Liposomal Bupivacaine, Scientific Evidence, and the Clinician’s Conundrum

On April 14, 2021, Pacira Biosciences, Inc., filed a complaint in the United States District Court, District of New Jersey, alleging a single count of trade libel against the American Society of Anesthesiologists (ASA; Schaumburg, Illinois), the editor-in-chief of the Journal, and the authors of two articles and an editorial published in the Journal. Here is a summary of the original complaint as it appears in the final decision issued by this lower court.  Pacira’s allegations stem from the February 2021 issue of Anesthesiology. The cover caption of the February 2021 issue stated that “Liposomal Bupivacaine Is Not Superior to Standard Local Anesthetics,” and the issue contained several articles that allegedly contained false and misleading statements disparaging Exparel. Pacira specifically challenged a meta-analysis of studies conducted on Exparel a narrative review of Exparel trials and an editorial based on the meta-analysis and narrative review.  Pacira alleged that each of the articles employed flawed methodologies by, among other things, cherry-picking data, relying on studies that Pacira believed were deficient, improperly discrediting studies favorable to Exparel, and failing to properly limit their conclusions that Exparel is not effective. ASA’s motion to dismiss the original complaint was granted by the New Jersey U.S. District Court in a decision filed on February 4, 2022. Pacira appealed to the United States Court of Appeals for the Third Circuit.

By March 2023, news of the decision of the appellate court was just reaching the public. The opinion of the court written by the Honorable Patty Schwartz,⁹  filed on March 24, 2023, affirmed the lower court’s ruling, which granted ASA’s motion to dismiss the complaint: “Pacira BioSciences, Inc. (‘Pacira’) sued the American Society of Anesthesiologists, Inc. (‘ASA’), the editor-in-chief of its medical journal, and the authors of three articles for statements made about one of Pacira’s drug products.^* Pacira claims that the statements constitute trade libel. Because the District Court correctly concluded that the statements that form the basis of Pacira’s trade libel claim are nonactionable opinions, Pacira has failed to state a basis for relief. We will therefore affirm.”

About the time of this ruling, Dr. Deborah Culley and I had begun our work as Interim Co-Editors-in-Chief of Anesthesiology. We discovered another meta-analysis on liposomal bupivacaine in the queue of articles awaiting peer review; uncertainty and uneasiness set in. In the wake of this ruling and the enormous costs borne by the ASA, how should we handle a similar article by some of the same authors named in the original lawsuit? A look at the court ruling brings some important cues and encouragement for us as scientists, but it also highlights the imperfect process of scientific discovery and the conundrum that clinicians face when trying to translate published findings into clinical practice.

Again, in Judge Schwartz’s words,“This trade libel action arises out of allegedly false and misleading statements about liposomal bupivacaine …” “Pacira complains that Defendants published statements in a variety of forms, all of which conveyed their view that EXPAREL is ‘not superior’ to standard analgesics or provides ‘inferior’ pain relief.”

In their complaint, Pacira raised issues with each of the two articles and the accompanying editorial that were published in the February 2021 issue of the Journal. Pacira claimed that the authors had selected articles that disfavored Exparel and employed flawed statistical methodologies. Pacira filed a complaint alleging a single count of trade libel, seeking remedies of harm to the reputation of their product. Pacira sought relief based on two statements: (1) that Exparel is “not superior” to local anesthesia, and (2) that it is an “inferior analgesic.” In their ruling, the Court concluded that these statements made in the published articles were nonactionable opinions. The Court offered several lines of reasoning for their conclusions. First, a “fair and natural” reading of these statements, meaning the understanding that reasonable people of ordinary intelligence would give to it, shows that these are nonactionable subjective expressions—they are just the opinions of the authors. Judge Schwartz also called on an earlier ruling by the Second Court of Appeals: “Most conclusions contained in a scientific journal article are, in principle, capable of verification or refutation by means of objective proof. Indeed, it is the very premise of the scientific enterprise that it engages with empirically verifiable facts about the universe. At the same time, however, it is the essence of the scientific method that the conclusions of empirical research are tentative and subject to revision, because they represent inferences about the nature of reality based on the results of experimentation and observation.” Judge Schwartz then concludes, “The statements here expressly claim they are tentative scientific conclusions.” The judge emphasized that the authors of these articles went to great lengths to discuss the limitations of their studies openly and honestly, freely admitting the flaws and the tentative nature of their conclusions.

Two further statements from Judge Schwartz’s Third Court of Appeals ruling are important to consider. She underscores the importance of this ruling in preserving scholarly debate: “Pacira’s critiques about the Articles’ data and methodology may be the basis of future scholarly debate, but they do not form the basis for trade libel under New Jersey law. To conclude otherwise would risk ‘chilling’ the natural development of scientific research and discourse.”

The Court goes on to tell us, “… the journal’s readers were provided the basis for the statements [in the published articles], have the expertise to assess their merits based on the disclosed data and methodology, and thus are equipped to evaluate the opinions the authors reached.”

The Court was clear: open scholarly debate is critically important, and anesthesiologists, scientists, and other expert readers of scholarly journals are fully capable of making their own assessments about the opinions offered by authors based on the strengths and weaknesses of the very arguments those authors make in their publications. Therein lies the clinician’s conundrum, deciding which among the constant stream of new scientific findings that are published every day are ready for translation into clinical practice.

This important ruling resonates. It is a ruling that upholds the imperfect process that we use as scientists and clinicians to evaluate new information and make decisions about the everyday care of our patients. We have new articles arriving every day and another well-crafted meta-analysis that our peer reviewers have deemed worthy of publication to decide about. Given the lengthy and expensive legal proceedings, can the Journal stay true to its purpose—to transform practice by disseminating the latest and best science to clinicians working at the bedside? Will the Journal editors decide what is published based on scientific merit alone, even if the threat of further legal action looms?

The answer is a resounding yes! The Journal will always stay true to its purpose and maintain its scientific integrity and critical editorial independence. The editors have reviewed, critiqued, and decided to publish this set of articles and editorials using the time-proven peer-review process. Here is our best effort to keep the argument out of yet another courtroom and assure that it stays in the scientific community, where we can make advances in our understanding of how and when to use new drugs and techniques for the benefit of our patients. The topic of just how much greater benefit this commonly used drug is to our patients beyond other existing treatments is deserving of debate in the “public square” of our profession, and clinicians need to hear all sides to help them form their own opinions.

We invited this series of editorial perspectives—yes, they are opinions—knowing full well that even the best conducted analyses will have flaws. These analyses add to our understanding of this drug and its use, and at the same time suggest new directions for future research. I hope you will take the time to read this new article and the varied opinion pieces. Understanding that the scientific process is messy and imperfect, let’s heed the courts’ direction by continuing open and respectful debate in the published literature, where our debates can lead to better treatments and outcomes for our patients.