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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:
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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.
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