CON: Liposomal Bupivacaine: A Mission Incomplete

May 1, 2019, 10:24 AM by Deepak Thapa, MB, BS, DNB, MNAMS, PDCC

An anesthetist’s dream of having a long-acting, nonaddictive solution for the management of postoperative pain is a long-standing affair. Liposomal bupivacaine (LB), with its prolonged half-life and a longer duration of analgesia,[1] was purported to meet that objective. Unfortunately, the available scientific data on LB has been inconclusive. Various publications have highlighted the dominance of LB over plain bupivacaine. However, the observed worthiness of LB calls for inclusion of more nonindustrial trials and consideration of additional viewpoints.[2]

To be useful for clinical practice, any new drug should have low cost, ease of availability, multiple routes of administration, explicit clinical benefits over the current standards of care, reduced toxicity, high-quality evidence-based indications, predictable pharmacology, and regulatory approval for its clinical use. In those contexts, the current evidence for LB has so far been inconsistent. A Cochrane review described some of LB’s usefulness in comparison to placebo but not to bupivacaine or other analgesics.[3]

The highlighted benefits of LB fail to extrapolate into clinical practice because of a deficiency in number of randomized controlled trials (RCTs) and advice on judicious interpretation of results.

Published scientific literature that includes phase II and III trials is inconclusive in building an opinion of approval or rejection of LB for management of postoperative pain. Pertinent issues requiring clarification include safety, analgesic efficacy, opioid-related issues, motor function, status of postoperative chronic pain, and cost effectiveness.[4],[5]

The highlighted benefits of LB fail to extrapolate into clinical practice because of a deficiency in a number of randomized controlled trials (RCTs) and advice on judicious interpretation of results.[6] Scarce data are available to approve LB for nerve blocks,[7] and widespread clinical use is not justified in the context of its exorbitant cost.[8] Supporting reviews on LB are also limited by publication bias and short-term follow-up.[9] Reviews and meta-analyses on LB lament issues related to limited sample size, number of RCTs, study design, and optimal dosing.[10],[11]

Nanolipid particles were acknowledged in 1965 as a drug vehicle to control the release and to improve the effects of local anesthetics.[12] In 2011, the United States Food and Drug Administration (FDA) granted approval to use LB as a single-dose surgical site infiltration intended to provide postoperative analgesia.[7],[13] However, despite a long history, LB is still considered investigational and is in pursuit of an appropriate representation in the armamentarium of anesthetists. A change in study design, inclusion criteria, and consideration of more painful surgeries has been advised for future trials.[7] Available studies with comparable,[14-16] negative,[5],[17-19] or beneficial outcomes[10],[20-22] on LB also suffer from suboptimal quantity and quality of evidence.

Regulatory Issues and Scope of Applicability

In the beginning, LB was granted approval for providing postoperative analgesia with surgical site infiltration in hemorrhoidectomy and bunionectomy. Later, approval was extended to include other surgeries as well.[23] Hence, most of the data on LB relate to infiltration use. Transverse abdominal plane block was later added,[24] but the data on those blocks have not been convincing.[7] Wider indications are being explored for LB.[25] Data on LB for perineural use and for postoperative pain management are scarce, and those available have been inconclusive to guide users, policy makers, or sponsors.[7]

Results on perineural use of LB have been discouraging too. LB was associated with increased nociception because of femoral nerve irritation following a femoral nerve block in anterior crucial ligament reconstruction surgeries.[26] Current data failed to demonstrate meaningful postoperative outcomes, including reduction in opioid consumption or resource use.[27] A meta-analysis demonstrated equivalent pain control with LB infiltration or interscalene block (ISB) and recommended additional high-quality RCTs and longer follow-up to properly compare LB’s efficacy and safety.[28]

Despite this, the FDA added ISB for shoulder surgeries to its approved list of LB indications, based on a single publication.[29]

Pharmacoeconomics of LB

The cost effectiveness of using LB is questionable and remains a barrier that limits more widespread use. A 20-mL vial of LB is $285, whereas the same volume of bupivacaine costs only $1.15.[30] This translates to LB being more than 100 times more expensive than conventional bupivacaine. The high cost of LB is prone to generate availability issues in developing countries; therefore, robust randomized trials are necessary to demonstrate LB’s actual cost effectiveness. In addition, no data are available on health economics for the use of analgesics after 72 hours.[7]

Pharmacologic Issues

Stability of LB solution in a mixture of other drugs is uncertain and the release for periarticular infiltration is unpredictable because of negligible data. In vitro pharmacologic studies are needed to assess potential systemic toxicities.[31]

Because of a paucity of data, commenting on LB’s adverse effects is difficult. The frequency of adverse effects is either comparable or lower than that of bupivacaine. Side effects include fever, gastrointestinal disturbances, and irritation at the site of injection.[32] Others have reported fecal incontinence,[33] platelets inhibition,[34] and femoral nerve palsy.[2] LB has also been implicated in prolonging inflammation and producing myotoxic effects.[33] LB should be used with caution in those at elevated risk for the development of compartment syndrome because of the scarcity of data regarding its onset of action, duration of sensorimotor blockade, and offsetting of effects.[35]

Newer, Extended-Release LB

In a recent review, extended-release LB like HTX-011 and SABER bupivacaine have shown promising initial results in safety and efficacy; however, the studies tend to be sponsored by drug companies and caution must be exercised when interpreting the findings. For now, only LB has FDA-approved indications for clinical use. More studies are thus required to formulate an opinion on these agents.[36] Extended-release LB SABER requires additional clinical studies to assess safety and efficacy.[37]

Final Verdict

LB is far from meeting expectations because of the paucity of robust studies. Additional areas of research could include robust comparisons of LB with continuous administration of conventional bupivacaine via perineural catheters or with single administration of conventional bupivacaine in combination with adjuvants. More studies on cost benefits are necessary, given LB’s cost. Newer evidence-based findings are essential to modify current judgement on LB.


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