The stark reality is that postoperative pain (POP) is usually a continuous experience for which intermittent therapy is classically provided. Developing long-lasting treatment options would facilitate the necessary flexibility in the total pain management program to achieve the desired goal of more accurately matching the duration of therapeutic choices with the period of most intense pain. The current thrust is to treat pain based on the mechanism of its causation rather than just focusing on the symptom. This is likely why, in this author’s view, that opioids are not always the most effective agent; they are given for the generic complaint of “pain” without careful regard to the specific mechanism that undergirds the offending insult. The challenge to treat POP is magnified by the fact that more and more surgical procedures are being done as ambulatory/outpatient or short-stay procedures, so the classic modalities, like patient-controlled analgesia and epidural analgesia, are not as practical.1 These patients need treatments that are portable and simple enough to be managed by the health care partners in the home environment.
Nonetheless, the dire consequences of inadequately/poorly managed POP pervade the perioperative period; unnecessary patient discomfort and dissatisfaction, increased costs for unexpected or extended hospital stay, impaired clinical outcomes, and the induction of chronic postsurgical pain syndromes.2 Among others, the American Society of Anesthesiologists Practice Guidelines fittingly advocate for the use of multimodal management strategies through which the essential objective is to use modest doses of a number of agents in a coordinated program to avoid the side effects of large doses of any 1 drug class.3 This approach not only targets the mechanism of the pain complaints but also acknowledges that pain can have many sources, that is, inflammation, reflex muscle spasm, anxiety, etc. The multimodal approach is dynamic and decreases the need for opioids, which frequently generate bothersome and adverse effects. The last-mentioned consequence is particularly important, given the proclivity with which opioids can incite side effects, a situation that can be difficult to manage when the patient is in the hospital setting, let alone at home with far fewer resources.
In this issue, Ilfeld et al.4 bring to light the reality that peripheral nerve blocks, although a recognized component of a multimodal management plan, do not last >6 to 12 hours, even with some of the touted additives. The lead author has admirably advocated for continuous infusion techniques now that there are reliable catheters and pumps for ambulatory use.5 However, this approach to patient management requires an expense for the drug and equipment, a secure phone contact pathway for care questions and (home) removal of the catheter, educated health care partners and carries the risk of bleeding and/or infection as with any invasive procedure. So there are limitations that need to be overcome. These considerations brought Ilfeld et al.4 to utilize an approved depo-formulation of a long-acting local anesthetic in a peripheral nerve block model, the ultimate goal being to demonstrate the potential for long-duration benefit with a pain management technique that is initiated at the time of the surgical procedure.4
Ilfeld et al.4 present their dose-response study, completed in 14 “healthy” volunteers. They used a liposomal preparation of bupivacaine (Exparel®, Pacira Pharmaceuticals, Parsippany, NJ), which is Food and Drug Administration-approved for infiltration of wound margins, as the agent for femoral nerve block.4 The authors6,7 gained the appropriate Investigational New Drug protocol registration and IRB approval to proceed with the prospective, randomized, clinical trial. Using a convenience sample, each volunteer received bilateral femoral nerve blocks under ultrasound guidance with a 30-mL injectate containing varying concentrations of Exparel® (from 0–80 mg liposomal bupivacaine in saline) in a double-blind manner. The end points were: maximum voluntary isometric contraction (MVIC) of the quadriceps muscle and tolerance to electrical stimulation in the femoral nerve distribution at the medial knee. Serial measurements were taken preblock and until the volunteers regained 80% of their baseline MVIC. The authors reveal that a dose response, as reflected by the MVIC and e-stim tolerance, was achieved but in the opposite direction than was expected (a higher dose of bupivacaine had lower observed effects). Yet at 24 hours post-block, 100% of the volunteers receiving doses greater than 40 mg depo-bupivacaine had evidence of sensory block and 90% of motor block. The authors logically conclude that the search for more convincing evidence must continue, as it will in appropriate, Food and Drug Administration-approved phase II and phase III studies.
We can wonder if there is anything in the infiltration data for Exparel® that would suggest that the preparation is suitable for peripheral nerve blocks. The liposomes do contain bupivacaine in the free-base form, which should enhance the availability of the drug for nerve penetration. But this study does not directly address this aspect of speculation. Rather, in studying the onset of nerve block effect, the authors found no association with the dose and sensory or motor effects. As to the magnitude of effect, there was no association of the dose with the time to maximum motor effect, although there was for the peak sensory effect. As to duration, many volunteers manifested evidence of a >24-hour effect.
These confusing results create further concern about this particular study design. It is difficult to thoroughly screen volunteers for the stated and relevant exclusion criteria, in particular neuromuscular diseases that could alter their clinical sensory and motor responses. Sedatives can impact a patient’s perception of pain.8 The effect might be enhanced in drug/substance-naïve volunteers, so some of the data obtained early in the study after the volunteers were premedicated with oral diazepam require cautious interpretation. Given that there was not an apparent, progressive increase in dose for each subsequent volunteer, such that some doses were repeated, this study doesn’t really qualify as a dose-response design, which was one of the authors’ study goals. An explanation as to why the authors chose 80 mg as the maximum dose of Exparel® to use, knowing that the infiltration dose is up to 260 mg, is not provided. It may simply be that the doses studied, even though the bupivacaine was in the free-base form, were simply too low to exert a profound enough, consistent effect on femoral nerves (that are thick structures compared with wound margin nerves) to demonstrate a clinical effect in this model. Another unexplained issue is why 80% return of the MVIC was chosen as the index of recovery; perhaps this is a level at which the volunteers could ambulate, as one would desire in an outpatient setting.
The obvious protocol deviations are both troubling and perplexing. Missing motor data, as from the first 4 of 14 volunteers, is a large percentage to overlook. The possible skullduggery of 2 volunteers in accurately reporting their clinical condition is another drastic flaw. As scientists, we conduct experiments with the expectation that they will percolate along an anticipated pathway. The misbehavior of 2 volunteers in this study reminds us that human subjects maintain their uniqueness even in scientific trials, perhaps being motivated by incentives separate and apart from the genuine pursuit of science! There are also significant data missing as to the duration of the sensory effects because the volunteers were sent home based on the recovery of motor function. The incomplete replacement of volunteers (why not replace all 4 rather than just 2?) only contributes to the dis ease with the data pool from the primary study group. It may be that the model was doomed to failure, given the low number of subjects included and/or the possible dilutional effects from mixing the liposomal preparation with saline. We are not assured that the liposomes maintain their integrity and thus follow the script of metered drug release with the saline admixture. Given the use-dependent nature of local anesthetic blocks, it is possible that the subsequent activity of the volunteers, as the blocks were resolving, impacted their clinical results.
Where does this study leave the clinician who is anxious to see the long wait for a reliable, extended-duration local anesthetic come to a fruitful end? We can extract some highlights from the research design. The authors did take a systematic approach in declaring a dominant side for each volunteer for the ordering of the nerve blocks and the follow-up evaluations. They assigned feasible working definitions of block onset and duration. They have profoundly demonstrated the critical needs for clinical studies to be both large enough and to utilize objective measures to assess the clinical effects. It is interesting that even the “…selected measures that have established reliability and validity and minimal interrater discordance…” weren’t as useful as hoped yet actually helped define the inadequate result of the study.4 The authors have also exposed that even with research volunteers there will be inter- and intrasubject variability of behavior and subjective clinical effects. Presumably, patients will only be more complicated! Thus, these results are not just related to concerns about the product studied. At least the authors have confirmed that there is a liposomal vehicle that is useful to emit drug over time.
Ilfeld et al.4 have raised more questions than they have answered. At a minimum, they have stirred our interest and fueled the fires of anticipation of practitioners. Their study is a jog along the path of what 1 day will become a reality. We need long-acting local anesthetics for injection, be that along an incision or for a variety of nerve blocks. Because there is a high concentration of inflammatory mediators at a wound margin, their infiltration with a local anesthetic, given the drug’s anti-inflammatory properties, is a coalescence of cause and effect. Use of this preparation as a peripheral nerve blocking agent is less so. But what an addition to our armamentarium for POP management, and especially for the ever-more-mobile postsurgical population of patients, a reliable depo-local anesthetic will be when the journey is ultimately concluded! More robust studies must follow, respecting the presently unknown tissue safety characteristics of Exparel® around peripheral nerves and using clinical effects measures that don’t confound the intended assessment, because the overarching therapeutic goal is admirable. A study with simpler statistical analysis of the data, because the results are more obvious, will engage the clinician and impel the hope of a new drug’s eminent release. Ilfeld et al.4 have grabbed our attention; the readership will remain patient but for a little while longer given the extensive time over which the road to discovery of a dependable encapsulated local anesthetic has been traveled. But perseverance is necessary when off-label, unstudied applications of approved drugs are broadcast. This concept is so vital that our major specialty journals adopted specific guidelines for authors when new uses of old drugs in new places are offered for publication.9 Obviating opioid-associated side effects with multimodal therapy will go a long way in benefiting all patients. But, there is the need to have readily available, safe options for broad application to replace these time-honored remedies. As health care moves towards a model in which patient satisfaction and patient outcome will be rewarded, the persistent challenge to effectively manage POP in and away from hospital settings looms large as an obstacle to our achieving these lofty goals. The drive to create a useful depo-local anesthetic preparation must continue and be successful.
Name: John C. Rowlingson, MD.
Contribution: This author wrote the manuscript.
Attestation: Dr. Rowlingson attests that the work is original and not under consideration for publication in another journal.
This manuscript was handled by: Terese T. Horlocker, MD.
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