug/kg unless deemed medically necessary).

Postsurgically, all patients received one post-operative dose of 1,000 mg IV acetaminophen, administered approximately 8 hours after the first dose (approximately 8 hours after incision). Patients were administered pain medications on an as needed basis for breakthrough pain; opioids were not given on a pre-determined schedule. Patients were allowed opioid rescue medication administered initially as oral immediate-release oxycodone (initiating at 5 mg and increasing the dose to 10 mg if initial opioid dose was insufficient). If a patient could not tolerate oral medication or the oral oxycodone pain relief was insufficient, IV morphine (initiated at 2 mg) or hydromorphone (initiated at 0.2 mg) could be administered. No NSAIDs or other opioids including tramadol were allowed for the breakthrough pain management and no acetaminophen (other than the scheduled IV acetaminophen) was used for breakthrough pain.

In Study 5, there was a statistically significant treatment effect for EXPAREL + IPACK block compared to bupivacaine HCl + IPACK in cumulative pain scores through 96 hours as measured by AUC of the NRS pain intensity scores. There were statistically significant differences in the total amount of postsurgical opioid medication used through 96 hours, the clinical benefit of which has not been demonstrated. For those patients who required postsurgical opioid medication, the mean amount of morphine-equivalent opioid rescue used over 96 hours was 102 mg for patients treated with EXPAREL + IPACK and 133 mg for patients treated with bupivacaine HCl+ IPACK. The median time to first postsurgical use was 4.2 hours for patients treated with EXPAREL + IPACK and 3.6 hours for patients treated with bupivacaine HCl + IPACK.

See Figure 3 for LS mean pain intensity scores after administration of either 133 mg of 1.3% EXPAREL admixed with 50 mg) of 0.5% bupivacaine HCl or 50 mg of 0.5% bupivacaine HCl.

Figure 3. NRS Pain Intensity After Administration of Study Drug by Adductor Canal Block