Analgesic Effect of Liposomal Bupivacaine: Comment

This is the authors' abstract. We don't add key points for this paper.

To the Editor: We read with interest the article by Chan et al.1 entitled, “Addition of Liposomal Bupivacaine to Standard Bupivacaine versus Standard Bupivacaine Alone in the Supraclavicular Brachial Plexus Block: A Randomized Controlled Trial,” in which the authors compared the analgesic efficacy of these two agents in patients undergoing surgeries for distal radial fractures. Unfortunately, problems with (1) the study design, specifically with differences between the quantity of the agents administered; (2) questionable clinical significance of the measured outcomes; and (3) appropriateness of off-label use of liposomal bupivacaine limit the utility of this publication. According to the package insert, the amount of bupivacaine in the liposomal form is expressed as the free base of bupivacaine. It recommends that when calculating the total dose of bupivacaine for coadministration, the amount of bupivacaine can be converted to the equivalent of bupivacaine HCl by multiplying by a factor of 1.128. Therefore, a 10-ml vial of liposomal bupivacaine contains 150 mg bupivacaine HCl, to which another 10 ml 0.5% (50 mg) of standard bupivacaine was added. This means that the liposomal bupivacaine group received approximately 200 mg, or twice as much bupivacaine, as was administered to the standard group (which received 20 ml 0.5% plain agent). The authors attempt to explain away this imbalance as needed to ensure primary brachial plexus anesthesia; however, 200 mg of plain bupivacaine would have better balanced comparative effectiveness and appropriateness for primary brachial plexus anesthesia. Alone this significantly different dosing plan could clearly have affected the results. More problematic, though, is the choice of primary and secondary outcomes. Although early mobilization of the wrist may have beneficial effects, it may also be associated with the loosening of the implant or fracture displacement, and thus most patients remain immobilized in a splint, with limited ability for movement (other than fingers) in this early postoperative period. Therefore, evaluating pain with activity might be problematic. Also, while statistically significant, a lack of clinical significance between a mean area under the receiver operating characteristics curve numerical rating scale pain score of 0.6 and 1.4 (P < 0.001) is evidenced by similarities in the oxycodone consumption, quality of recovery, and sleep disturbances between the groups. Notably, the editorial in the issue by Ilfeld and Sessler confirms that, by the second day, the results of this study did not provide strong evidence of benefit of liposomal bupivacaine, and the authors remind us of the 100-times difference in the cost of liposomal bupivacaine as compared to plain bupivacaine.2 Last, off-label medication use is legal and does not necessarily mean that drugs currently not approved by the Food and Drug Administration (Silver Spring, Maryland) are being used inappropriately. However, off-label use becomes an ethical issue when it is unclear if patients exposed were properly informed of liposomal bupivacaine’s off-label use for supraclavicular brachial plexus blockade in this study.3 The fact that research of clear benefit of liposomal over plain bupivacaine is lacking should be considered a risk worth disclosing to patients. Importantly, those using this study’s data to support expanded off-label use of liposomal bupivacaine for other peripheral nerve blocks should proceed cautiously and clearly inform future patients of its clinical equipoise. Controversy about the utility of liposomal bupivacaine versus plain bupivacaine persists, but we will never come to a definitive conclusion while the quality of studies comparing the two remains murky. Competing Interests Drs. Rosenblatt and Johnson are directors on the ASRA Pain Medicine (Pittsburgh, Pennsylvania) Board of Directors. Dr. Rosenblatt edits several chapters of regional anesthesiology topics for UpToDate.