Background: DepoBupivacaine (DB) is a controlled-release formulation of
bupivacaine contained within multivesicular liposomal [DepoFoam®]
particles that release bupivacaine over several days, prospectively designed
to provide three days of analgesia following a single administration to
patients undergoing surgery.
Objectives: In this study, we sought to evaluate the efficacy, safety, and
comparative systemic bioavailability of a single administration of DB
compared with bupivacaine HCl with epinephrine (Bup/epi) in patients
undergoing unilateral total knee arthroplasty (TKA).
Methods: We compared three doses of DB to commercial Bup/epi in the
first two cohorts of an ongoing, randomized, double-blind, parallel-group,
dose-ranging study. During surgery, 60 mL of DB or Bup/epi was infiltrated
into the tissue surrounding the wound. Ketorolac 30 mg was administered
to all subjects at the end of surgery. Subjects also received acetaminophen
1000 mg orally three times a day for at least 24 h preoperatively and for
96 h postoperatively. Rescue medication consisted of parenteral opioid
followed by oral oxycodone. In the first cohort, 15 subjects were randomized
into three groups: Bup/epi 150 mg, or DB 150 mg, or DB 300 mg.
Following review by an unblinded safety and efficacy committee, an
additional 10 subjects were randomized into each of the three groups, and
a fourth group of 25 subjects received DB 450 mg. After surgery, the
following decision-making top-line results were assessed by an unblinded
safety and efficacy committee: safety, pain, and total opiate rescue.
Results: DB administration was associated with wound-healing scores
equivalent to Bup/epi over the first five days following surgery and was not
associated with clinical signs of cardiac or CNS adverse events. DB 150 mg
was ineffective in reducing pain compared with an equivalent dose of
Bup/epi. DB at 450 mg statistically significantly reduced pain (P<0.05)
when assessed at the end of general anesthesia (mean 7.0, 6.2, and 5.0 for
DB at 150, 300, and 450 mg, respectively, compared with 7.0 Bup/epi). DB
300 mg and 450 mg statistically significantly reduced pain at the time of first
rescue opioid use (mean 7.7, 6.4, and 6.1 for DB at 150, 300, and 450 mg,
respectively, compared with Bup/epi, 7.8). DB 450 mg reduced opioid rescue
(cumulative mg morphine equivalents) throughout the observation period:
