In this issue of Anesthesia & Analgesia, Davidson et al.1,2 debut their new technology for preparing and using proliposomal nanoemulsions of ropivacaine in both piglet and human subjects exposed to painful stimuli. Nano is an expression adopted from the Greek word “νãνος” meaning “dwarf” and was approved in 1960 as an International Systems of Units prefix to mean a 10−9 (i.e., billionth) scale descriptor for base units describing mass, time, length, and others. With further specification, nanotechnology was coined by Taniguchi in 1974 to explicitly name the length scalar to denote nanometer dimensions of materials and “…mainly consists of the processing of separation, consolidation and deformation of materials by one atom or one molecule.”3 At these sizes, quantum effects become important, and these materials may display seemingly bizarre behavior unfamiliar to us living at the full-meter scale. For example, gold nanoparticles may visually appear crimson in color because of electron confinement and melt at only 300°C (in contrast, a gold bar melts at approximately >1000°C). Thaxton et al.4 used some unique properties of nanogold to develop a “…gold nanoparticle bio-barcode assay probe for the detection of prostate-specific antigen at 330 femtograms/mL.” A femtogram is 10−15 g. Indeed, nanotechnology has grown in every sector of the economy with health care functions now coming into development. In anesthesiology, nanotechnology has been reported primarily related to the areas of drug delivery (e.g., propofol, local anesthetics, volatile anesthetics).5–9 The present articles on proliposomal emulsions go further to articulate the use of nanotechnology in medicine.1,2
Liposomes are one type of nanotechnology, with the word simply meaning “fat body.” This class was created in the 1960s with a central compartment surrounded by a spherical shell-like assembly of surfactants (e.g., phospholipids) with nanometer-to-micrometer diameters. For years, scientists have inserted a variety of drugs (especially hydrophobic medications) into the central compartment in hopes of using liposomes as a drug delivery vehicle. Indeed, the very first report (identified by the present author) of local anesthetics bound within liposomes for anesthesia was reported in Anesthesia & Analgesia in 1988 by Gesztes and Mezei,10 wherein tetracaine was encapsulated in liposomes to provide effective topical anesthesia. Nearly 3 decades later, the potential for deposition of local anesthetic-loaded liposomes is still recognized although only 1 product (ExparelTM; Pacira Pharmaceuticals, Inc., San Diego, CA) is available currently in the United States and then it is only approved for surgical site infiltration, whereas central and regional anesthesia is not recommended.11 Why? The reasons are clear and not new. Others have previously editorialized to wonder whether liposomal formulations are safe for perineural injection.12,13 For example, what are the effects, if any, of injection of 1, 2-dierucoylphosphatidylcholine, 8.2 mg/mL (an inactive ingredient of Exparel), or other surfactants in close proximity to the brachial plexus for a large population (e.g., 100,000) of patients? Until safety issues can be definitively addressed, enthusiasm for liposome-based bupivacaine and other nanotechnology will be markedly diminished. Also, liposome manufacturing is not as highly developed as it is for single-molecule formulations (e.g., conventional bupivacaine). Indeed, it can be difficult to achieve the high degree of chemistry, manufacturing, and control between batches the public expects of US Food and Drug Administration-approved products. Finally, our only experience using liposomal bupivacaine for femoral nerve block resulted in unexpected, “…biologically implausible…” results, wherein the magnitude of femoral nerve block was inversely related to the bupivacaine dose.14 Bizarre behavior indeed. Clearly, more work needs to be done to understand the effects of local anesthetics bound in liposomes on peripheral nerves.
Moreover, this proliposomal technology is so novel that one must first think about the evolving definition of a prodrug. In referencing “pro” in the name of a pharmaceutical, one may think of prodrugs that are already routinely used in modern medicine such as clopidogrel, fospropofol, and others. From this perspective, a classic prodrug does not possess any intrinsic pharmacologic activity but instead serves as a substrate for the endogenous metabolism to produce a metabolite that causes a pharmacologic effect. The proliposomal emulsions described in the accompanying articles are not the type of classic prodrug you studied in medical school. Instead, in recent years, a number of “prodrugs” have been developed that attach an active drug to a carrier moiety of some type. These pharmaceuticals are now also called prodrugs, although this new designation adds confusion about the traditional definition of a prodrug. For example, the proliposomal emulsions described in this month’s issue actually carry a drug, ropivacaine, that can potentially be immediately active on administration without the need for additional processing by a patient’s native enzymes into a pharmacologically active form. The pro in this case references separation from the carrier molecule or matrix. Other, similar examples are manmade viral or enzyme-directed drugs. The addition of these newer prodrugs created sufficient nomenclature angst that Wu15 at the US Food and Drug Administration Center for Drug Evaluation and Research developed a contemporary classification system in 2009 to accommodate this new class of agents. In this system, prodrugs are typed by their site of conversion (intracellular [type I] or extracellular [type II]) and are then subtyped by the location of pharmacologic activity. If the nomenclature were caught up to the science, then one might classify proliposomal emulsions of ropivacaine as a type IIB or IIC prodrug.
The innovation of Davidson et al.,1,2 however, has outpaced even this new classification system. In referencing a prodrug, the authors mean even more by the “proliposomal” term than Wu envisioned. That is, liposomes are only formed from oil when injected into subcutaneous tissue, because proliposomes require extracellular fluid as a bulk matrix to convert into the liposomal form. In essence, the human body is required to “put together” the liposomes before they are more slowly “taken apart” over time as ropivacaine is released. Out of the bottle, the injectate is “…particle free and no liposomes or any lamellar structures were observed. In-vitro exposure to either saline or plasma caused the formation of an emulsion containing multilammelar [sic] vesicles…”1 The human body participates in creating the proliposomes, a fascinating and novel drug manufacturing and delivery approach. Thus, these new local anesthetic agents in the bottle might be better termed preproliposomal ropivacaine emulsions, similar to the preproinsulin from, in which the body’s 2-step process forms the biologically active hormone insulin. Notwithstanding, our vocabulary still lags behind the ever more rapidly expanding vistas of human imagination and experience.
Where would these new therapeutic agents fit into an anesthesiologist’s armamentarium? Depot forms of local anesthetics to create long-term analgesia have great attraction to anesthesiologists because of the simplicity of sustained analgesia with a single injection. Davidson et al.1,2 studied local anesthesia limited to a subject’s back, although interest will likely turn to applications in regional anesthesia as it did for liposomal bupivacaine with recent reports on intercostal, femoral, and ankle nerve blocks.16 The chief benefits encompass sustained postoperative analgesia without the need for management services and patient inconvenience that are associated with prolonged delivery of local anesthetics using a perineural sheath catheter(s) or use of adjuvants added to a local anesthetic injectate to prolong activity.17 Also, the absence of perineural sheath catheters might address concerns about postoperative anticoagulation.18 Moreover, a single, long-acting regional analgesic may well increase patient satisfaction, because this technique obviates the requirements for indwelling catheters, pumps, daily telephone calls from the pain management team, and family anxiety about removal of catheters at home to name a few benefits. On the con side of the pro technique, the release characteristics of the formulation suggest that it may be unlikely that surgical anesthesia can be achieved with proliposomes because sufficient concentrations of free ropivacaine may be insufficient to overcome the diffusion barrier to the site of action or, if anesthesia can be achieved, proliposomes may suffer from a significant delay in the time-pressured operating room environment. Indeed, such a phenomenon relegated the prodrug fospropofol to a sedation drug only because the time requirements for metabolism by alkaline phosphatase could not compete with the reference drug, propofol, although the exact pharmacokinetics of fospropofol remain unclear because of “analytical propofol assay inaccuracies” resulting in publication retractions.19–21 One might also concurrently inject nonliposomal-bound ropivacaine with the proliposomal formulation to achieve surgical anesthesia (either as a single injection or a catheter to be removed later), although the interactions of liposomes with this additional anesthetic formulation are not known. Likewise, we cede all additional control regarding modification of the analgesic intensity postoperatively, because there is no catheter that could allow patient-controlled analgesia on demand. With a view toward these issues, discrimination studies of the proliposomal technology would be best designed if compared with a “best available” treatment (i.e., perineural sheath catheter-based with continuous pump analgesia) and not to IV and/or oral analgesics in future studies of postoperative analgesia. Notwithstanding, the rapid pace of development of new methods to treat pain for our patients continues to make anesthesiology an exciting specialty encompassing the scientific practice of medicine, a point illustrated well by the work of Davidson et al.1,2 in this issue of Anesthesia & Analgesia.
Name: Timothy E. Morey, MD.
Contribution: This author helped write the manuscript.
Attestation: Timothy E. Morey attests to having approved the final manuscript.
Conflicts of Interest: Timothy E. Morey owns equity in and consults for Xhale, Inc. (Gainesville, FL) and NanoMedex Pharmaceuticals, Inc. (Madison, WI). In addition, the University of Florida owns equity in these companies. If a product is sold commercially, then the author and the University of Florida could benefit financially.
This manuscript was handled by: Terese T. Horlocker, MD.
1. Davidson EM, Haroutounian S, Kagan L, Naveh M, Aharon A, Ginosar Y. A novel proliposomal ropivacaine oil: pharmacokinetic-pharmacodynamic studies after subcutaneous administration in pigs. Anesth Analg. 2016;122:1663–72
2. Ginosar Y, Haroutounian S, Kagan L, Naveh M, Aharon A, Davidson EM. Proliposomal ropivacaine oil: pharmaokinetic and pharmaodynamic data after subcutaneous administration in volunteers. Anesth Analg. 2016;122:1673–80
3. Taniguchi N. On the Basic Concept of ‘NanoTechnology.’ In: Proceedings of the International Conference of Production Engineering, Vol II. 1974 Tokyo Japan Society of Precision Engineering:18–23
4. Thaxton CS, Elghanian R, Thomas AD, Stoeva SI, Lee JS, Smith ND, Schaeffer AJ, Klocker H, Horninger W, Bartsch G, Mirkin CA. Nanoparticle-based bio-barcode assay redefines ‘undetectable’ PSA and biochemical recurrence after radical prostatectomy. Proc Natl Acad Sci USA. 2009;106:18437–42
5. Morey TE, Modell JH, Shekhawat D, Shah DO, Klatt B, Thomas GP, Kero FA, Booth MM, Dennis DM. Anesthetic properties of a propofol microemulsion in dogs. Anesth Analg. 2006;103:882–7
6. Morey TE, Modell JH, Shekhawat D, Grand T, Shah DO, Gravenstein N, McGorray SP, Dennis DM. Preparation and anesthetic properties of propofol microemulsions in rats. Anesthesiology. 2006;104:1184–90
7. Jee JP, Parlato MC, Perkins MG, Mecozzi S, Pearce RA. Exceptionally stable fluorous emulsions for the intravenous delivery of volatile general anesthetics. Anesthesiology. 2012;116:580–5
8. Salama IE, Jenkins CL, Davies A, Clark JN, Wilkes AR, Hall JE, Paul A. Volatile fluorinated nanoemulsions: a chemical route to controlled delivery of inhalation anesthesia. J Colloid Interface Sci. 2015;440:78–83
9. Fukazawa K, Pileggi A, Fraker C, Ricordi C, Pretto E. In vivo safety studies of a 4.5% isoflurane/intralipid nano-emulsion in rats. In: Anesthesiology 2012. October 13–17, 2012 Washington, DC American Society of Anesthesiologists
10. Gesztes A, Mezei M. Topical anesthesia of the skin by liposome-encapsulated tetracaine. Anesth Analg. 1988;67:1079–81
12. Duncan L, Wildsmith JA. Liposomal local anaesthetics. Br J Anaesth. 1995;75:260–1
13. Rowlingson JC. We’re on the road to depo-local anesthetics, but we aren’t there yet. Anesth Analg. 2013;117:1045–7
14. Ilfeld BM, Malhotra N, Furnish TJ, Donohue MC, Madison SJ. Liposomal bupivacaine as a single-injection peripheral nerve block: a dose-response study. Anesth Analg. 2013;117:1248–56
15. Wu K-M. A new classification of prodrugs: regulatory perspectives. Pharmaceuticals. 2009;2:77–81
16. Ilfeld BM, Viscusi ER, Hadzic A, Minkowitz HS, Morren MD, Lookabaugh J, Joshi GP. Safety and side effect profile of liposome bupivacaine (Exparel) in peripheral nerve blocks. Reg Anesth Pain Med. 2015;40:572–82
17. Rahangdale R, Kendall MC, McCarthy RJ, Tureanu L, Doty R Jr, Weingart A, De Oliveira GS Jr. The effects of perineural versus intravenous dexamethasone on sciatic nerve blockade outcomes: a randomized, double-blind, placebo-controlled study. Anesth Analg. 2014;118:1113–9
18. Horlocker TT, Wedel DJ, Rowlingson JC, Enneking FK, Kopp SL, Benzon HT, Brown DL, Heit JA, Mulroy MF, Rosenquist RW, Tryba M, Yuan CS. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010;35:64–101
19. Ilic RG. Fospropofol and remimazolam. Int Anesthesiol Clin. 2015;53:76–90
20. Struys MM, Fechner J, Schüttler J, Schwilden H. Erroneously published fospropofol pharmacokinetic-pharmacodynamic data and retraction of the affected publications. Anesthesiology. 2010;112:1056–7
21. Struys MM, Fechner J, Schüttler J, Schwilden H. Requested retraction of six studies on the PK/PD and tolerability of fospropofol. Anesth Analg. 2010;110:1240