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REGIONAL ANESTHESIA: Edited by Jacques E. Chelly

Liposomal bupivacaine for regional anesthesia

Uskova, Anna; O’Connor, Jessica E.

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Current Opinion in Anaesthesiology: October 2015 - Volume 28 - Issue 5 - p 593-597
doi: 10.1097/ACO.0000000000000240
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Abstract

INTRODUCTION

Approximately, 70 million surgical procedures are performed annually in the USA with 21–30% of the patients experiencing moderate-to-severe pain in the postoperative period [1,2]. This inadequate relief of postoperative pain has adverse physiologic effects that can contribute to significant morbidity and mortality, resulting in the delay of patient recovery and return to daily activities [3]. Instituting a multimodal and multidisciplinary approach to postoperative analgesia provides the benefits of improved cardiac, respiratory, and gastrointestinal function, fewer thromboembolic events, more rapid patient mobilization, improved healing, reduced healthcare costs, improved patient satisfaction, and reduced chronic after surgical pain [4].

Regional and local anesthesia plays an important role in multimodal postoperative pain management. Single-injection peripheral nerve blockade with bupivacaine local anesthetic has been shown to provide pain control that is superior to opioids with fewer side-effects [4]. This technique, however, is limited by the short duration of analgesic effect after bolus dose administration (typically <24 h) and the maximal dose that may be safely administered. Prolonging the effect with perineural catheters and mechanical pumps to deliver the local anesthetic increases the duration of postoperative analgesia, but requires specialized training for placement and maintenance, increases overall expense, and introduces complications including infection, intravascular placement, and intravascular migration with associated local anesthetic toxicity. An attempt has been made to circumvent these constraints with the creation of a depot formulation of bupivacaine that provides a slow drug release at the site of injection. By doing so, the plasma peak drug concentration is reduced thereby allowing the well controlled administration of a larger dose of local anesthetic to prolong the analgesic effect [5].

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BUPIVACAINE LIPOSOME INJECTABLE SUSPENSION

An extended-release bupivacaine formulation, DepoFoam bupivacaine (EXPAREL, Pacira Pharmaceuticals, Inc., Parsippany, New Jersey, USA), was approved in the USA by the Federal Drug Administration in October 2011. The DepoFoam bupivacaine is encapsulated by lipid-based particle layers that form multiple aqueous chambers which resemble a spherical honeycomb [6]. As the body resorbs the lipid walls, the unaltered bupivacaine is slowly released into the surrounding tissue. This design allows diffusion of the drug over 96 h after a single administration [6]. The product is currently available only in a 20 mL single-use vial 1.3% (13.3 mg/mL) with the total dose of the vial being 266 mg, which is the recommended maximum dosage of liposomal bupivacaine [7].

In the pharmacokinetic study of human volunteers, Davidson et al.[8] compared subcutaneous injection of 20 mL of 2% liposomal bupivacaine versus 20 mL of 0.5% plain bupivacaine. They found no difference in the Cmax between the two groups (0.87 ± 0.45 versus 0.83 ± 0.34 in plain and liposomal groups, respectively) despite a four-fold increase in bupivacaine dose and a 9.8-fold increase in the terminal half-life displayed by the liposomal bupivacaine group (131 ± 58 versus 1294 ± 860 min in plain and liposomal groups, respectively). The Tmax increased seven-fold in the liposomal bupivacaine group compared with the group administered plain bupivacaine, which was attributable to the slow release of liposomal bupivacaine and has been confirmed in a subsequent Phase II, multicenter clinical trial conducted by Langford et al.[9].

EFFICACY IN POSTOPERATIVE PAIN

Currently, liposomal bupivacaine is only indicated for local infiltration for pain relief after bunionectomy and hemorrhoidectomy and has not yet been approved for other routes of administration including intra-articular use, peripheral nerve blocks, and intravascular use, although trials are currently ongoing [7]. In September 2014, the Food and Drug Administration (FDA) [10] issued a Warning Letter focused on the expansion of Exparel's claims beyond two specific surgeries, promoting its use in various other surgical procedures, other than those for which the drug has been shown to be well tolerated and effective. Recently, FDA ordered Pacira to issue corrective messaging to all affected audience that ‘pain control beyond 24 h has not been demonstrated’, based on Phase III clinical trials.

SURGICAL FIELD BLOCK

In a Phase III, multicenter, double-blind study conducted by Gorfine et al.[11], 189 adults undergoing excisional hemorrhoidectomy were randomized to receive either 300 mg of liposomal bupivacaine (EXPAREL) or placebo by surgical site infiltration. The primary outcome measure was cumulative pain score, calculated from the Area under the Curve (AUC) of a graph of pain severity monitored at regular intervals over 72 h. Results demonstrated a 30% reduction in cumulative pain score in liposomal bupivacaine versus the placebo (AUC0–72 h 141.8 versus 202.5; P < 0.0001). In addition, patients required less rescue analgesia and had increased time to first opioid use in the liposomal bupivacaine group compared with placebo. The difference in mean pain intensity between treatment groups, however, occurred only during the first 24 h following study drug administration. Between 24 and 72 h after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity.

Golf et al.[12] conducted a multicenter, parallel group, placebo-controlled, randomized, double-blind study in which they compared liposomal bupivacaine with placebo in patients undergoing bunionectomy. The patients received either a single dose of 120 mg (8 ml) liposomal bupivacaine or placebo (8 ml 0.9% sodium chloride) by local infiltration with the outcome measures including the AUC of Numerical Rating Scale (pain measurement) pain scores through regular intervals up to 72 h, proportion of patients who were pain free, time to first rescue medication use, and total oxycodone/acetaminophen consumption through the 72 h period. Patients receiving liposomal bupivacaine experienced a statistically significant reduction in pain compared with the placebo group as evidenced by the 24 h AUC (123.9 versus 146.2; P = 0.0005). Patients who reported no pain were significantly different at 2, 4, 8, and 48 h in the liposomal group compared with placebo (P < 0.05). The time to first opioid use was longer (7.2 h versus 4.3 h, P < 0.0001) and cumulative dose of oxycodone/acetaminophen was less through 24 h in the liposomal bupivacaine group compared with the placebo (3.8 versus 4.7 tablets, P = 0.0077). Standard bupivacaine hydrochloride (HCL) was not evaluated in this study.

Rolando et al.[13] evaluated the use of EXPAREL in abdominal field block injections for postoperative pain management in 64 women undergoing abdominoplasty with rectus placation. Afterwards, both delivery of intramuscular, intravascular, and oral pain medication and length of time to resume normal activity were recorded. Average pain scores were 3.5 (postoperative visit 1) and 2.8 (visit 2) with the average number of oral pain pills required being 14 at visit one and 11.5 at visit two. Patients were able to resume normal activity at an average of 6.4 days. The results suggest that patients experienced reduced postoperative pain, required less postoperative narcotics, and resumed both ambulation and normal activity earlier with EXPAREL local injections. Several major limitations in the study warrant further investigation. No comparison groups were evaluated, multiple procedures were performed in conjunction with the primary surgery, and pain scale and normal activity evaluation was subjective.

PERIARTICULAR INJECTION

Bagsby et al.[14▪▪] performed a retrospective cohort study, which compared 85 patients undergoing a total knee arthroplasty with a traditional periarticular injection of ropivacaine, epinephrine, and morphine to 65 patients with a liposomal bupivacaine injection. Findings reported after the initial 24 h demonstrated higher self-described pain scores in the liposomal bupivacaine group compared with the traditional injection group (P = 0.04). A smaller percentage (16.9%) of patients in the liposomal bupivacaine group rated their pain as ‘mild’ compared with the traditional group (47.6%). The inferior pain control in the liposomal bupivacaine group may be explained by the slow release of the drug from the liposomes, which can alter the pharmacodynamic properties of the drug. This has been demonstrated in lidocaine, a structural cousin of bupivacaine, in a previous study by Mashimo et al.[15]. The current study is limited by several factors: it is not a randomized, prospective study, the effect of the periarticular injection may be technique dependent although only two surgeons performed the procedure, and documentation of opiate administration and recording of pain scores may have varied among the nursing staff. It was concluded that there is no benefit to intra-articular injection of liposomal bupivacaine when compared with traditional ropivacaine and epinephrine injection.

Bramlett et al.[6] completed a double-blinded, dose-ranging study assessing four-dose levels of liposomal bupivacaine compared with plain bupivacaine in local wound infiltration for patients undergoing total knee arthroplasty. They concluded that there was no statistically significant trend toward lower pain scores in liposomal bupivicaine 266, 399, and 523-mg groups through days 2, 3, and 5. The mean pain scores, total consumption of rescue opioids, and time to resumption of work, or normal daily activities were not statistically different across the treatment groups.

According to Barrington et al.[16▪], the technique for periarticular injection of liposomal bupivacaine is critical to a successful result of infiltration. It is recommended that a smaller needle (22 gauge versus 18 gauge) be utilized for administration and that the distribution of medication be in small amounts over a larger number of locations. The method of administration in earlier studies is not well defined and should be investigated further.

PERIPHERAL NERVE BLOCKS

In a dose–response cohort study by Ilfeld et al.[17], bilateral single-injection femoral nerve blocks with varying doses of EXPAREL were administered randomly in a double-blinded fashion to investigate the onset, magnitude, and duration of the sensory and motor block produced in 14 patients. Motor effects of study drug were assessed via measurement of maximum voluntary isometric contraction (MVIC) of quadriceps femoris muscles; sensory effects were measured via evaluation of tolerance to transcutaneous electrical stimulation. Results demonstrated statistically significant dose responses in MVIC and tolerance to cutaneous current with a higher dose of EXPAREL producing a lower observed effect, a paradoxical finding. This may be attributed to small sample size and subjective measurement instruments. With each milligram increase in bupivacaine, MVIC increased by a mean of 0.09% [standard error (SE) = 0.03; 95% confidence interval (CI): 0.04–0.14; P = 0.002] and tolerance to cutaneous current decreased by 0.03 mA (SE = 0.01; 95% CI: −0.04 to −0.02; P < 0.001). The correlation between dose and sensory block was nonsignificant and the correlation between dose and motor blockade reversed to the expected direction. There was no correlation between motor block duration and bupivacaine dose. These results suggest that EXPAREL deposited next to the femoral nerve results in a partial sensory and motor block lasting more than 24 h, although with a very high degree of intersubject variability within a narrow dose range, making clinical application/results unpredictable. Limitations included small sample size, nonsurgical healthy volunteer patients, and observation error during MVIC testing.

SAFETY

Local anesthetics, in particular bupivacaine, are known to cause serious cardiotoxic and neurotoxic side-effects [18]. The introduction of slow release liposomal bupivacaine may significantly improve the postoperative pain control in surgical patients with reduced risk of toxicity and side-effects. Liposome bupivacaine has been well tolerated in studies conducted, thus, far with a higher safety profile when compared with bupivacaine HCL and control groups [19]. The most common side-effects of liposomal bupivacaine in clinical trials included nausea, vomiting, constipation, pyrexia, dizziness, and headache [6].

Prolonged duration local analgesia releasing systems are associated with myotoxicity and inflammation that outlasts the duration of nerve blockade [20▪▪]. Local tissue injury including inflammation, myotoxicity, and neurotoxicity from EXPAREL was investigated in a rat model sciatic nerve regional blockade study by McAlvin et al.[21▪▪]. The duration of sensory block achieved by EXPAREL was, approximately, twice that achieved with commonly used bupivacaine HCL 0.5%. It was found that EXPAREL caused the same degree of myotoxicity as the 0.5% bupivacaine HCL group, but less than the 1.31% bupivacaine HCL group. Two weeks postinjections, inflammation in the EXPAREL group was greater than the 0.5% bupivacaine HCL and similar to that from 1.31% bupivacaine HCL. This long-lasting inflammation was also documented in previous EXPAREL studies. Surveillance for local tissue injury is recommended for future clinical use.

A study by Richard et al.[22] involving the multidose administration of EXPAREL (9, 18, 25, or 30 mg/kg) for brachial plexus nerve blockade in rabbits and dogs in comparison with bupivacaine HCL (9 mg/kg) and saline demonstrated to be well tolerated with a nearly four-fold lower CMAX in the EXPAREL group and only mild granulomatous inflammation of adipose tissue around nerve roots at postinjection days 3 and 15. The results indicated that EXPAREL was well tolerated and did not cause irritation or significant local tissue damage.

According to the EXPAREL pharmaceutical guidelines, DepoFoam bupivacaine should not be coadministered with any other local anesthetic or be allowed to come in contact with wet topical antiseptics like chlorhexidine or povidine iodine [7]. Disruption of the liposomal carrier may result in an uncontrolled immediate release of bupivacaine, resulting in toxicity.

Liposomal bupivacaine is metabolized mainly in the liver, with a small amount excreted unchanged in the urine. Onel et al.[23] found that in patients with moderate hepatic impairment, the differences were small enough not to warrant dose adjustments as per FDA guidelines. It has not been evaluated for safe usage in pediatric or obstetric patients.

CONCLUSION

DepoFoam-encapsulated bupivacaine (EXPAREL) is a promising local anesthetic drug formulation for postoperative analgesia that provides a slow sustained release of bupivacaine from multivesicular liposomes. Compared with placebo, it has been shown to produce prolonged analgesia with an opioid sparing effect. However, recently FDA requested correction to ‘pain control beyond 24 h has not been demonstrated’, based on clinical trials. Furthermore, Exparel's increased analgesic efficacy and cost-effectiveness compared with plain bupivacaine and other standard local anesthetics in various clinical settings needs to be evaluated in adequately powered clinical trials.

The safety profile of EXPAREL is comparable to standard bupivacaine. It has not been shown to be more toxic and does not have markedly different cardiac effects. It is well tolerated for use in patients with moderate hepatic impairment. Further investigation is required to determine safe usage in pediatric and obstetric patients, as well as in peripheral nerve blocks and neuraxial anesthesia.

Currently, the FDA approved clinical use for EXPAREL is for local site infiltration only. It may have potential utility in other forms of local and regional anesthesia. More multicentered trials with larger patient groups are needed to evaluate its efficacy and safety for perineural, intrathecal, and epidural administration. Until then, the advantage of liposomal bupivacaine over standard bupivacaine is speculative.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

REFERENCES

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Keywords:

bupivacaine; DepoFoam bupivacaine; EXPAREL; liposomal bupivacaine

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