Abstract
The need for better post-surgical pain management continues to be unmet, despite clinicians’ awareness and concern for many years. Opioids remain the standard of care because of their analgesic efficacy; however, opioid use is often associated with adverse effects and poor patient outcomes. Multimodal analgesic regimens have recently been endorsed as a way to provide adequate post-surgical pain control while reducing opioid consumption. Liposome bupivacaine is a liposomal formulation of bupivacaine indicated for a single administration into the surgical site. Based on the available clinical trial data compiled to date, as well as the author’s review of publicly available post-marketing safety information, liposome bupivacaine may be a viable addition to currently available therapeutic options for post-surgical analgesia while reducing potential risks associated with use of opioid analgesics, and may represent a useful addition to the multimodal analgesic modalities currently used for post-operative pain management. The potential for its use in other areas is also being investigated. The purpose of this review is to examine the currently available post-marketing safety information on liposome bupivacaine.
1. Introduction
Most surgical patients experience pain of moderate to extreme intensity during the first few days of post-surgical recovery Citation[1]. Although the past two decades have been characterized by heightened awareness of pain as a medical concern and the need for better pain management, patient surveys show that the patient experience with respect to post-surgical pain has not improved over that time period Citation[1]. The American Society of Anesthesiologists, one of the institutions to provide guidance on post-surgical pain management, has endorsed the use, whenever possible, of multimodal analgesic regimens Citation[2]. These regimens involve the use of two or more analgesic agents with different analgesic mechanisms Citation[2].
One important consideration in providing adequate post-surgical analgesia is the need for repeated dosing of analgesics to overcome their short duration of activity relative to the duration of post-surgical pain, which typically extends for several days after surgery. Use of intravenous opioids delivered via patient-controlled analgesia devices is a frequently employed technology to provide point-of-care continuous analgesia. However, delivery of opioid analgesics via patient-controlled analgesia devices is associated with more than 10,000 adverse events and more than 100 patient deaths each year Citation[3]. Similarly, elastomeric pump devices are frequently used to extend duration of post-surgical analgesia by continuous delivery of standard local anesthetics. These devices have been associated with a number of device failures leading to safety reports and a recall Citation[4,5].
2. Liposome bupivacaine safety
Liposome bupivacaine (EXPAREL®; bupivacaine liposome injectable suspension, Pacira Pharmaceuticals, Inc., Parsippany, NJ, USA) is an extended-release formulation of the local anesthetic bupivacaine designed to provide post-surgical analgesia, via administration into surgical wounds, for up to 72 h. The efficacy and safety of liposome bupivacaine, established in controlled Phase II and Phase III clinical studies across a range of surgical settings (including hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation and bunionectomy), have been well described in recent publications Citation[6,7]. As yet, there have been no published reports in the peer-reviewed medical literature regarding post-marketing safety data associated with liposome bupivacaine.
In order to obtain a ‘real-world’ picture of potential safety issues associated with liposome bupivacaine, adverse events reported via the US FDA MedWatch system and the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database during the first 2 years of liposome bupivacaine availability (April 2012–March 2014) were tallied. The MedWatch databases were queried using the terms ‘Exparel’, ‘liposome bupivacaine’ and ‘bupivacaine HCl’. The liposome bupivacaine search returned a total of 174 adverse event incidents reported across 54 cases. The most frequently reported liposome bupivacaine-related adverse events were hypotension, which occurred in 15% (8/54) of the evaluable cases, and bradycardia, which occurred in 11% (6/54) cases. The bupivacaine HCl search returned a total of 318 adverse incidents reported across 113 evaluable cases. The most frequently reported bupivacaine HCl-related adverse events were inadequate analgesia (12% [13/113]), pain (10% [11/113]) and convulsion/seizure (10% [11/113]). As an informal comparison, the FDA’s MAUDE database was also searched for adverse events reported during the first 2 years of availability (2006–2007) for the most popular elastomeric pump device (ON-Q®, Halyard Health, Inc., Alpharetta, GA, USA). In the MAUDE database, there was a total of 139 safety reports during 2006–2007, an average of about 70 per year.
Obviously, no scientific conclusions can be drawn based on an informal search for anecdotal product-related reports on a few government-sponsored post-marketing databases, with no ability to compare the number of anecdotal safety reports associated with each product relative to the total number of uses for each product. Indeed, frequently reported adverse events in patients treated with liposome bupivacaine in clinical studies included nausea (33%), constipation (18%) and vomiting (12%); these were also the most frequently reported adverse events observed in patients treated with bupivacaine HCl in those studies (nausea [42%]; constipation [24%]; vomiting [13%]) Citation[7]. The overall rate of adverse events observed across the Phases II and III clinical studies of patients treated with liposome bupivacaine was 62% (compared with 75% with bupivacaine HCl and 43% with placebo) Citation[7]. Nevertheless, the findings from this informal search are interesting.
3. Conclusion
Based on the available clinical trial safety data compiled to date, as well as the author’s review of publicly available post-marketing safety information, liposome bupivacaine may be a viable addition to currently available therapeutic options for post-surgical analgesia with an acceptable tolerability while reducing potential risks associated with the use of opioid analgesics. Safety and efficacy data for liposome bupivacaine administered into the surgical site continue to accrue from studies in a variety of surgical models, including open and laparoscopic colectomy Citation[8,9], ileostomy reversal Citation[10,11], abdominal hernia repair Citation[12] and robotic prostatectomy Citation[13]. This formulation is also being evaluated for use in peripheral nerve block Citation[14].
4. Expert opinion
The goals of post-surgical pain management are to reduce or eliminate pain after surgery, while minimizing the risk of unwanted treatment-related effects. Despite the increased demand over the past few decades for clinicians to do a better job in achieving these goals, the need for effective, longer-acting analgesics that reduce post-surgical opioid consumption has remained largely unmet. Over-reliance on opioids continues to be the usual practice, despite the associated burdensome and costly adverse effects, and the growing concern among healthcare providers regarding opioid overuse and misuse. Advances in post-operative pain management may likely move toward delivery without indwelling catheters and pumps to avoid the inherent limitations associated with these devices. Non-opioid analgesics, extended-release local anesthetics and sublingual or transdermal patient-controlled analgesia may become the norm. Liposome bupivacaine represents one such extended-release, non-opioid therapeutic option that holds promise for advancing the current approaches for pain management in surgical patients. This local anesthetic formulation may offer clinicians the ability to provide prolonged analgesia and reduced reliance on opioids with a single administration that can be given during surgery. The efficacy and tolerability profile of this agent is supported by level II evidence from trials involving administration into the surgical site as part of multimodal analgesic regimens across 10 randomized, multi-center, double-blind, active- and placebo-controlled Phase II and III trials in numerous surgical models, including inguinal hernia repair, total knee arthroplasty, hemorrhoidectomy, breast augmentation and bunionectomy Citation[6,7]. While more clinical experience and data will be needed before definitive conclusions can be made regarding the ‘real-world’ safety and efficacy of liposome bupivacaine, this local anesthetic formulation may represent a potentially important step forward in the management of post-surgical pain.
Declaration of interest
This paper has been funded by Pacira Pharmaceuticals, Inc. ER Viscusi is a board member of the American Society of Regional Anesthesia and Pain Medicine, has received research funding through Thomas Jefferson University from AcelRx Pharmaceuticals, Inc., Cumberland Pharmaceuticals and Pacira Pharmaceuticals, Inc., has received honoraria/consulting fees from AcelRx Pharmaceuticals, Inc., Merck & Co., Inc., Mallinckrodt Pharmaceuticals, Pacira Pharmaceuticals, Inc., Salix Pharmaceuticals, and Trevena, Inc. Editorial assistance was provided by M Morren of Peloton Advantage, LLC, and supported by Pacira Pharmaceuticals, Inc. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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