Published 6/1/2017

Setting AAOS Now Straight

Regarding the recent AAOS Now article "Study: No Advantage to Liposomal Bupivacaine for TKA" (April 2017 issue) about work presented at the AAOS annual meeting by DeClaire et al, there appears to be a significant methodologic problem that likely resulted in a misleading outcome. Prior study (1) has shown that liposomal bupivacaine, when mixed with other local anesthetics, undergoes a process of disruption, leading to release of free bupivacaine and negating any advantage of the liposomal encapsulation. Per the article, patients undergoing total knee arthroplasty (TKA) were randomized to two cohorts and received a drug "cocktail" consisting of multiple medications, with liposomal bupivacaine mixed with regular bupivacaine prior to injection.

Patients in the first group (control, n = 49) received a standard periarticular 100 mL "pain cocktail" injection of ropivacaine, ketorolac, morphine, and epinephrine in saline. Patients in the second group (experimental, n = 47) received a similar cocktail with bupivacaine substituted in an 80-mL preparation, plus a 20-mL injection of liposomal bupivacaine (1.3 percent).

The preparation of this cocktail likely resulted in liposomal disruption, leading to release of free bupivacaine. The end result is that this study merely demonstrates that there is no clinical difference between ropivacaine and bupivacaine after TKA. No meaningful information about liposomal bupivacaine can be drawn from this data, given the likely drug interaction that was inadvertently caused by use of a drug cocktail. The authors are quoted as being "surprised" by the study outcome; this is likely due to this unaccounted-for drug interaction that invalidates their data.

Clear guidelines against mixing liposomal bupivacaine (Exparel) have been previously developed (reference 1) and are listed in the U.S. Food and Drug Administration (FDA)–required product prescribing information (2) for this medication, as follows:


  • EXPAREL should not be admixed with lidocaine or other nonbupivacaine-based local anesthetics.
  • EXPAREL may be administered after at least 20 minutes or more have elapsed ­following local administration of lidocaine.
  • Bupivacaine HCl, when injected immediately before or admixed with
  • EXPAREL may impact the pharmacokinetic and/or physicochemical properties of the drugs

Cost effectiveness of medications is both pertinent and important, but we must be careful not to discard potentially valuable treatments with poorly designed studies.

Robert Henshaw, MD
Professor, Clinical Orthopedic Surgery (Orthopedic Oncology), Georgetown University School of Medicine

Response from Jeffrey H. ­DeClaire, MD:
In response to Dr. Henshaw's questions regarding the concern for mixing the liposomal bupivacaine with other local anesthetics, such mixing absolutely was not the case in this study. The study was conducted with anesthetics administered exactly as recommended by the guidelines as described by Pacira Pharmaceuticals, Inc., as well as the guidelines recommended by the FDA.

The liposomal bupivacaine was administered separately and was not admixed with any other medications or local anesthetics.

I hope this clarifies this question. The conclusions drawn are based on the data obtained from this randomized, double-blinded, prospective, Level I evidence study.


AAOS Now welcomes reader comments and efforts to "set AAOS Now straight." We reserve the right to edit your correspondence for length, clarity, or style. Send your letters to the Editor, AAOS Now, 9400 W. Higgins Rd., Rosemont, Ill. 60018, fax them to (847) 823-8033, or email them to aaoscomm@aaos.org