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Re: "Which Drug is Better for Post-op Pain Control?" (July Manager's Guide to Ambulatory Anesthesia, osmag.net/hBpEP3). I was disappointed to read your article, which seemingly set out to objectively evaluate the value of Exparel based on a thorough review of available clinical data. The article's central premise is that the value of Exparel is derived from its ability to provide "better pain control" than standard bupivacaine. This narrow interpretation leaves out a crucial and measurable benefit associated with Exparel, one that has broad-ranging implications for patient care and healthcare costs: opioid minimization. The ability to reduce the consumption of opioids has been shown to trigger a cascade of value-driving outcomes: lower rates of opioid-related adverse events and complications, faster recovery, shorter hospital length of stay, lower costs of care, and improved patient satisfaction and quality of recovery after surgery. The impact of Exparel on opioid consumption has been well-documented in literature,1-3 but was overlooked in the article in favor of a simple and one-dimensional measure: pain scores.
Pain, and hence pain scores, are highly subjective in nature, and while they must be a part of the equation when evaluating a new pain modality, they cannot be the only endpoint reviewed. In our institution, we've evaluated the impact of Exparel across surgical procedures, with research presented at the Society of Critical Care Medicine4 and accepted at this year's American College of Surgeons meeting demonstrating a reduction in opioids in both orthopedic and soft tissue procedures that lead to an improvement in other clinical outcomes examined (ambulation, time to flatus and others, for example). In our evaluations, which looked at Exparel compared to PCAs and epidurals, we saw no clinically significant differences in pain scores — a nod to the efficacy of Exparel, which seems to rival considerably potent treatment modalities — but the decrease in opioid consumption gave way to markedly better clinical outcomes.
Regardless, if this article decided that the battle between Exparel and standard bupivacaine would be won or lost based solely on pain scores, then it should have factored in the results of 2 important, peer-reviewed studies presenting Level I evidence demonstrating the statistically significant decrease in pain scores associated with Exparel:
- A double-blind, randomized, active-controlled prospective study5 found that colorectal surgery patients in the Exparel arm had statistically superior post-operative NRS (numeric rating scale) pain scores and significantly less opioid use than patients in the standard bupivacaine arm.
- A pooled analysis of efficacy and safety data from 9 double-blind, placebo- or active-controlled multimodal analgesia studies comparing liposome bupivacaine to standard bupivacaine across 5 surgical models1 found that Exparel in a multimodal setting was associated with statistically significant and clinically meaningful lower cumulative pain scores at 72 hours, delayed and less consumption of opioids, and fewer ORAEs (opioid-related adverse events) than bupivacaine HCl.
While a deep data dive serves a critical function when making evidence-based decisions, it is most meaningful when viewed through the lens of clinical experience and real-world outcomes. I sincerely hope your readers will take an independent view of all the available data on Exparel, weigh it against their own clinical experience, and that of their peers and peer institutions, and formulate an evidence-based assessment of its value to patients and the healthcare system.
Outpatient Surgery Magazine responds: We thank Dr. Faley for his comments. We agree with Dr. Faley that pain is notoriously difficult to study, and we agree that personal clinical experience is an important aspect of evaluating medications. We respectfully disagree with the remainder of his points.
Dr. Faley says, "The impact of Exparel on opioid consumption has been well-documented in literature," citing 3 studies. We find no convincing support for that statement in the studies he cites.
In the first study, a Pacira employee and Pacira consultants aggregated the results of 9 small Pacira clinical trials into one large patient group. They found that Exparel patients took 1 to 2 fewer 5 mg Percocets over a 3-day post-op period. Weak as those results are, even they are in question, because the authors appear to have included data from 2 placebo-controlled studies in addition to the studies with active controls, potentially making the data look better than they actually are.
The second and third studies suggest that Exparel may help to reduce opioid consumption, but fail to address whether bupivacaine in the exact same dosage would have produced the exact same result. Therefore, they are irrelevant to this discussion. The first was a study of colectomy patients; it compared PCA opioid analgesia (rather than bupivacaine) to a multimodal analgesic approach that included Exparel. It was also underpowered, with only 39 patients. The second study looked at microvascular breast reconstruction. It compared multimodal anesthesia including Exparel to an unspecified (and apparently highly variable) retrospective cohort of patients who received "traditional care after surgery." The lead author of the second study is a Pacira consultant and the lead author of the third study is a Pacira stockholder.
While we haven't seen Dr. Faley's study, it also appears to be of questionable relevance, since it compares Exparel to PCAs and epidurals, not bupivacaine.
Finally, Dr. Faley writes that we should have factored in the results of 2 more studies in our analysis of Exparel vs. bupivacaine. We've addressed one of the studies above. The second study is likewise unconvincing:
- While it shows that 266 mg Exparel is superior to 75 mg bupivacaine, the other 2 formulations of Exparel did not exhibit statistically significant differences from 75 mg bupivacaine. That result begs the question: If the researchers had tested 75 mg bupivacaine against 266 mg bupivacaine, would they have arrived at the same result?
- The study is underpowered, with only 25 patients in each arm. The authors admit that the "study was not originally powered to take multiple comparisons into account."
- The bupivacaine study group is significantly skewed toward women. It's 42% female. By contrast, the 266 mg Exparel group is only 12% female. That's important because studies show women feel pain more intensely than men.
- The difference the study found in opioid consumption is very small, just one 5 mg Percocet more per day.
- The lead author of the study received $50,000+ from Pacira in 2013, and a Pacira employee is the second author.
The question we raise in our article is not whether Exparel works. Clearly it does. The question is whether the data show that it works any better than bupivacaine. From our analysis of the data, the answer appears to be no.
- Dasta J, Ramamoorthy S, Patou G, Sinatra R. Bupivacaine liposome injectable suspension reduces opioid burden compared with bupivacaine HCl in the postsurgical setting. CMRO 2012 September (online).
- Cohen S, Vogel J, Marcet J, Candiotti K. J Pain Research. 2014;7: 359—366.
- Batdorf N, Lemaine V, Lovel J, et al. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2015;68(3):395-402.
- Kaplan J, Faley B, Thomas Z, Chang T, Levine H, Klein G. Evaluation of liposomal bupivacaine for pain management after total knee arthroplasty. [Abstract #629] Society of Critical Care Medicine 1/15.
- Haas E, Onel E, Miller H, Ragupathi M, White P. American Surgeon. 2012;78:574-581.
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