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Breast Surgery The Efficacy and Safety of DepoFoam Bupivacaine in Patients Undergoing Bilateral, Cosmetic, Submuscular Augmentation Mammaplasty: A Randomized, Double-Blind, Active-Control Study Aesthetic Surgery Journal 32(1) 69–76 © 2012 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: http://www.sagepub.com/ journalsPermissions.nav DOI: 10.1177/1090820X11430831 www.aestheticsurgeryjournal.com John D. Smoot, MD; Sergio D. Bergese, MD; Erol Onel, MD; Hayes T. Williams, MD; and William Hedden, MD Abstract Background: Breast augmentation can result in significant postsurgical pain. Objectives: The authors evaluate the extent and duration of analgesia achieved with extended-release DepoFoam bupivacaine (Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) in patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty under general anesthesia. Methods: In this randomized, multicenter, double-blind study, patients received a single dose of DepoFoam bupivacaine 600 mg or bupivacaine HCl 200 mg divided into the implant pockets at the conclusion of surgery. The primary efficacy measure was cumulative pain score with activity through 72 hours postoperatively. Secondary efficacy measures included pain intensity with activity and at rest, postsurgical consumption of rescue opioids, and integrated rank analysis combining pain scores at rest with the amount of opioid used. Results: One hundred thirty-six patients were randomized and treated (DepoFoam bupivacaine, n = 66; bupivacaine HCl, n = 70). Reflecting the underpowered nature of the study, the mean cumulative pain score (numeric rating scale with activity through 72 hours) was 441.5 with DepoFoam bupivacaine versus 468.2 with bupivacaine HCl (P = .3999). Total amounts of opioid consumed were significantly lower in the DepoFoam bupivacaine group through 24 hours (P = .0211) and through 48 hours (P = .0459). The prespecified integrated rank analysis showed statistically-significant differences at multiple time points up to and including 60 hours; results on most other efficacy measures trended in favor of DepoFoam bupivacaine. No serious adverse events were reported, and no patients discontinued the study due to adverse events. Conclusions: DepoFoam bupivacaine trended toward benefit versus bupivacaine HCl on most efficacy measures. Due to early termination, the study was underpowered to achieve statistical significance. Level of Evidence: 2 Keywords anesthesia, infiltration, mammaplasty, DepoFoam bupivacaine Accepted for publication September 19, 2011. Augmentation mammaplasty, one of the most common plastic surgery procedures in the United States, is often performed in the ambulatory setting. Cosmetic submuscular breast augmentation typically results in moderate-tosevere postsurgical pain,1,2 which originates almost entirely from the manipulation of the muscles in and around the incision area.3 Thus, locally administered analgesics are particularly useful in this type of pain model, as part of a multimodal approach to postsurgical pain management.4,5 Multimodal analgesia has been established as the preferred method for postsurgical pain control due to its evident advantages over monotherapies (ie, lower pain Dr. Smoot is a plastic surgeon in private practice in San Diego, California. Dr. Bergese is Division Chief of Neuroanesthesia, Director of Neuroanesthesia Fellowship, and Director of Clinical and Neurological Research, Departments of Anesthesiology and Neurological Surgery, The Ohio State University, Columbus, Ohio. Dr. Onel is Executive Medical Director, Pacira Pharmaceuticals, Inc., Parsippany, New Jersey. Dr. Williams is Medical Director, West Alabama Research Inc., Northport, Alabama. Dr. Hedden is a plastic surgeon in private practice in Birmingham, Alabama. Corresponding Author: Dr. John D. Smoot, 9850 Genessee Ave, Suite 300, San Diego, CA 92037 USA. E-mail: [email protected] 70 scores, lower analgesic need) and subsequent reduction in opioid usage (and therefore opioid-related adverse events [AE]).4,5 Bupivacaine and other local anesthetics are often administered for postsurgical analgesia after breast augmentation surgery.3,6-9 Bupivacaine is usually infiltrated into the implant pocket, either as a single local dose or via continuous infusion. The duration of action of bupivacaine HCl is typically limited to six to eight hours when administered via local infiltration.10 DepoFoam bupivacaine (bupivacaine liposome injectable suspension marketed as EXPAREL, Pacira Pharmaceuticals, Inc., Parsippany, New Jersey) is an extended-release multivesicular liposome formulation of bupivacaine. The purpose of this prospective, randomized, doubleblind study was to evaluate the extent and duration of the analgesic effect achieved by DepoFoam bupivacaine or bupivacaine HCl/epinephrine administered locally into the implant pocket of each breast in patients undergoing bilateral, cosmetic, submuscular breast augmentation under general anesthesia. The study also evaluated additional efficacy parameters and characterized the safety profile of DepoFoam bupivacaine compared with bupivacaine HCl. Methods This Phase 3, randomized, multicenter, double-blind, parallel-group, active-control study evaluated the efficacy and safety of a single local administration of DepoFoam bupivacaine 300 mg compared with bupivacaine HCl 100 mg (Marcaine 0.5% with epinephrine 1:200,000; Hospira, Inc., Lake Forest, Illinois) administered locally into the implant pocket of each breast for postsurgical analgesia. The milligram dose of DepoFoam bupivacaine is expressed as bupivacaine HCl equivalent (i.e., 300 mg of bupivacaine HCl is chemically-equivalent to 266 mg of bupivacaine base). Each patient received a total of either 600 mg DepoFoam bupivacaine or 200 mg bupivacaine HCl. Because epinephrine prolongs the duration of action of bupivacaine HCl, this allowed for a direct comparison with DepoFoam bupivacaine. The dose of bupivacaine HCl was selected based on current standard of practice and published clinical studies,3,6,7 which showed bupivacaine HCl doses of 100 to 150 mg to be effective for the management of postsurgical pain in patients undergoing breast augmentation or reduction surgery. The dose of DepoFoam bupivacaine was selected based on the findings of a Phase 2 study of DepoFoam bupivacaine (data on file, Pacira Pharmaceuticals, Inc.), which signaled better efficacy with a 300-mg dose compared with a 150-mg dose and a similar safety profile. The study was conducted at 11 clinical sites in the United States between November 2008 and February 2009 (Trial Registration Info: IND #69,198; US clinical trials identifier NCT00813111; date registered: November 2008 [http://clinicaltrials.gov/ct2/show/NCT00813111]). All study procedures were conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Aesthetic Surgery Journal 32(1) Good Clinical Practices and the Declaration of Helsinki and its amendments.11,12 The study protocol and informed consent forms were approved by an Institutional Review Board (Aspire IRB, La Mesa, California, and Brookwood Medical Center, Birmingham, Alabama), and written informed consent was obtained from all patients before study enrollment. The study was stopped early due to administrative reasons unrelated to safety. Patients Eligible participants included nonpregnant women 18 years of age or older with an American Society of Anesthesiologists (ASA) physical status classification of 1 to 4 who were scheduled to undergo primary, bilateral, cosmetic, submuscular breast augmentation under general anesthesia. Patients had to be surgically sterile, postmenopausal, or willing to use an acceptable means of contraception for at least 30 days postsurgery. Patients were excluded if they weighed less than 50 kg, were undergoing reconstructive surgery following mastectomy, or had used long-acting opioids within three days or any opioid medication within 24 hours before surgery. Also excluded were patients with a concurrent painful physical condition or concurrent surgery that could have required analgesic treatment in the postsurgical period for pain that was not strictly related to the surgical site receiving the study drug, significant medical conditions or laboratory results that indicated an increased vulnerability to study drugs and/or procedures, and any clinically significant event or condition uncovered during the surgery (ie, excessive bleeding, acute sepsis) that might have rendered the patient medically unstable or complicated the postsurgical course. Study Design The parallel-group study design included a screening visit during which informed consent, medical history, and surgical history (including presence and location of any scars that crossed or were in the same area as the planned surgery) were obtained; eligibility criteria were assessed; vital signs (temperature, heart rate, blood pressure) were measured; training was provided on self-assessment measures; and data were recorded regarding all AE. At baseline (presurgery), a physical examination and urine pregnancy test were performed, concomitant medications were recorded, and the Brief Pain Inventory (BPI) Short Form questionnaire13,14 was administered to assess quality of life. Patients were then randomized in a blinded manner to receive either DepoFoam bupivacaine 600 mg (300 mg/20 mL in each implant pocket) or bupivacaine HCl 200 mg (100 mg/20 mL in each implant pocket) in a 1:1 ratio within each study site. Randomization codes were generated via a centralized computer randomization system, which was used to communicate patient randomizations to the study sites. Smoot et al At the end of the surgical procedure (Day 1), the study drug was administered locally into the right and left breast implant pockets of each patient by the surgeon’s preferred technique. All postsurgical procedures and assessments were timed from the start of study drug administration. Only unblinded study personnel not involved with protocolspecific postsurgical assessments prepared and administered the study drug; staff members conducting study-specific postsurgical assessments and patients remained blinded to the assigned treatment throughout the study. Postoperatively, patients received treatment with acetaminophen 1000 mg three times daily and rescue analgesia with oxycodone, as needed, for breakthrough pain through 96 hours after study drug administration. Patients meeting the discharge criteria were discharged from the postanesthesia care unit at or after their final scheduled study site assessment but not less than one hour after study drug administration. Pain intensity at rest and with activity was assessed hourly after surgery until discharge using a numeric rating scale (NRS-R and NRS-A, respectively; 0 = no pain and 10 = worst possible pain). For the NRS-A pain intensity assessment, the prescribed activity consisted of raising both arms above the head and holding this position for five seconds. Adverse events (including incidence of nausea and vomiting), medications taken, and time of first bowel movement (BM) were also recorded during the postsurgical period prior to discharge. After leaving the study site, patients used study diaries to record their pain scores at four, eight, 12, 24, 36, 48, 60, 72, 84, and 96 hours after study drug administration, along with incidence of nausea/vomiting, concomitant medications, AE (with specified times), and time of first BM (if it had not occurred prior to discharge). Patients also completed the BPI at 24, 48, 72, and 96 hours and rated their satisfaction with postsurgical analgesia (extremely dissatisfied to extremely satisfied) at 72 hours after study drug administration. Follow-up visits were scheduled on Days 8 and 30. Outcomes Assessments The primary efficacy measure was the cumulative pain score as reflected in the area under the curve (AUC) of NRS-A scores through 72 hours after study drug administration. Other efficacy measures included cumulative pain scores at time points other than 72 hours, total amount (mg) of rescue opioid medication consumed, proportion of patients receiving no rescue opioid medication, and integrated rank assessment (which incorporates the pain score and the postsurgical opioid used to achieve that pain score) through multiple time points. Occurrences of postsurgical nausea and vomiting, quality of life (BPI scores), patients’ satisfaction with postsurgical analgesia, time to first BM, and date patients returned to work or normal daily activities were also included as efficacy measures. The study was designed to assess efficacy measurements through 96 hours postsurgery. However, the efficacy results at 72 hours are highlighted here in order to remain consist- 71 ent with other studies in the DepoFoam bupivacaine clinical development program. Safety outcomes measured included AE through Day 30; vital signs (temperature, heart rate, and blood pressure) at screening, baseline, and 0.5, one, 1.5, and two hours after study drug administration; blinded care provider’s satisfaction with wound healing status (0 = completely unsatisfied; 10 = completely satisfied) on Days 8 and 30; and assessment of wound scarring (assessed using the Vancouver Scale for Scarring15) on Day 30. Data Analysis A sample size of approximately 240 patients was planned (120 in each treatment group). Based on a two-sided t-test with a significance level of 0.05 and a common standard deviation of 140, a sample size of 120 patients per treatment group would yield 91% power to detect a difference in NRS-A AUC0-72 of 60. All statistical analyses were conducted with SAS software Version 9 or higher (SAS, Inc., Cary, North Carolina) against a two-sided alternative hypothesis with a significance level of 0.05. The safety population included all patients who were randomized and received any portion of a dose of study drug; safety analyses were based on treatment actually received. The full analysis population included all patients in the safety population who underwent the surgical procedure and for whom NRS-A AUC0-72 could be calculated. Efficacy analyses were based on randomized treatment regardless of treatment actually received. Data for the primary efficacy measure (NRS-A AUC0-72) were input with the windowed worst observation carried forward plus last observation carried forward (wWOCF + LOCF) method. For patients who used opioid rescue medication, their NRS scores recorded within the window of controlled-type rescue medication (one half-life of the rescue medication) were replaced by the “worst” observation (ie, the highest score prior to taking their first rescue medication). Missing scores were replaced in one of three ways: (1) by the median score from other patients at the same time point in the same treatment group if before the first nonmissing score, (2) by LOCF if after the last nonmissing score, and (3) by linear interpolation if between two nonmissing scores. Between-group differences in AUC were calculated with an analysis of variance (ANOVA) model with treatment and site as main effects. Treatment comparisons for the secondary efficacy measures were calculated with ANOVA, analysis of covariance, Cochran-Mantel-Haenszel tests, and log-rank tests as appropriate. For total consumption of rescue opioid medication, all opioids were converted to an equianalgesic parenteral morphine amount with standard conversion factors.16 To account for the use of supplemental opioid pain medication on pain intensity, the pain intensity data were analyzed as an integrated rank using the NRS-R pain intensity scores and the supplemental opioid pain medication data, according to the methods of Silverman et al.17 For this 72 Aesthetic Surgery Journal 32(1) Table 1. Patient Demographics and Baseline Characteristics (Safety Population) N Age, mean (SD), y DepoFoam Bupivacaine 600 mg (n = 66) Bupivacaine HCl 200 mg (n = 70) 64 70 30.8 (7.3) 30.6 (7.6) Race/ethnicity, No. (%)a White 61 (92.4) 64 (91.4) Asian 2 (3.0) 2 (2.9) Native Hawaiian/Other Pacific Islander 1 (1.5) 2 (2.9) Black 1 (1.5) 2 (2.9) Figure 1. Patient disposition. *Sponsor terminated study. Table 2. Total Consumption of Rescue Opioid Medication (mg)a: Full Analysis Set ASA physical status classification, No. (%) DepoFoam Bupivacaine 600 mg (n = 60) Bupivacaine HCl 200 mg (n = 62) P Value 1 59 (89.4) 50 (71.4) Time From 0 to: 2 5 (7.6) 18 (25.7) 12 hours postdose 3.8 4.9 .1614 3 0 0 24 hours postdose 6.1 9.3 .0211 4 0 0 36 hours postdose 9.3 13.1 .0751 N 66 68 48 hours postdose 11.0 16.4 .0459 60 hours postdose 12.7 18.4 .0785 72 hours postdose 13.5 20.4 .0579 Weight, mean (SD), kg N Height, mean (SD), cm 59.1 (7.0) 66 164.6 (5.9) 59.7 (9.0) 68 164.8 (7.2) ASA, American Society of Anesthesiologists. Patients may have been counted in more than one category. a All opioids were converted to equianalgesic parenteral morphine amounts (mg). a analysis, both the NRS score and amount of rescue opioid medication were ranked in the combined treatment groups. Each patient’s NRS, rank, and total rescue opioid medication consumption rank were subtracted from the respective mean overall rank and expressed as a percentage difference of the respective mean overall rank. A patient’s integrated rank was the sum of the percentage difference for the NRS score and the percentage difference for the total rescue opioid consumption. Treatment-emergent AE were summarized by system organ class and preferred term in each treatment group. Results This study was designed to enroll approximately 240 patients. However, the study was stopped early due to administrative reasons unrelated to safety. A total of 146 patients were randomized and 136 patients were treated; 66 received DepoFoam bupivacaine 600 mg and 70 received bupivacaine HCl 200 mg. Patient disposition is shown in Figure 1; demographics and baseline characteristics are summarized in Table 1. Efficacy Pain intensity, as reflected in the mean (standard error [SE]) NRS-A score in the DepoFoam bupivacaine 600-mg group, was significantly lower at eight hours (4.9 [0.41], P = .0016) and 12 hours (5.6 [0.40], P = .0143) compared with the bupivacaine HCl group (6.7 [0.40] and 6.9 [0.37], respectively). Differences in mean (SE) NRS-R scores were also statistically significant in favor of DepoFoam bupivacaine versus bupivacaine HCl at eight hours (3.5 [0.35] vs 5.0 [0.34], respectively; P = .0027). Pain intensity scores in the treatment groups were not significantly different at the other timed assessments. For the primary efficacy measure (NRS-A AUC0-72), the mean (SE) value in the DepoFoam bupivacaine group was 441.5 (23.6) compared with 468.2 (23.0) in the bupivacaine HCl group (P = .3999). Mean cumulative pain scores at rest and with activity were numerically lower in the DepoFoam bupivacaine group at all time points; however, due to the underpowered nature of the study, the between-group differences did not reach statistical significance. Smoot et al 73 Figure 2. Percentage of patients avoiding opioid rescue medications postsurgery. Figure 3. Mean scores for integrated rank assessment using adjusted mean numeric rating scale of pain intensity at rest (NRS-R) pain scores and supplemental opioid usage. *P < .05, DepoFoam bupivacaine versus bupivacaine HCl. The mean total amount of postsurgical rescue opioid medication consumed was lower in the DepoFoam bupivacaine group at all time points evaluated through 72 hours (Table 2). Total amounts consumed were significantly lower in the DepoFoam bupivacaine group through 24 hours (P = .0211) and through 48 hours (P = .0459). Overall, the proportion of patients who avoided use of rescue opioid medication was low. About twice as many patients in the DepoFoam bupivacaine group avoided rescue opioid medication than in the bupivacaine HCl group at every time point after 12 hours (Figure 2), although given the underpowered nature of the study, the differences were not statistically significant. As shown in Figure 3, integrated rank assessments with NRS-R scores and total postsurgical opioid use numerically favored DepoFoam bupivacaine over the bupivacaine HCl through 12, 24, 36, 48, 60, and 72 hours, with betweengroup differences reaching statistical significance at 12, 48, and 60 hours postoperatively. The percentage of patients with at least one occurrence of postsurgical nausea and vomiting was lower at every time point (12, 24, 36, 48, 60, and 72 hours) in the DepoFoam bupivacaine group compared with the bupivacaine HCl group; however, the differences were not statistically significant. There were statistically significant differences in favor of DepoFoam bupivacaine in the mean responses to 74 Aesthetic Surgery Journal 32(1) Table 3. Summary of Treatment-Emergent Adverse Eventsa: Safety Analysis Set Patients with ≥1 AE, No. (%) DepoFoam Bupivacaine 600 mg (n = 66) Bupivacaine HCl 200 mg (n = 70) 48 (72.7) 51 (72.9) Most common AE (≥3% of patients), No. (%) Nausea 29 (43.9) 37 (52.9) Constipation 11 (16.7) 13 (18.6) Vomiting 10 (15.2) 14 (20.0) Muscle spasm 10 (15.2) 11 (15.7) Tachycardia 3 (4.5) 7 (10.0) Insomnia 4 (6.1) 4 (5.7) Headache 2 (3.0) 5 (7.1) Hypoesthesia 4 (6.1) 3 (4.3) Chills 4 (6.1) 2 (2.9) Myalgia 6 (9.1) 0 Back pain 2 (3.0) 2 (2.9) Local swelling 1 (1.5) 3 (4.3) Pruritus 2 (3.0) 2 (2.9) Anxiety 3 (4.5) 0 Pain 2 (3.0) 1 (1.4) Decreased appetite 2 (3.0) 0 Erythema 2 (3.0) 0 Musculoskeletal discomfort 2 (3.0) 0 AE, adverse event. a If a patient experienced more than one episode of a particular AE, the patient was counted only once for that AE. several items on the BPI questionnaire; no significant differences in favor of bupivacaine HCl were observed on any BPI items. More patients reported being “extremely satisfied” or “satisfied” with their postsurgical analgesia at 72 hours following administration of DepoFoam bupivacaine (80%) compared with bupivacaine HCl (74%). The mean time to first BM was similar for patients in the DepoFoam bupivacaine (53.7 hours) and bupivacaine HCl (57.5 hours) groups, and there was no clinically meaningful difference between the groups in the proportion of patients who returned to work or normal activities by the end of follow-up. Safety A total of 99 patients (72.8%) reported at least one treatment-emergent AE during the study: 48 (72.7%) in the DepoFoam bupivacaine group and 51 (72.9%) in the bupivacaine HCl group. The majority of AE were mild or moderate in severity. Treatment-emergent AE are summarized in Table 3. The most frequently reported treatment-emergent AE were nausea, constipation, vomiting, and muscle spasm. Two patients in each group reported episodes of nausea and muscle spasm that were considered by investigators to be related to the study drug. Other AE considered to be related to DepoFoam bupivacaine were noncardiac chest pain, pyrexia, somnolence, bradycardia, and skin irritation (one incident each). One patient in the bupivacaine HCl group reported an event of sensory disturbance that was considered related to the study drug. There were no serious treatment-emergent AE reported, and no patients discontinued participation in the study due to AE. There were no clinically significant changes in vital signs from baseline to Day 8 in either treatment group, and no signals related to cardiac safety were observed. There were also no clinically significant differences in mean scores on the assessment of blinded care provider’s satisfaction with wound healing on Days 8 and 30. Wound status (erythema, drainage, edema, and induration) was evaluated on Days 8 and 30; there was statistically significantly less induration in patients treated with DepoFoam bupivacaine (P = .0313). No other differences reached statistical significance. Mean scores for wound scarring (Day 30) were the same in both treatment groups and thus were not significantly different. However, these results should be interpreted with caution since 44% of the patients receiving DepoFoam bupivacaine and 37% receiving bupivacaine HCl were not evaluated for wound status on Day 30. Discussion Bupivacaine HCl (ie, Marcaine 0.5% with epinephrine 1:200,000) was chosen as a meaningful comparator for extended-release DepoFoam bupivacaine in this study because the two formulations contain the same active, local anesthetic. The dose of bupivacaine HCl was selected based on the standard of practice and the extent of the local administration procedure in this study. A comparison of identical milligram dosages, DepoFoam bupivacaine 75 mg and bupivacaine HCl 75 mg, was included in a previous hemorrhoidectomy study, which compared DepoFoam bupivacaine 75, 225, or 300 mg to bupivacaine HCl 75 mg (with epinephrine 1:200,000) for the management of postsurgical pain.18,19 All three dose levels of DepoFoam bupivacaine were statistically superior to bupivacaine HCl 75 mg, as reflected in cumulative pain scores through 72 hours after surgery, with incrementally greater reductions in pain scores observed with increasing doses of DepoFoam bupi- Smoot et al vacaine. Interestingly, the DepoFoam bupivacaine 300-mg group had the most favorable tolerability profile of any treatment group in this hemorrhoidectomy study. Only 4% of patients in the DepoFoam bupivacaine 300-mg group experienced AE compared with 42% in the bupivacaine HCl group, and these included AE typically associated with opioids used for rescue. Another study evaluated the safety/efficacy of DepoFoam bupivacaine in patients undergoing inguinal hernia repair and also assessed the single-dose pharmacokinetics of DepoFoam bupivacaine 175, 225, 300, or 350 mg and bupivacaine HCl 100 mg.20 The observed mean maximum plasma bupivacaine levels (Cmax) following administration of DepoFoam 300 mg (365 ng/mL) was similar to Cmax for bupivacaine HCl 100 mg (336 ng/mL). Thus, DepoFoam bupivacaine 300 mg appears to provide better pain relief than bupivacaine HCl 75 mg to 100 mg in these surgical models, with similar tolerability and similar maximum plasma bupivacaine levels compared with bupivacaine HCl 100 mg. Based on these data, a milligram comparison ratio of 3:1 appears appropriate for DepoFoam bupivacaine and bupivacaine HCl in the setting of breast augmentation. In addition to the breast augmentation data presented here, data from clinical studies of DepoFoam bupivacaine in other surgical settings (total knee arthroplasty, inguinal hernia repair, hemorrhoidectomy, and bunionectomy) have been submitted to the US Food and Drug Administration (FDA) for review. The proposed formulation concentration is 15 mg per mL, and the standard recommended doses submitted for FDA approval are as follows: surgical procedures with incisions less than 3 cm length (ie, bunionectomy), 120 mg/8 mL; surgical procedures with incisions greater than or equal to 3 cm length (ie, hemorrhoidectomy), 300 mg/20 mL; and orthopedic/reconstructive surgeries (ie, total knee arthroplasty), 600 mg/40 mL. Consistent with other locally-acting analgesics, the manufacturer has proposed that no dosage adjustments are necessary based on patient weight or body mass index. This study was terminated early because of administrative reasons unrelated to safety and was thus underpowered to detect statistically significant differences between treatment groups. Assessments of cumulative pain score and opioid usage trended in favor DepoFoam bupivacaine, but neither reached a P value of less than .05. However, the integrated rank assessment (which combines both pain intensity and amount of rescue opioid medication needed to treat pain) showed that DepoFoam bupivacaine was statistically-significant at multiple time points for both pain at rest and pain with activity. Other end points that showed statistically significant differences at multiple time points through 72 hours in favor of DepoFoam bupivacaine compared with bupivacaine HCl were the NRS-A, NRS-R, the use of supplemental opioid pain medication, and several items on the BPI. Moreover, the mean total amount of postsurgical rescue opioid medication used was numerically lower in the DepoFoam bupivacaine group at all time points through 72 hours. Finally, at every time point after 12 hours postsurgery, at least twice as many patients in the DepoFoam bupivacaine group avoided opioid use entirely compared with the bupivacaine HCl group. Study drugs were well tolerated. 75 The strengths of this study include the high-tier evidence-based study design, homogeneity of the patient population, and use of validated outcomes instruments. Study limitations include the inherent subjectivity in patients’ pain perception and potential confounding of observed results by the early termination of the study. Conclusions In this population of patients undergoing bilateral, cosmetic, submuscular augmentation mammaplasty under general anesthesia, DepoFoam bupivacaine trended toward better efficacy compared with bupivacaine HCl and required less opioid rescue medication to achieve those results. Due to early termination, the study was underpowered to detect statistically significant differences between treatment groups regarding the primary efficacy end point. However, a prespecified secondary end point, which took into account both pain score and amount of opioids required to achieve that pain score, did show statistical significance at multiple time points. Based on these findings, DepoFoam bupivacaine may be a clinically meaningful addition to current practice. Acknowledgments The authors acknowledge the contribution of Elizabeth DalyDeJoy, MPH, who provided compensated writing assistance in preparing this manuscript. Editorial assistance was provided by Peloton Advantage, LLC and supported by Pacira Pharmaceuticals, Inc. Disclosures Drs. Smoot, Bergese, Williams, and Hedden received research support from Pacira Pharmaceuticals, Inc. for the conduct of this study consisting of supplies and a per-patient stipend. Dr. Onel is a paid employee of Pacira Pharmaceuticals, Inc. and was involved in study conception and design, provision of study materials, study supervision, collection and assembly of data, data analysis and interpretation, statistical analysis, manuscript development, and final approval of manuscript. Financial disclosure information was provided to the study patients. Funding This study was funded by Pacira Pharmaceuticals, Inc. References 1. Gramke HF, de Rijke JM, Van Kleef M, et al. The prevalence of postoperative pain in a cross-sectional group of patients after day-case surgery in a university hospital. Clin J Pain 2007;23:543-548. 2. Wallace MS, Wallace AM, Lee J, Dobke MK. 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