Onset, defined as a decrease of 10% from baseline quadriceps MVIC, occurred within the first 10 and 20 minutes in 80% and 95% of subjects, respectively (1 subject exhibited onset between 40 and 50 minutes). There was no association between bupivacaine dose and onset time for motor (<0.01 hour/mg, SE = 0.01, 95% CI, −0.01 to 0.01, P = 0.95) or sensory (hazard ratio = 1.01 per mg, 95% CI, 0.99–1.03, P = 0.31) block.
Peak effects occurred within 24 hours after block administration in 75% of subjects (95% CI, 43%–93%). There was no association between bupivacaine dose and time until maximum motor block (MVIC nadir, Fig. 1; 0.04 hour/mg, SE = 0.10, 95% CI, −0.18 to 0.26, P = 0.67). In contrast, the association between dose and the time until sensory block peak was statistically significant (Table 3, Fig. 1). Each milligram increase in bupivacaine increased the time until sensory block peak 13 minutes (0.22 hour/mg, SE = 0.09, 95% CI, 0.01–0.43, P = 0.04). The linear mixed-effects model also found significant dose responses in MVIC (Fig. 2) and tolerance to cutaneous current (Fig. 3): for each milligram increase in bupivacaine, the MVIC increased an average of 0.09% (SE = 0.03, 95% CI, 0.04–0.14, P = 0.002) and tolerance to cutaneous current changed −0.03 mA per milligram of bupivacaine (SE = 0.01, 95% CI, −0.04 to −0.02, P < 0.001). In other words, the magnitude of motor and sensory block as measured by quadriceps MVIC and tolerance to cutaneous electrical current within the femoral nerve distribution both correlated with local anesthetic dose, but in the opposite direction than expected (the higher the dose, the lower the observed effect). The Akaike Information Criterion preferred the model with time treated as a categorical value and random subject-specific intercepts rather than models with time treated as continuous and/or compound symmetric covariance. The MVIC residual plots revealed skewness and heavy tails; the significant effect of dose on MVIC was robust to log transformation of the outcome and removal of outlier residuals, which yielded reasonable residual plots.
MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI, 54%–100%); and, for bupivacaine doses >40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 hours in 100% of subjects (Table 3, Fig. 4; 95% CI, 56%–100%). However, motor block duration was not correlated with bupivacaine dose (0.06 hour/mg, SE = 0.14, 95% CI, −0.27 to 0.39, P = 0.707).
There was 1 adverse event that occurred in the 12th subject (27 years of age; 180 cm; 77 kg; body mass index 24 kg/m2). The day after block administration, the subject noted pruritus around the needle entry site on the right side. The following day he complained of worsening pruritus in the same area, and a mild erythematous area of 10 cm diameter to the needle entry point was observed. The area was not contiguous, and there was no erythema within 2 cm of the entry site. There was no exudate or induration, and the site was not tender to palpation. The subject never exhibited fever, chills, rigors, or nausea/vomiting. Within the next 2 days, the rash and pruritus resolved completely without treatment. The subject was discharged home, per study protocol. The side that had developed the rash had received only normal saline within the femoral nerve block, while the opposite side, without any rash or pruritus, had received 80 mg of study medication. Per protocol, both needle sites had been prepared with chlorhexidine gluconate and isopropyl alcohol. The rash and pruritus were deemed unrelated to the study medication, but the etiology remains undetermined.
This dose-response study suggests that deposition of a liposomal bupivacaine formulation adjacent to the femoral nerve results in a partial sensory and motor block of over 24 hours for the highest doses examined, with a very high degree of intersubject variability. However, we emphasize that because the formulation used in our investigation is currently approved by the FDA exclusively for surgical infiltration, our protocol was executed only after an Investigational New Drug application was approved by this regulating body. In addition, its use in peripheral nerve blocks must still be considered experimental. Of relevance, the current study suggests that the interindividual response to the microsomal bupivacaine varies widely even within a narrow dose range, possibly making clinical application/results unpredictable.
Quadriceps MVIC data are unavailable from 4 of the initial subjects due to inaccurate recording of measurements by a research nurse. Two of these subjects had received placebo injections, and therefore we repeated placebo injections in 2 subsequent volunteers who received active treatment (80 mg) in their contralateral limb. For these 2 subjects, there was extraordinary correlation between active treatment and placebo for both quadriceps MVIC and tolerance to cutaneous electrical current (for these subjects, results of the 2 limbs receiving 80 mg are presented separately from the other subjects to help demonstrate these findings in Fig. 4). These findings are both curious and concerning, and we can only speculate on possible etiologies. The first is a placebo effect, in which each subject experienced quadriceps weakness and decreased cutaneous sensation in the limb that had received active treatment, and this carried over to the contralateral limb. Although possible, we believe it is improbable given this same model of bilateral femoral nerve blocks in volunteers has resulted in different results for different intrasubject treatments.34 Another conceivable etiology is a previously unreported effect of perineural normal saline on the femoral nerve. However, we find this explanation unconvincing given the near-perfect correlation of the limb that received placebo with the side receiving active treatment. Finally, while it is unsettling to raise this possibility, we would be remiss to exclude it: subjects were compensated for their time and efforts on a nightly basis—the more time they spent in the research center, the higher their total compensation. Thus, it is possible that these 2 subjects (who shared a research center room) purposefully and artificially reproduced their active treatment side findings in their contralateral limbs, in an effort to maximize study participation duration and compensation.
The inclusion of nonsurgical volunteers makes direct extrapolation to clinical practice difficult since the degree of postoperative analgesia correlating with the level of tolerance to cutaneous electrical current remains undetermined. Discerning the effects of liposomal bupivacaine on postoperative analgesia and optimizing dosing for various peripheral nerve blocks requires phase 2 and 3 clinical trials involving patients undergoing multiple types of surgical procedures. A related limitation of this investigation is the extremely limited number of subjects, common to all early phase studies. The study protocol produced considerable inter- and intrasubject variation in measured sensory and motor responses. There are several potential sources of such variability including the “noise” when small numbers of subjects are studied, the subjective nature of the perception of pain and muscle weakness in this experimental setting involving healthy volunteers, and the potential for variability in responses to the study medication, particularly at the lower dose levels.
Tolerance to cutaneous electrical current in 16 limbs (57%) failed to return to baseline because subject discharge was determined by a bilateral return of quadriceps strength, and not sensory deficit resolution. Thus, the maximum duration of sensory effects remains unknown. In addition, the doses chosen for each subject were not based on a predetermined algorithm, which resulted in some doses being more represented than others. Last, there is a loss of quadriceps MVIC data from 4 of the initial subjects due to observation error that decreases the available information for doses from 0 to 20 mg.
Our data also suggest that the study medication resulted in longer sensory block than motor block and did not produce substantial motor blockade of a prolonged nature greater than placebo. Combined with the relatively rapid onset time (95% of cases within 10–20 minutes), this liposomal bupivacaine formulation may provide an effect profile at least as favorable as currently available local anesthetic drugs. Nonetheless, the biologically implausible inverse relationship between dose and response magnitude attests to the need for a phase 3 study with a larger sample size; and, the results should be viewed as suggestive, requiring future confirmation. Finally, we emphasize this bupivacaine formulation is currently approved by the FDA exclusively for infiltration of surgical wounds. Therefore, for use in peripheral nerve blocks, a phase 3 trial involving surgical patients is the next logical step.
Funding for this project was provided by the Department of Anesthesiology, University of California San Diego (San Diego, CA); the Clinical and Translational Research Institute, University of California San Diego, with funding provided by the National Institutes of Health National Center for Research Resources grant UL1RR031980; and Pacira Pharmaceuticals, Inc. (Parsippany, NJ) provided a research grant and product (liposomal bupivacaine) used in this investigation. Dr. Ilfeld conceptualized the study and performed the protocol development, data collection and interpretation, and manuscript preparation, with limited input from Pacira Pharmaceuticals. Dr. Ilfeld and the University of California San Diego, retained full legal control over the resulting study data and its publication. Pacira Pharmaceuticals had the opportunity to review and comment—but not approve—the data analysis and resulting manuscript. Dr. Ilfeld was compensated as a consultant when writing the study protocol and manuscript (the consulting agreement was suspended during enrollment per University of California San Diego requirements, and Dr. Ilfeld’s nonclinical time during enrollment was partially funded by the research contract between Pacira Pharmaceuticals and the University of California San Diego). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the funding entities.
Name: Brian M. Ilfeld, MD, MS (Clinical Investigation).
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Brian M. Ilfeld has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Conflicts of Interest: Brian M. Ilfeld consulted for Pacira Pharmaceuticals (during protocol and manuscript authorship periods) and received research funding from Pacira Pharmaceuticals for this investigation, including funding for his nonclinical time used working on this project during enrollment.
Name: Nisha Malhotra, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Nisha Malhotra approved the final manuscript.
Conflicts of Interest: Nisha Malhotra received research funding from Pacira Pharmaceuticals for this investigation used to compensate nursing staff, volunteers, and the clinical research center.
Name: Timothy J. Furnish, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Timothy J. Furnish approved the final manuscript.
Conflicts of Interest: Timothy J. Furnish received research funding from Pacira Pharmaceuticals for this investigation used to compensate nursing staff, volunteers, and the clinical research center.
Name: Michael C. Donohue, PhD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Michael C. Donohue approved the final manuscript.
Conflicts of Interest: Michael C. Donohue received research funding from Pacira Pharmaceuticals for this investigation used to compensate nursing staff, volunteers, and the clinical research center, as well as funding for the nonclinical time Dr. Donohue used for this project.
Name: Sarah J. Madison, MD.
Contribution: This author helped design and conduct the study and write the manuscript.
Attestation: Sarah J. Madison has seen the original study data and approved the final manuscript.
Conflicts of Interest: Sarah J. Madison received research funding from Pacira Pharmaceuticals for this investigation used to compensate nursing staff, volunteers, and the clinical research center.
This manuscript was handled by: Terese T. Horlocker, MD.
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