Chapter 7 Newer Amide Local Anesthetics & Sustained-Release Local Anesthetics

Newer Amide Local Anesthetics: Introduction

The use of regional anesthesia has been increasing not only in obstetrics, where it is the predominant anesthetic technique used, but also during surgery and for acute postoperative pain management. This has been partly due to the safety of regional anesthesia because of better injection techniques and equipment, increased attention to detecting (preventing) misplaced injection, greater vigilance/monitoring, and the introduction of newer long-acting amide local anesthetics. The increasing demand for regional anesthesia is nowhere more true than in obstetric anesthesia, where local anesthetics have become the most frequently administered drugs for obstetric pain relief or cesarean delivery. When injected epidurally or intrathecally, local anesthetics provide effective labor analgesia that is superior to that of systemic opioids and without the attendant risks of maternal sedation and neonatal depression. Regional anesthesia is now the most frequently used technique for cesarean section delivery in the U.S.1

Historical Perspective

Why the need for new amide local anesthetics? The answer is partly related to the history of bupivacaine use, particularly in North America and Europe. After its introduction into clinical practice, bupivacaine quickly became very popular for several reasons, particularly for use in obstetrics. It has a longer duration of action than 2-chloroprocaine and lidocaine and thus requires less frequent supplemental doses, a feature that is less important now with the widespread use of continuous epidural infusion techniques. More important and in contrast to other local anesthetics, bupivacaine has a motor-sparing effect; it produces less motor block for a comparable degree of sensory analgesia. This is particularly true at the low concentrations used for labor epidural analgesia and acute postoperative pain management. Furthermore, bupivacaine has excellent compatibility with neuraxial opioids, and this allows for concentrations as low as 0.03% and 0.04% bupivacaine to be used successfully so that many patients are pain-free and even able to ambulate during labor or with regional analgesia after surgery. Less motor block also improves expulsive efforts during the second stage of labor and may reduce the need for an instrumental vaginal or abdominal delivery.2 The ability of bupivacaine to provide good sensory analgesia with little motor block is essential for management of postoperative, during which early mobilization may decrease the risk of deep venous thrombosis and result in better respiratory mechanics. Nonetheless, despite its many advantages, there have been some concerns regarding bupivacaine, particularly in obstetric anesthesia.

Clinical experience has been that cardiac arrest after unexpected intravascular injection of clinical doses of local anesthetics could be prevented by prompt oxygenation, ventilation, and, if necessary, cardiovascular support. However, in 1979, George Albright3 alerted anesthesia practitioners to a cluster of six anecdotal cases of sudden cardiac arrest after unexpected intravascular injection of what then were the newer amide local anesthetics, bupivacaine and etidocaine. In his editorial, Albright3 suggested that intoxication with bupivacaine (and etidocaine), in contrast to lidocaine and mepivacaine, could result in almost simultaneous onset of convulsions and circulatory collapse without antecedent hypoxia and acidosis.

Since then, bupivacaine has been shown to have a narrower margin of safety than lidocaine and mepivacaine.4–6 The ratio of the doses or plasma concentrations required to produce cardiovascular collapse compared with those associated with convulsions is lower for bupivacaine than for the other two drugs.5,6 Also, in contrast to the intermediate-acting local anesthetics, bupivacaine intoxication is associated with malignant ventricular arrhythmias, which may be difficult to treat.5,6 This is because unlike other amide local anesthetics, bupivacaine dissociates from blocked sodium channels at a much slower rate, resulting in a prolongation of the maximal rate of depolarization (Vmax) and creating the potential for reentrant-type ventricular arrhythmias.7

The epidemic of bupivacaine-related cardiac arrests, particularly among parturients in the U.S., directed interest toward discovering whether pregnancy itself enhances the arrhythmogenicity of bupivacaine.8 Indeed, in vitro studies conducted on rabbit heart preparations have demonstrated that myocardial muscle treated with progesterone and exposed to bupivacaine showed greater depression of Vmax than those exposed to lidocaine, thus increasing susceptibility to malignant reentrant-type ventricular arrhythmias.9

In vivo experiments have been less conclusive. In an early study using a small number of animals given a continuous intravenous infusion of bupivacaine, circulatory collapse occurred at lower doses and lower plasma drug concentrations in pregnant than in nonpregnant ewes.5 However, a subsequent study involving a larger group of animals and the use of blinding and randomization failed to confirm these findings.10 Cardiac arrest also occurred in surgical patients after intoxication with bupivacaine, but less frequently.

Some suggested that the disproportionate number of cardiac arrests among parturients compared with surgical patients was not related to increased sensitivity to the drug during pregnancy but to the widespread use of bupivacaine in obstetrics and, in some instances, to inadequate cardiopulmonary resuscitation.11 In many of these cases that were fatal, the fetus had not been delivered immediately, thus hampering efforts to restore maternal circulation as a result of aortocaval compression.11

Nonetheless, the U.S. and Drug Administration (FDA) proscribed the use of the higher concentration of bupivacaine, that is,. 0.75%, in pregnant women; by clinical practice, this was extended to surgical patients as well. Since then, anesthesiologists have perceived a need for alternative amide local anesthetics with the beneficial blocking properties of bupivacaine but with a greater margin of safety.

Chirality

Amide local anesthetics of the mepivacaine homologue type are known as chiral drugs because they can exist in isomeric (enantiomeric) forms, which are mirror images of each other (Figure 7–1). The isomers are defined according to the direction that a molecule rotates polarized light: dextrorotary (+ or rectus) and levorotary (– or sinister). Isomers of the same compound may have different biologic activities. For instance, it was suggested in early studies, that the levo-isomers of amide local anesthetics tend to produce greater vasoconstriction but have lower systemic toxicity than the dextro form of the drug.12–14

However, until the 1990s, the formulations of amide local anesthetics used in clinical practice contained a racemic mixture (approximately 50:50) of both the levo- and the dextro-isomers because single-isomer preparations were costly to produce. Fortunately, with technologic advances and an interest in a less toxic alternative to bupivacaine, single-isomer preparations of local anesthetics are now available. The first to be approved for clinical use was ropivacaine, followed shortly by levobupivacaine.

Physicochemical Properties

Ropivacaine (1-propyl-2′, 6′-pipecoloxylidide) is a homologue of mepivacaine and bupivacaine (Figure 7–2). It differs from bupivacaine in having a propyl rather than a butyl group attached to the pipechol ring). Ropivacaine is formulated as the single levo-isomer (99.5% purity) rather than as a racemic mixture. As would be expected, ropivacaine's physicochemical properties are intermediate between those of mepivacaine and bupivacaine15 (Table 7–1). Ropivacaine, like other amide local anesthetics, is used in its water-soluble form as the hydrochloride monohydrate salt (molecular weight [MW] 329) of the base (MW 275).15 The pKB value of ropivacaine is 8.07 and similar to that of bupivacaine (8.1). Ropivacaine, like bupivacaine, is highly protein-bound at 94% and thus has a long duration of action. However, it is considerably less lipid-soluble than bupivacaine.15 This may be important for two reasons. It may explain why bupivacaine has greater motor-blocking effects than ropivacaine because the greater lipid solubility of the former may result in enhanced penetration into the heavily myelinated, large motor neurons. Second, it raises the question as to whether ropivacaine is truly equipotent to bupivacaine.

Levobupivacaine (Chirocaine, Chiroscience, Ltd) is the other single levorotary isomer formulation of local anesthetic available for clinical use. Its physicochemical characteristics are virtually indistinguishable from those of bupivacaine15 (see Table 7–1). Unfortunately, although a promising drug, financial and economic considerations have resulted in levobupivacaine no longer being available for use in North America, although it is available in other parts of the world. The advantage of levobupivacaine is that it may be closer in its in vitro potency and efficacy to the currently used clinical formulation of racemic bupivacaine,12,16 whereas ropivacaine is 20–30% less potent.17,18 Thus, in contrast to ropivacaine, any expected benefits to be gained from the lower cardiotoxicity of levobupivacaine do not appear to be at the expense of potency.

Pharmacokinetics

Ropivacaine

Generally speaking, ropivacaine has lower lipid solubility and slightly lower protein binding than racemic bupivacaine15 (see Table 7–1). Note that the elimination half–life (T{1/2}B) of ropivacaine is shorter than that of bupivacaine after intravenous administration to animals and humans.19–21 The shorter elimination half-life of ropivacaine has been attributed to a faster clearance and shorter mean residence time than bupivacaine.21

In sheep, pregnancy is associated with smaller volumes of distribution during the terminal phase of drug elimination and steady state and a slower clearance for both drugs.21 In pregnant animals, ropivacaine also had shorter elimination half-life and mean residence times and a faster clearance than bupivacaine.21 Similarly, ropivacaine has been shown to have a lower T{1/2}B value than bupivacaine in women having epidural anesthesia for cesarean section delivery.22

Levobupivacaine

Levobupivacaine has similar protein binding and lipid solubility to those of racemic bupivacaine15 (see Table 7–1). However, there are differences between the two optically active isomers of bupivacaine. Levobupivacaine exhibits a slightly greater degree of protein binding, lower volume of distribution, higher plasma clearance, and shorter elimination half-life than the dextrorotary form of the drug.23 However, in pregnant women given levobupivacaine or bupivacaine for epidural anesthesia during cesarean section delivery, there was no significant difference between the two drugs in the maximum concentration of drug in the plasma and the area under concentration versus time curve.24

Systemic Toxicity

Ropivacaine

In vitro studies using isolated rabbit Purkinje fibers have shown that ropivacaine depresses electrophysiologic parameters such as Vmax, much less than does bupivacaine.25 A number of studies performed in laboratory animals have also demonstrated that ropivacaine has a greater margin of safety than bupivacaine. In dogs, the margin of safety, defined as the ratio between the dose required to produce cardiovascular collapse and the dose associated with convulsions, was greater for ropivacaine than for bupivacaine.26 In another study, almost twice the dose of ropivacaine compared with bupivacaine was necessary to prolong the QRS interval after intravenous administration to pigs.27 In sheep, the mean fatal dose of ropivacaine was greater than that of bupivacaine at 60 and 45 mg, respectively.28

In human volunteers, the doses of ropivacaine required to produce premonitory signs of central nervous system (CNS) toxicity during slow intravenous infusion were approximately 25% greater than for bupivacaine.29,30 Furthermore, bupivacaine depressed cardiac conduction and contractility at lower dosages and plasma concentrations than did ropivacaine.29

Pregnancy does not enhance the systemic toxicity of ropivacaine. In vitro studies have shown that progesterone has little effect on myocardial sensitivity to ropivacaine.31 In sheep, the doses and plasma concentrations required to produce convulsions and circulatory collapse were similar in pregnant and nonpregnant animals.10,32 However, in pregnant animals, the doses required to produce circulatory collapse were approximately 40–50% greater for ropivacaine than for bupivacaine, but the corresponding serum concentrations of the two drugs were similar.10 This has been attributed to a shorter elimination half-life and faster clearance of ropivacaine.21

Levobupivacaine

Levobupivacaine has less of an inhibitory effect on inactivated cardiac sodium channels than dextro or racemic drug.33 Using isolated perfused rabbit hearts, Mazoit et al.34 demonstrated that levobupivacaine caused less QRS widening and less severe ventricular arrhythmias than dextro or racemic bupivacaine. Similarly, levobupivacaine produced less atrial–ventricular conduction delay and second-degree heart block in isolated perfused guinea pig hearts than the other two forms of the drug.35

In vivo toxicity also appears to be less with levobupivacaine than with bupivacaine. For instance, the convulsant dose range for levobupivacaine was greater (75–100 mg) than for the racemate (50–75 mg) in sheep given graded intravenous doses of the drug.36 Levobupivacaine was also associated with a lower incidence of cardiac arrhythmias, whereas 43% of sheep given racemic bupivacaine died as a result of irreversible malignant ventricular arrhythmias.36

In healthy male volunteers, intravenous infusion of levobupivacaine until premonitory symptoms of toxicity resulted in a smaller reduction in mean stroke index, acceleration index, and ejection fraction than racemic bupivacaine.37

Comparative Systemic Toxicity

The most useful studies compare the systemic toxicity of bupivacaine, levobupivacaine, and ropivacaine under a single methodology. For the most part, the results of these studies indicate that bupivacaine has a narrower margin of safety compared with that of ropivacaine, with levobupivacaine being intermediate. In vitro studies performed on isolated and perfused rabbit heart preparations suggest that bupivacaine, levobupivacaine, and ropivacaine prolong the duration of the QRS interval in a potency ratio of 1.0:0.4:0.3.34.

Studies comparing the three drugs have also been performed using various laboratory animals. In one study, chronically prepared sheep were randomized to receive a constant intravenous infusion of bupivacaine, levobupivacaine, or ropivacaine at an equal rate until circulatory collapse occurred.38 The cumulative dose of local anesthetic required to produce convulsions and circulatory collapse was lowest for bupivacaine and highest for ropivacaine, with levobupivacaine being intermediate38 (Figure 7–3). The incidence of ventricular arrhythmias as the terminal event, was similar among the three drugs. In another study, anesthetized swine were given an intracoronary injection of one of the three local anesthetics.39 The lowest lethal dose occurred with bupivacaine, with ropivacaine and levobupivacaine being somewhat greater.39 Application of high concentrations of local anesthetics to specific areas of the brainstem can result in ventricular arrhythmias. In sheep, CNS-directed (carotid artery) infusion of all three local anesthetics resulted in increased arrhythmias, but the overall rank order of potency was ropivacaine < levobupivacaine < bupivacaine.40

The Controversy Regarding Systemic Toxicity

It is well accepted that lipid solubility usually goes hand in hand with local anesthetic potency. All things being equal, greater lipid solubility is related to increasing length of the aliphatic chain on the amino ring. Structurally, ropivacaine has one less carbon on the aliphatic chain (C3) than bupivacaine, which has four carbons (see Figure 7–2). This difference in the length of the aliphatic chain between the two drugs renders bupivacaine approximately 10 times more lipid-soluble than ropivacaine15 (see Table 7–1). In vitro studies performed on rat sciatic nerve indicate that bupivacaine is approximately 25% more potent in blocking conduction than ropivacaine.12,13 However, the argument has been made that although bupivacaine is slightly more potent than ropivacaine, the two drugs would be equieffective in producing clinical regional anesthesia. Because of this, most of the studies of systemic toxicity have compared equal doses of the two drugs. Thus, these studies did not resolve the controversy as to whether ropivacaine is truly less cardiotoxic than bupivacaine because it is also 20–30% less potent. However, this would be of clinical significance only if greater doses of ropivacaine than bupivacaine would be needed to produce a comparable level of regional blockade. In fact, we now know that in some situations bupivacaine and ropivacaine are not equieffective. For instance, the median local analgesic concentration of local anesthetic for epidural analgesia in laboring woman is approximately 40% greater for ropivacaine compared with bupivacaine18 (Figure 7–4).

In a recent study, the median analgesic (effective) dose for intrathecal labor analgesia was lowest for bupivacaine (2.37 mg) and highest for ropivacaine (3.64 mg), with levobupivacaine being intermediate (2.94 mg).41 In other studies, greater doses of ropivacaine compared with bupivacaine were required to produce comparable surgical spinal anesthesia.42 This is important because if larger doses of ropivacaine compared with bupivacaine are required to produce comparable regional anesthesia, then the anticipated benefit of lower cardiotoxicity with ropivacaine compared with bupivacaine may be reduced. However, the results of a recently published study performed in rats suggests that ropivacaine is still less cardiotoxic than bupivacaine, even when given at equipotent doses.43

Regardless of the controversy, our belief is that these new single-isomer preparations of long-acting local anesthetics, namely, ropivacaine and levobupivacaine, are very potent, and, if injected intravenously or with a relative overdose, can cause severe manifestations of cardiotoxicity, though easier to treat than with racemic bupivacaine. Indeed, there already have been three published reports of cardiac arrest following intoxication with ropivacaine.44–46 In contrast to the reported cases of bupivacaine cardiotoxicity in humans,3 two patients44,45 had progressive bradycardia and asystole rather than a lethal ventricular arrhythmia, and all patients were able to be resuscitated easily.44–46 Nonetheless, there is no substitute for adhering to maximum recommended dosage guidelines, using appropriate test doses to identify misplaced needles/catheters, always fractionating the total dose of local anesthetic, and carrying out heightened monitoring and vigilance in preventing toxic reactions with local anesthetics.47

Ease of Resuscitation

Two studies, performed in animals, suggest that cardiac resuscitation after intoxication with the newer amide local anesthetics is easier than with bupivacaine.48,49 In the first study, Groban et al.48 administered incremental doses of bupivacaine, ropivacaine, or levobupivacaine to anesthetized dogs until cardiac arrest. At the point of cardiovascular collapse, the dogs were treated with epinephrine, open chest cardiac massage, and an advanced life support protocol. Mortality was greatest at 50% with bupivacaine, followed by levobupivacaine at 30%, ropivacaine at 10%, and lidocaine at 0%. Unfortunately, these differences did not achieve statistical significance because of the small number of dogs studied. In another study, anesthetized rats given an infusion of bupivacaine, ropivacaine, or levobupivacaine until cardiovascular collapse were resuscitated with epinephrine and closed-chest cardiac massage.49

Although the total number of successful resuscitations did not differ among the groups, less epinephrine was required with ropivacaine compared with the other two drugs. It is interesting that in the two aforementioned case reports of cardiac arrest after ropivacaine intoxication, one patient was resuscitated easily with atropine 1 mg and ephedrine 12 mg, and the other with epinephrine 1 mg.44,45

Effects on Uterine Blood Flow & Placental Transfer

All local anesthetics can reduce uterine blood flow at plasma levels that greatly exceed those occurring during routine obstetric anesthesia.50 However, because the levo-isomers of amide local anesthetics tend to produce vasoconstriction at clinically relevant plasma concentrations, there has been an added concern that their use could result in a decrease in uteroplacental perfusion. It is reassuring that neither bupivacaine, ropivacaine, nor levobupivacaine affected uterine tone or blood flow during intravenous infusion to pregnant sheep.51,52 Furthermore, even at relatively high drug concentrations, fetal heart rate, blood pressure, and acid–base state were not affected by the three drugs.52 In humans, Doppler velocimetry studies have shown that ropivacaine has negligible effects on the uteroplacental circulation during epidural anesthesia for cesarean section delivery.53

The placental transfer of levobupivacaine and ropivacaine is similar to that of bupivacaine.52 Intravenous infusions of ropivacaine, levobupivacaine, or bupivacaine for 1 hour to pregnant sheep resulted in steady-state maternal plasma concentration of 1.5–1.6 mcg/mL and fetal concentrations of approximately 0.25 mcg/mL (Figure 7–5).52 More important, there was no significant difference in brain and myocardium drug concentrations among the three drugs52 (Figure 7–6).

Clinical Use

The clinical use of each drug is covered in chapters pertaining to specific regional techniques. Generally speaking, there are two important advantages of the newer amide local anesthetics. First, they tend to produce less motor than sensory block compared with racemic bupivacaine, particularly at the low concentrations used for pain management and obstetrics.54,55 This is important in allowing patients with continuous epidural/peripheral nerve block to ambulate, thus decreasing the potential for deep venous thrombosis. It is also important in obstetric patients, by allowing ambulation during labor and more effective expulsive efforts during the second stage of labor. Indeed, the ratio of the median local anesthetic concentration to achieve a Bromage score less than 4 was 0.66 for ropivacaine:bupivacaine and 0.87 for levobupivacaine:bupivacaine. This indicates that bupivacaine produced greater motor block than either ropivacaine or levobupivacaine.54,55 Second, as mentioned earlier, the levorotary isomers of local anesthetics tend to produce vasoconstriction rather than vasodilation56 (Figure 7–7) This could be useful in some clinical scenarios in prolonging the duration of block.23

Summary

The introduction of stereospecific levorotary isomers of the amide local anesthetics, ropivacaine and levobupivacaine, is important because these drugs, although more costly, appear to have a wider margin of safety but blocking properties similar to the currently available formulation of racemic bupivacaine. Because studies have compared the systemic toxicity of these local anesthetics at equal doses with that of bupivacaine, this would apply only if equal concentrations of drug are used clinically across the board. Although this may hold true with levobupivacaine and bupivacaine, it appears that in clinical use, anesthesiologists are using higher concentrations of ropivacaine (0.75%). Regardless, it is noteworthy that, even before the introduction of ropivacaine and levobupivacaine, modifications in clinical practice, such as the use of appropriate test doses and fractionation of the therapeutic dose, have made regional anesthesia a very safe procedure.57 In no situation should a greater margin of safety be a substitute for proper technique.

General Considerations

Local anesthetics temporarily block neural transmission and are used extensively for surgery and obstetrics. In addition, local anesthetics are an important component of the management of acute postoperative and chronic pain conditions.58 Unfortunately, even the longest-acting local anesthetics have a short duration of action relative to the prolonged analgesia that is required for acute and chronic pain management. Adjuvants such as vasoconstrictors and opioids have been added to local anesthetics in an attempt to prolong their effects, but with limited success. Continuous delivery systems using infusion catheters have been successfully used, but these have limitations, for instance, in the patient having anticoagulation prophylaxis against deep venous thrombosis. Recently, there has been interest in using liposomes loaded with local anesthetics to provide sustained analgesia/anesthesia. Initial testing suggests that liposome encapsulation of local anesthetic offers a simple, economical, and theoretically nontoxic delivery system to prolong local anesthetic effect with a single injection of drug.

Chemistry

Liposomes are lipid vesicles that contain an aqueous compartment. The aqueous compartments can be loaded with various drugs, including local anesthetics. Because liposomes are biocompatible, biodegradable, and nonimmunogenic, they are ideally suited to function as carrier vehicles.59 Developed over 30 years ago, liposomes were initially used as vehicles for the sustained delivery or enhanced targeting of various chemotherapeutic agents. Liposomes may be constructed as small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles, or multivesicular vesicles. The alternating aqueous and lipid bilayers of liposomes permit the incorporation of either lipophilic or water-soluble drugs into their structure. Being amphipathic, local anesthetics can be encapsulated within the aqueous and/or lipid bilayers.60 Naturally occurring biocompatible materials, such as phospholipids (derived from soy or egg sources) and cholesterol typically are used to construct the lipid bilayer. Because liposomes are composed of these naturally occurring materials, liposomes resemble biologic membranes, which render them neither antigenic nor toxic.58

Preparation

Liposomes are microscopic spheres containing an aqueous core surrounded by a phospholipid bilayer.61 Typically, a phospholipid moiety is first dissolved in a solvent that is subsequently evaporated. This leaves a residual lipid film into which lipophilic active agents can be dissolved. For incorporation of aqueous drug, the lipid film is reconstituted, and the aqueous drug becomes trapped between the concentric phospholipid layers. Liposomes take on a spherical shape through several thawing/freezing cycles.62,63 For a liposomal formulation to be suitable for use in humans, the drug-to-phospholipid ratio is crucial. A higher drug-to-phospholipid ratio allows more of the drug to be delivered with less liposome, whereas a low drug-to-phospholipid ratio requires administration of a very large lipid load to achieve the desired drug effect. The large lipid mass of the latter would make this formulation unsuitable for use in a defined area, such as injection into subcutaneous tissue.59 Because the major goal of a liposomal formulation of local anesthetic is to prolong analgesia rather than anesthesia, much of the initial work using liposomes has been done with bupivacaine. However, similar effects of liposomal encapsulation have been shown for other local anesthetics, such as lidocaine.62

Currently, liposomes are formulated to encapsulate ∼80% active drug, which gives them a desirable drug-to-phospholipid ratio. There are two methods of loading drug into the liposome. In the passive loading method, the liposomes are formed in an aqueous solution that already contains the drug to be encapsulated. With liposomal bupivacaine, the highest drug-to-phospholipid ratio that can be used with passive loading is approximately 36%.59 Remote loading relies on a transmembrane pH gradient to encapsulate bupivacaine within a preexisting liposomal carrier. By using a pH gradient, 64–82% of bupivacaine can be loaded in a large unilamellar vesicle.61 The use of large multivesicular vesicles and remote loading enable the encapsulation of large amounts of bupivacaine within a relatively small total volume.59

Liposomes have also been loaded with tetracaine for topical anesthesia of the skin. This formulation enhances drug delivery to the dermis by increasing the rate of dermal penetration of tetracaine and is highly effective. For instance, in one study, liposome-encapsulated tetracaine was compared with EMLA (eutectic mixture of local anesthetic) for the prevention of discomfort related to intravenous catheterization in healthy adult volunteers.64 In this study, patients reported lower visual analog pain scores during intravenous cannulation on the arm treated with liposome-encapsulated tetracaine than on the arm treated with EMLA.64

Pharmacokinetics

Liposomes prolong neural blockade or spinally mediated opioid effects by extending and controlling the release of local anesthetic or opioid.58 Liposomes provide a depot from which the local anesthetic can be released into the surrounding tissues, since they are cleared slowly after intradermal or subcutaneous injection.61 Furthermore, liposomal preparations encapsulate high drug concentrations and maximize the active release of drug in a controlled–sustained manner.61 Plain liposomes are devoid of inherent pharmacologic activity65–68 and are unable to cross the blood–brain barrier or blood–nerve barrier.69

Early trials used relatively simple liposomal delivery systems, such as multilamellar vesicles , or small unilamellar vesicles. Multilamellar vesicles tend to remain in the epidural space longer than small unilamellar vesicles.61 Within these early liposomes, the local anesthetic was either partially encapsulated in the aqueous core or associated hydrophobically as the free base within the liposomal bilayer. Because of this simple construction, no mechanism existed to control drug release rates, and therefore duration of action. The advantage of large unilamellar vesicles over multilamellar vesicles is that they contain a relatively large trapping volume, thus allowing greater quantities of drug to be encapsulated.61 Large unilamellar vesicles with a pH gradient can be efficiently loaded with a high mass of bupivacaine, because the drug is both amphipathic and a weak base. In addition, the larger size of large unilamellar vesicles compared with the multilamellar vesicles causes them to remain at the site of injection for longer periods.61 Large unilamellar vesicles are typically greater than 300 nm, whereas small liposomes are usually 80–90 nm. Moreover, the latter may drain into the blood via the lymphatic system after subcutaneous injection, whereas vesicles of larger diameter (greater than 120 nm) have not been detected in the blood to any appreciable extent.70

More recently, technologic advances that result in an increase in the drug-to-phospholipid ratio have yielded a large multivesicular vesicle. These vesicles are much larger than the large unilamellar vesicles (mean size 2,439 ± 544 nm) and have a fivefold greater drug-to-phospholipid ratio.59 The pharmacodynamic effects of liposomal-encapsulated local anesthetic is related to the release of active drug from the liposomal matrix rather than from neural uptake of the combined liposomal–drug moiety.69

Plasma levels after epidural injection of liposome-encapsulated local anesthetic may exhibit a brief initial peak, regardless of the size of the vesicle used to encapsulate the drug. This initial peak in drug concentration has been attributed to free drug contained within the diluent/liposome solution62 and to drug residing on the surface of the liposome.58 Onset of action after subcutaneous injection of liposomal bupivacaine is similar to that of aqueous bupivacaine. However, after injection of subcutaneous liposomal bupivacaine, there is a delay in achieving peak plasma levels. These levels are approximately 20% lower than those observed with plain bupivacaine.66 The initial bupivacaine plasma level achieved remains constant for a short period of time before gradually rising as residual drug is released from the liposome and absorbed into the plasma. In contrast, injection with plain bupivacaine results in a significantly higher peak plasma level that occurs rapidly, and systemic absorption of drug is complete within 60 minutes of injection.66

Liposomes are cleared by the lymphatic system and macrophages. Intravascular liposomes are cleared by several processes, including circulating monocytes, the reticular endothelial system, and high-density lipoproteins. Cholesterol is added to phospholipids during liposome construction to enhance stability by counteracting the effects of high-density lipoproteins.62,63

Clinical Effects

Liposome-encapsulated local anesthetics have been shown to produce prolonged nerve blockade in animals owing to the controlled, sustained release of local anesthetic.58 Sensory block lasted five times longer after subcutaneous injection of multivesicular vesicle bupivacaine in rats—447 ± 29 minutes compared with 87 ± 7 minutes with plain bupivacaine.66 Similarly, local anesthetic duration of bupivacaine was three times longer in guinea pigs given intradermal liposomal bupivacaine compared with plain bupivacaine61 and nearly two times longer when injected into the root of mice tails compared with bupivacaine plus epinephrine.71 In rabbits, motor block was nearly two times longer after intracisternal injection of liposomal bupivacaine than plain bupivacaine (126 versus 70 minutes, respectively).72

Other than topical administration, there are only four published reports of liposome administration in humans for regional analgesia/anesthesia.58 An open-label, nonrandomized trial compared postoperative epidural administration of 0.5% liposomal bupivacaine (14 patients) with aqueous 0.5% bupivacaine with epinephrine (12 patients) for pain relief after various major surgeries.73 The onset of block and visual analog pain scores were similar between the two preparations of bupivacaine, but the duration of analgesia was almost two times longer in patients receiving liposomal bupivacaine compared with plain bupivacaine and nearly four times greater in a small subset of patients undergoing abdominal surgery.73 Multilamellar vesicle bupivacaine has been successfully used for brachial plexus block using a supraclavicular approach for chronic arm pain in a single patient.74

In another patient with lung cancer-related pain, liposomal bupivacaine was administered through a thoracic epidural and provided 11 hours of complete pain relief compared with only 4 hours after the administration bupivacaine with epinephrine.75 In this patient, no motor block was detected with the liposomal bupivacaine injection, whereas a grade 1 (Bromage scale) motor block was observed with the plain bupivacaine/epinephrine injection.75 Using bupivacaine and large multivesicular vesicles, analgesia is prolonged in a dose-dependent manner.59 For instance, six healthy male volunteers were given injections of 0.5% plain bupivacaine or liposomal 0.5%, 1%, and 2% bupivacaine. The median duration of analgesia after each was 1 hour, 19 hours, 38 hours, and 48 hours, respectively.59

Systemic Toxicity

Local anesthetics can produce both CNS and cardiovascular toxicity. Bupivacaine is known to cause both CNS and cardiovascular toxic effects. However, in contrast to other local anesthetics, cardiovascular toxicity with bupivacaine can be particularly serious.3 Liposomal encapsulation of bupivacaine appears to offer some protection against the CNS and cardiovascular toxic effects when the drug is injected intravascularly. For instance, in a study using rabbits,76 the lethal dose of a continuous infusion of 0.25% plain bupivacaine was 15.7 ± 2.5 mg/kg, compared with 22.43 ± 2.63 mg/kg of bupivacaine in multilamellar vesicles. Some of this “protection” may be related to the fact that multilamellar vesicles are unable to cross the blood–brain barrier; however, more work needs to be done in this area.77

Tissue Toxicity

Liposomes are created using naturally occurring phospholipids and cholesterol. In theory, these should not cause neurotoxic effects. Bupivacaine 0.75%, encapsulated in Multilamellar vesicles, has not been shown to cause neurotoxicity when injected into the brachial plexus of rabbits.78 After injection, the brachial plexus was dissected on either day 2 or day 7 and examined histologically. Light microscopy demonstrated weak perineural inflammation, but electron microscopy did not show any changes of the myelin sheath.78 A single rat study has associated demyelination with the intrathecal administration of lysophosphatidyl choline.79 Neurotoxicity, if any, with liposomes may be related to the choice of lipid used to formulate the liposomes, and further study is required.58

Summary

Liposome encapsulation may become useful in prolonging the duration of action of local anesthetics and perhaps diminishing some toxic effects. However, there is no FDA-approved formulation of liposomal local anesthetic at this time. Clinical experience with recent FDA approval and clinical use of a sustained-release liposomal preparation of morphine have been encouraging. Although initial studies suggest that sustained, controlled-release local anesthetic formulations are possible using liposomes, their ultimate contribution to clinical anesthesia remains to be determined.58