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Local anesthetics (LAs) are among the most useful drugs in anesthesiology practice and pain management. They are cornerstones in postoperative pain management within a multimodal analgesic pathway to reduce or eliminate opioids and their resulting adverse events. However, currently available LAs display a considerable range of onset and duration as well as tolerability across a wide range of uses, including infiltration, peripheral blocks, and epidural and spinal anesthesia. Their main limitation is duration of action, which in the treatment of postoperative pain may prevent adequate therapy of sufficient duration. For that reason, continuous catheter infusion systems are widely used but introduce challenges, such as catheter placement, catheter migration and maintenance, and the burden of the external pump. Therefore, long-acting LAs with predictable onset, delivery, and duration of action would be a near-ideal solution.
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Local anesthetics can have considerably different properties depending on the body compartment where they are placed. Controlled-release LAs must be well studied for clinical efficacy and reliability in the various sites and modes of application. At this time, only one controlled-release drug is approved by the Food and Drug Administration (FDA) and is commercially available, although there are several others in development. In this chapter, we summarize the currently available information.
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LOCAL ANESTHETIC CARRIERS
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Since the 1970s, drug delivery systems for LAs have been the subject of considerable research efforts.1,2,3 Development strategies are typically based on interdisciplinary approaches that combine polymer science, pharmaceutics, bioconjugate chemistry, and molecular biology.4 The goals of these carriers are to provide a LA depot at the target site to prolong the drug effect and to decrease local and systemic toxicity by reducing the LA concentration and increasing LA permeability and absorption. These factors determine the concentration and the effect of the LA on the nervous tissue, influencing the latency, spread, intensity of the blockade, and the duration of action.1
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Formulation approaches to systemically deliver LA have included the encapsulation in liposomes, complexation in cyclodextrins, association with biopolymers, transdermal nonliposomal carriers, and other carrier systems. Topical delivery systems for LA comprise of a wide spectrum of adjuvants, including viscosity-inducing agents, preservatives, permeation enhancers, and emollients. The physical state of these carriers varies from semisolid (gel, cream, ointment); liquid (emulsion, dispersion); to solid (patch) pharmaceutical forms.1
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Liposome-Based Local Anesthetic Formulations
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Liposomes, widely investigated as drug carriers for improving the delivery of therapeutic agents to specific sites in the body, are nonimmunogenic, biodegradable, nontoxic and work by encapsulating both hydrophilic and hydrophobic materials to deliver drugs.4 The structural versatility combined with the ability to encapsulate different compounds, such as LAs, is due to microscopic mono- or bi-layer phospholipid vesicles.1 The polar core of the liposphere allows hydrophilic drug molecules to become encapsulated. Amphiphilic and lipophilic molecules are solubilized within the phospholipid bilayer according to ...