See Article, p 1843
Liposomal bupivacaine was first made available for Food and Drug Administration (FDA)-approved use in 2011 with the promise of obtaining long-lasting analgesia with only a single injection. It is only clinically available in one form (Exparel; Pacira Pharmaceuticals Inc, Parsippany, NJ) and has been advertised as being effective for up to 72 hours. In light of the opioid epidemic, providers from many specialties hoped the prospect of effective prolonged pain relief would be achieved with this new long-lasting formulation. However, clinical trials comparing liposomal bupivacaine to conventional long-lasting local anesthetics are generally unsupportive of these claims,1–3 especially if industry-driven studies are excluded. Despite the lack of evidence of superiority over conventional local anesthetics, liposomal bupivacaine continues to be widely used in clinical practice.
One challenge with liposomal bupivacaine is the limitation it places on supplemental local anesthetic administration to address inadequate analgesia. The FDA label for Exparel states that no additional local anesthetic should be used within 96 hours of liposomal bupivacaine administration. What are the options if a patient who had local infiltration of liposomal bupivacaine for an abdominal surgery incision, periarticular injection, or intercostal nerve blocks experiences uncontrolled pain? To date, no study has been published evaluating the safety of subsequent conventional local anesthetic administration after using liposomal bupivacaine. For the regional anesthetist, determining if, when, and how to safely dose additional local anesthetic for rescue blocks is a difficult challenge.
PHARMACOKINETICS OF LIPOSOMAL BUPIVACAINE
In this issue, Manson et al4 report serum bupivacaine concentrations over 96 hours following intercostal injection of 266 mg of liposomal bupivacaine for open thoracotomy surgery. Understanding the pharmacokinetics and duration of effect of liposomal bupivacaine in all its varied uses is important and we applaud the authors for their contribution to this understudied area.
Although there is a relative paucity of available data, their results are for the most part consistent with prior work.5–9 They highlight the considerable interpatient variability in drug pharmacokinetics and effects. For example, with regard to pharmacokinetics, they reported a median time to maximum concentration (Tmax) of 24 hours with a range of 0.5–48 hours. Compared to other liposomal bupivacaine studies, this is longer than the Tmax of 10 hours for epidural injection6 (no range reported), similar to the Tmax (range) of 24 hours (8–48) for subcutaneous infiltration5 and the Tmax of 24 hours (0.5–49) after periarticular infiltration.9 It is shorter than the Tmax of 48 hours for periarticular infiltration using a mixture of liposomal and conventional bupivacaine.8 The variability about the reported mean or median is of particular interest as their large range spans from minutes to days after administration.
With respect to maximum serum concentration (Cmax), Manson et al4 reported a median value of 0.6 with a range of 0.3–1.2 µg/mL. Subjects had serum concentrations of ≥1 µg/mL as early as 15 minutes and as late as 24 hours after injection. Detectible levels persisted up to 72 hours, albeit at levels <0.3 µg/mL. The Cmax was higher than what has been reported in the other studies, even compared to a study that used a dose twice as large (566 mg) for subcutaneous injection.7 This is likely a function of the increased vascularity of the intercostal site of injection and is consistent with observations of conventional local anesthetic.10 Perhaps the most important point regarding Cmax of liposomal bupivacaine is that none of the reported peak concentrations were above levels considered at risk for toxicity. It is also important to point out that the levels can remain high enough for many days after administration to be of concern for potential toxicity when combining with additional local anesthetic.
The work by Manson et al4 and other studies demonstrate consistent themes. Liposomal bupivacaine injection results in (1) prolonged serum bupivacaine levels that can persist up to 72 hours, (2) variability in the time to maximal concentration that can occur within minutes or as late as ≥48 hours, and (3) variability in maximal concentration. Given the wide ranges, it is fair to say that it is difficult to predict the time course of plasma bupivacaine concentrations.
Some of the most interesting findings from this study were in regard to duration of drug effect. The authors reported a median time to loss of sensory nerve block as 48 hours with all but 3 subjects reporting sensory blockade at 24 hours and a quarter of subjects reporting sensory blockade at 72 hours. However, it is particularly worth noting that serum bupivacaine concentration levels had no correlation to the presence or absence of a clinical nerve block. Even when liposomal bupivacaine appeared to have no effect, serum concentrations levels remained detectable for up to 72 hours. Also of interest, the reported pain scores didn’t appear to correlate with the presence or absence of a clinical nerve block, although pain assessments were made in the presence of a comprehensive multimodal pain regimen, including intrathecal morphine and intravenous ketamine.
PHARMACOKINETICS OF CONVENTIONAL BUPIVACAINE
Serum concentrations after conventional bupivacaine peak within minutes and can reach undetectable levels in <12 hours.11–13 Cmax can be significantly higher than liposomal bupivacaine, with levels that can surpass conservative serum bupivacaine toxicity thresholds of 2.0–3.0 µg/mL. For example, a study evaluating serum bupivacaine concentrations in subjects who received 300 mg of conventional bupivacaine in combined sciatic/lumbar plexus blocks reported Cmax values that ranged from 0.23 to 4.8 µg/mL with a mean (±standard deviation) Tmax of 29.3 (±13.5 minutes).14 Another study for transversus abdominis plane blocks also demonstrated elevated serum levels that ranged from 0.23 to 3.5 µg/mL with a mean Tmax of 30 minutes after a 100 mg dose of conventional bupivacaine.15
This presents a challenge to regionalists called upon to address inadequate pain control with the administration of additional local anesthetic before 96 hours has elapsed from the liposomal bupivacaine administration. As there is no study evaluating serum bupivacaine levels when combining liposomal bupivacaine with subsequent conventional bupivacaine, it is currently unknown what the resulting serum concentrations would be. It is reasonable to assume that there would at least be an additive effect. The concern of course is that of local anesthetic systemic toxicity (LAST).
LOCAL ANESTHETIC SYSTEMIC TOXICITY
Prior work has established that the local anesthetic dose required to produce LAST is variable and influenced by site of injection, type of local anesthetic, use of epinephrine, hepatic dysfunction, muscle mass, age, and presence of underlying heart disease.16 Additionally, measured serum local anesthetic concentrations vary even when controlling for dose, volume, type, and site of injection.14 Even more, onset of LAST can occur at highly variable serum concentrations. In a study by Knudsen et al,13 healthy volunteers receiving intravenous infusions of bupivacaine first complained of LAST symptoms with serum concentrations as low as 1.3 µg/mL and as high as 5.1 µg/mL.
While studies have shown that liposomal bupivacaine serum concentrations remain well below what is considered a safe limit, levels can peak as early as 15 minutes after injection and persist for up to 72 hours. Serum levels after nerve blocks performed with conventional bupivacaine have been reported to be above the conservative cutoff of 2.0 µg/mL. This should be taken into consideration when contemplating whether or when to administer additional local anesthetic after administering liposomal bupivacaine.
There are several important findings of the pharmacokinetic behavior of liposomal bupivacaine highlighted by the study from Manson et al4: (1) After a substantial dose of liposomal bupivacaine in the intercostal space, peak plasma concentrations remain well below conservative toxic thresholds. (2) Peak plasma concentrations can occur within minutes or as late as 48 hours after injection. (3) Plasma concentrations remain elevated for as long as 72 hours but diminish before the 96-hour limit recommended by the FDA for use of additional local anesthetic. (4) Prior experience has taught us that conventional local anesthetics are absorbed differently at different locations throughout the body. This is primarily a function of the vascularity of the tissue bed infiltrated with local anesthetic. Liposomal bupivacaine exhibits the same behavior. (5) Plasma bupivacaine concentrations are not related to duration of sensory changes and may be elevated even in the absence of clinical nerve block.
Some useful recommendations can be made thanks to the work by Manson et al4 along with the results of prior studies. First, the FDA recommendation of no additional local anesthetics within 96 hours of liposomal bupivacaine is likely overly conservative. Additional local anesthetic after 72 hours appears to be more reasonable. Second, assuming an additive effect, performing a rescue block with conventional local anesthetic within minutes up to 48 hours later may place a patient at increased risk for LAST, especially when risk factors for increased susceptibility to LAST are present. If the practitioner determines that a rescue block is in the best interest of the patient, we recommend decreasing the dose of conventional local anesthetic used to 50% of the recommended weight-based dose.
The significant variability in both Tmax and Cmax after administration of liposomal bupivacaine makes it challenging for the regional anesthetist to determine when it may be safe to perform a rescue nerve block. In effect, the practitioner is “blocking blindly” with respect to local anesthetic toxicity risks. Further studies are needed to characterize the pharmacokinetics of combining liposomal administration with subsequent conventional local anesthetics.
Finally, some clinicians have failed to embrace liposomal bupivacaine as a replacement for regular bupivacaine. There are several reasons. Chief among them are the lack of nonindustry-driven trials showing positive results in head-to-head comparisons as well as clinician suspicion of overstated benefits by the manufacturer, which drew an official rebuke from the FDA. We postulate that a well-conducted clinical trial that provides convincing evidence that liposomal bupivacaine improves outcomes in postoperative pain control compared to less expensive conventional local anesthetics is needed to sway skeptical clinicians to endorse and use liposomal bupivacaine.
Name: Michael J. Buys, MD.
Contribution: This author helped write and edit this manuscript.
Name: Ken B. Johnson, MD.
Contribution: This author helped write and edit this manuscript.
This manuscript was handled by: Markus W. Hollmann, MD, PhD.
1. Ilfeld BM, Gabriel RA, Eisenach JC. Liposomal bupivacaine infiltration for knee arthroplasty: significant analgesic benefits or just a bunch of fat? Anesthesiology. 2018;129:623–626.
2. Bravin LN, Ernest EP, Dietz MJ, Frye BM. Liposomal bupivacaine offers no benefit over ropivacaine for multimodal periarticular injection in total knee arthroplasty. Orthopedics. 2020;43:91–96.
3. Patel KM, van Helmond N, Kilzi GM, et al. Liposomal bupivacaine versus bupivacaine for intercostal nerve blocks in thoracic surgery: a retrospective analysis. Pain Physician. 2020;23:E251–E258.
4. Manson WC, Blank RS, Martin LW, et al. An observational study of the pharmacokinetics of surgeon-performed intercostal nerve blockade with liposomal bupivacaine for posterior-lateral thoracotomy analgesia. Anesth Analg. 2020;131:1843–1849.
5. Davidson EM, Barenholz Y, Cohen R, Haroutiunian S, Kagan L, Ginosar Y. High-dose bupivacaine remotely loaded into multivesicular liposomes demonstrates slow drug release without systemic toxic plasma concentrations after subcutaneous administration in humans. Anesth Analg. 2010;110:1018–1023.
6. Viscusi ER, Candiotti KA, Onel E, Morren M, Ludbrook GL. The pharmacokinetics and pharmacodynamics of liposome bupivacaine administered via a single epidural injection to healthy volunteers. Reg Anesth Pain Med. 2012;37:616–622.
7. Rice D, Heil JW, Biernat L. Pharmacokinetic profile and tolerability of liposomal bupivacaine following a repeated dose via local subcutaneous infiltration in healthy volunteers. Clin Drug Investig. 2017;37:249–257.
8. Buys MJ, Murphy MF, Warrick CM, et al. Serum bupivacaine concentration after periarticular injection with a mixture of liposomal bupivacaine and bupivacaine HCl during total knee arthroplasty. Reg Anesth Pain Med. 2017;42:582–587.
9. Bramlett K, Onel E, Viscusi ER, Jones K. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee. 2012;19:530–536.
10. Tucker GT, Mather LE. Properties, absorption, and disposition of local anesthetic agents. Neural Blockade in Clinical Anesthesia and Management of Pain. 1988:Philadelphia: Lippincott Company; 47–111.
11. Bardsley H, Gristwood R, Baker H, Watson N, Nimmo W. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol. 1998;46:245–249.
12. Scott DB, Lee A, Fagan D, Bowler GM, Bloomfield P, Lundh R. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg. 1989;69:563–569.
13. Knudsen K, Beckman Suurküla M, Blomberg S, Sjövall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth. 1997;78:507–514.
14. Eljebari H, Jebabli N, Salouage I, et al. Population pharmacokinetics of bupivacaine in combined lumbar and sciatic nerve block. Indian J Pharmacol. 2014;46:201–206.
15. Trabelsi B, Charfi R, Bennasr L, et al. Pharmacokinetics of bupivacaine after bilateral ultrasound-guided transversus abdominis plane block following cesarean delivery under spinal anesthesia. Int J Obstet Anesth. 2017;32:17–20.
16. Weinberg G, Rupnik B, Aggarwal N, Fettiplace M, Gitman M. Local anesthetic systemic toxicity (LAST) revisited: a paradigm in evolution. apsf Newsletter. 2020;35:1–32.