Liposomal Delivery Systems for Local Anesthetics

The use of local anesthetics to treat pain has many potential advantages compared to the systemic administration of opioid analgesics. Local infiltration of an analgesic at the painful site avoids possible opioid side effects, including respiratory depression, sedation, nausea, vomiting, pruritus, urinary retention, impaired bowel motility, and development of tolerance. However, the results of clinical trials of local anesthetic infiltration to manage postoperative pain have often been disappointing, primarily due to local pharmacokinetic factors. Being relatively small-sized molecules, local anesthetics readily traverse blood vessel walls and are thus removed from the injection site. This rapid redistribution from the site limits the duration of effective analgesia, and the usefulness of this approach to pain control. Despite this limitation, the concept of local anesthetic infiltration to manage postoperative or posttraumatic pain remains appealing. Often in the past, research efforts to prolong local anesthetic duration centered on structural alterations of the local anesthetic molecule and identification of new agents with local anesthetic action. More recently, the focus has shifted to drug delivery systems that act as reservoirs for local anesthetics. Two essential criteria for an effective drug delivery system are residence time at the injection site and drug release rate. The carrier vehicle must be of sufficient size to resist rapid redistribution from the injection site. Furthermore, slow and sustained drug release from the carrier vehicle is needed to produce significant prolongation of analgesia. Investigators have been experimenting with a variety of matrices as carrier vehicles for local anesthetics. This review is limited to examining one type of carrier vehicle, liposomes, which have already been shown to effectively prolong analgesia in an animal-wound model.1 Liposomes, microscopic lipid vesicles formed when dry lipids are suspended in an excess of water, were first described in 1965. Since then, many types of liposomes have been elaborated. When amphipathic lipid molecules with a polar “head” and 2 hydrophobic hydrocarbon “tails” are suspended in aqueous medium, they spontaneously associate into bilayers. The structure of each bilayer resembles that of animal cell membranes, with the hydrocarbon chains oriented toward one another and the polar head group moieties in contact with the surrounding aqueous phase. The resulting vesicle structure consists of an aqueous compartment surrounded by one or more lipid bilayer(s). The lipid bilayer is relatively impermeable to entrapped substances. Liposome architecture is determined by the nature of the interactions between the lipids and the aqueous medium that occur during the preparation process. Liposomes with a single bilayer, or lamella, are known as unilammellar vesicles, and liposomes with many concentric bilayers are known as multilamellar vesicles. Other liposomes, composed of many smaller vesicles within larger vesicles, are known as multivesicular vesicles. In addition to differing structures, liposome size may vary from less than 20 nm to many microns in diameter. Both water-soluble and lipid-soluble drugs may be incorporated into the aqueous and lipid phases of liposomes, respectively. The liposomes function as vehicles to deliver drugs in high concentrations to specific targets while avoiding systemic drug toxicity, because only a fraction of the drug is bioavailable at any time. Liposomal behavior in vivo and drug release characteristics are dictated by liposome size, structure, and composition. Liposomal size affects in vivo distribution. For example, after subcutaneous administration, liposomes less than 120 nm in diameter readily gain access to capillaries and are thus rapidly redistributed from the site of injection, whereas relatively large liposomes tend to remain From the Department of Anesthesiology, New York University School of Medicine, New York, New York. Accepted for publication August 12, 2000. Reprint requests: Gilbert J. Grant, M.D., Associate Professor, Department of Anesthesiology, New York University School of Medicine, 550 First Ave, New York, NY 10016. E-mail: gilbert.grant@med.nyu.edu © 2001 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/01/2601-0013$5.00/0 doi:10.1053/rapm.2001.19166