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Clinical use of local anesthetics in anesthesia

Clinical use of local anesthetics in anesthesia
Literature review current through: Jan 2024.
This topic last updated: Nov 16, 2023.

INTRODUCTION — Local anesthetics (LAs) are used to block transmission of impulses in nerve fibers, to reduce or eliminate sensation. LAs may be used for neuraxial analgesia and anesthesia, peripheral nerve blocks, subcutaneous and tissue infiltration, and topical anesthesia. This topic will discuss the mechanism of action of LAs, the properties that distinguish LAs and determine their effects, and the ways in which LAs are used in anesthesia.

The doses and effects of LAs used for specific regional anesthesia techniques are discussed separately. (See "Spinal anesthesia: Technique", section on 'Local anesthetics' and "Epidural and combined spinal-epidural anesthesia: Techniques", section on 'Local anesthetics' and "Overview of peripheral nerve blocks", section on 'Local anesthetics'.)

Mechanism of action of local anesthetics — LAs reversibly inhibit nerve transmission by binding voltage-gated sodium channels (Nav) in the nerve plasma membrane. Nav channels are integral membrane proteins, anchored in the plasma membrane. When LAs bind the sodium channel, they render it impermeable to Na, which prevents action potential initiation and propagation [1]. (See "Subcutaneous infiltration of local anesthetics", section on 'Anatomy and physiology'.)

Basic structure/classes — As noted above, the commonly used LAs have similar structural characteristics and (with the sole exception of articaine) consist of a lipophilic aromatic ring and a hydrophilic tertiary amine. These two moieties are linked by either a carboxylic ester (-COO-) or amide (-NCO-) bond. This linkage determines whether a LA is designated an amino ester or amino amide. Commonly used ester LAs include chloroprocaine, procaine, and tetracaine. The commonly used amide LAs include lidocaine, bupivacaine, ropivacaine, mepivacaine, and outside the United States, levobupivacaine. Articaine is an amide LA used primarily in dentistry.

LAs are weak bases that exist in solution in both charged and uncharged forms. All clinically-used LAs share certain structural features. The aromatic (benzene) ring leads to greater lipid solubility. Lipid solubility declines (and aqueous solubility increases) when the amine nitrogen (at the end of the molecule opposite to the aromatic ring) is protonated (quaternary). When this amine nitrogen is in a tertiary form, it is uncharged and more lipid soluble. The uncharged, more lipophilic form more readily permeates nerve membranes, whereas the charged, more water soluble form binds with greater affinity for the sodium channel. LAs (save for benzocaine) are supplied by the manufacturer in quaternary form as hydrochloride salts. The proportion of charged and uncharged forms (and, as a consequence, the speed with which they permeate the plasma membrane and produce their clinical effects) is determined by the pKa of the drug, and in vivo, by tissue pH.

The mechanism of metabolism, and potential for allergic reaction differ between the two classes of LAs. (See 'Metabolism of local anesthetics' below and 'Allergic reactions' below and "Allergic reactions to local anesthetics".)

LOCAL ANESTHETIC PHARMACODYNAMICS — The potency, speed of onset, duration of action, and differential sensory versus motor block in isolated nerves are determined by the physicochemical characteristics of the LA. In vivo, these characteristics are also affected by the site of injection, drug concentration and volume, technical aspects of nerve block, vasodilatory properties of the drug, and tissue conditions (eg, pH).

Potency — Potency of an LA is strongly associated with lipid solubility, as LAs with greater lipid solubility are able to permeate nerve membranes more readily than less lipid soluble LAs [2]. As an example, bupivacaine is more lipid soluble than lidocaine, and is also more potent, such that 2% lidocaine would be used for epidural anesthesia, versus 0.5% bupivacaine. LA molecules with greater molecular weight more readily permeate nerve membranes and have a greater affinity for binding the Na channel than smaller LA molecules. As molecular weight increases, so generally does lipid solubility.

In addition, the larger, more lipid-soluble LAs are more highly protein bound.

Speed of onset — The speed of onset of LA conduction block depends on the physicochemical properties of the specific drug, the concentration of the solution, and the site of injection. In general, the time to onset increases with increasing lipid solubility. All other factors being equal, a more rapid onset is expected when the solution contains a greater fraction of nonionized molecules (eg, at increased pH). When the dose is held constant, increasing the concentration of the injected LA has been demonstrated to decrease the time to onset of peripheral nerve block [3].

Site of injection Onset of anesthesia is almost immediate with subcutaneous or tissue infiltration with any LA. Onset is also very rapid (ie, within several minutes) with intrathecal injection for spinal anesthesia, because the drug is deposited close to the nerve roots and spinal cord, without having to diffuse through tissue. In contrast, onset of brachial plexus block is prolonged (ie, 20 to 30 minutes), because the drug may be deposited at some distance from the target nerves, and must diffuse through tissues. Ultrasound guidance allows injection of LAs close to target nerves for individual nerve blocks, and may speed onset [4].

Alkalinization When speed of onset is of particular importance for peripheral nerve block or epidural anesthesia, some LA solutions may be alkalinized with the addition of sodium bicarbonate, thereby increasing the fraction of nonionized LA molecules. This strategy is most successfully employed with LA solutions premixed with epinephrine at the factory. These solutions are prepared in a considerably more acidic solution than "plain" LAs to increase the shelf life of the epinephrine [5].

As an example, 1 and 2% lidocaine with 1:100,000 epinephrine have a pH of approximately 4. The volume of 8.4% sodium bicarbonate required to raise the pH to physiologic range is 1 mL per 10 mL of LA. At this ratio, the lidocaine solution is unlikely to precipitate, which is of concern at higher pH. Plain solutions are packaged at a pH of 6 and further alkalinization does not confer any advantage in onset time [6].

Alkalinization is generally not used for solutions of bupivacaine or ropivacaine, as onset times are not consistently shortened, and other LAs would typically be chosen if rapid onset is desirable. Bupivacaine can easily precipitate when alkalinized, and a smaller amount of sodium bicarbonate should be added if it is used (ie, 0.1 mL of bicarbonate per 10 mL of bupivacaine). (See "Epidural and combined spinal-epidural anesthesia: Techniques", section on 'Sodium bicarbonate'.)

Alkalinization of LA solutions can also be used to decrease the pain associated with subcutaneous or tissue infiltration. (See "Subcutaneous infiltration of local anesthetics", section on 'Methods to decrease injection pain'.)

Duration of action — The duration of action of LAs varies widely, and in the isolated nerve is associated with the degree of lipid solubility, and the chemical structure of the drug. Chloroprocaine and procaine are short acting LAs, lidocaine, mepivacaine, and prilocaine result in moderate duration of action, and bupivacaine, ropivacaine, levobupivacaine, tetracaine, and etidocaine are the longest acting of the commonly used LAs (table 1). The more potent LAs are the longest-persisting, most likely because their increased lipid solubility leads to slower uptake and removal by the blood stream.

In vivo, the duration of action of a specific LA varies widely, and is affected by other factors, including the intrinsic vascular effects of the specific drug, concentration of the LA, protein binding, metabolism of the drug, local tissue conditions, and the site of injection. As an example, spinal anesthesia with bupivacaine resolves over approximately 2.5 hours (table 2), whereas single injection brachial plexus block with bupivacaine can result in 5 to 15 hours of anesthesia, and up to 30 hours of analgesia (table 1).

Differential blockade — Nerve fiber characteristics that lead to differing susceptibility to LA conduction block include the following:

For nerve fibers with a relatively small diameter, a lower concentration of LA is required to achieve blockade than for a larger diameter fiber of the same type [7,8].

A shorter length of exposure to LA is required to block smaller fibers [9].

Myelinated fibers require exposure of three or more adjacent nodes of Ranvier to LA for successful block [10].

On the other hand, in general and based on animal studies, unmyelinated (C) fibers are more resistant to inhibition by LAs than many myelinated fibers even though myelinated fibers are larger [11].

Nerve blocks in the clinical setting typically impair sympathetic function most expeditiously, followed by loss of sensation to sharp pain, temperature, and then pressure. Motor function is typically lost last. As a consequence, after LA injection for a nerve block, sympathectomy with vasodilation is often the first marker of a successful block. As the block develops, painful sensations will be blocked before motor function is lost. Differences in onset between motor and sensory function are more apparent with some LAs (eg, bupivacaine and ropivacaine) than with others (mepivacaine or lidocaine). Spinal and epidural anesthesia will demonstrate zones of differential block at the uppermost dermatomes of block, where one can observe clearly more widespread inhibition of cold sensation versus pinprick sensation. (See 'Spinal anesthesia' below and 'Epidural anesthesia' below.)

SERUM CONCENTRATION OF LOCAL ANESTHETICS — Serum levels of LA can be the result of systemic absorption from block sites, or accidental intravascular injection. High serum levels can cause both minor signs and symptoms of LA systemic toxicity (LAST; eg, perioral numbness, metallic taste, mental status changes or anxiety, visual changes), or major LAST events (ie, seizures or cardiac arrest) [12].

LAs bind to plasma proteins, primarily to alpha1-acid glycoprotein and secondarily to albumin. The fraction of protein binding of LA molecules in the blood increases with the drug's lipid solubility. Importantly, acidosis decreases the degree of protein binding by increasing the fraction of protonated LA molecules, thereby enhancing the unbound fraction of the drug. This is one of the reasons that acidosis must be avoided during treatment of LAST, since the unbound drug produces systemic toxic effects. (See "Local anesthetic systemic toxicity", section on 'Management of LAST'.)

The factors that determine systemic absorption and the risk of LAST, preventive measures, and treatment of LAST are discussed separately. (See "Local anesthetic systemic toxicity".)

Maximum allowable doses — Maximum allowable doses of LA that appear in various publications are at best rough guides, and are not consistent across publications. They are not evidence based, and don't take into account the site or technique of LA administration, or patient factors that increase the risk of toxicity. Systemic toxicity may occur with doses within the recommended ranges, while doses in excess of the recommended maximums have been administered without toxicity. Nonetheless, published maximum recommended doses can be used as a starting point for deciding on a dose. The total dose of LA administered should be the lowest dose that is required for the desired extent and duration of block (table 1). (See "Local anesthetic systemic toxicity", section on 'Local anesthetic dose'.)

Metabolism of local anesthetics — The metabolism of a LA is dictated by its chemical structure and differs between ester and amide classes.

Ester LAs are hydrolyzed by plasma cholinesterase, and conditions in which cholinesterase activity is reduced (ie, atypical pseudocholinesterase or pseudocholinesterase deficiency) theoretically predispose to reduced metabolism. In one case report, a patient who was ultimately found to have atypical pseudocholinesterase exhibited markedly prolonged epidural anesthesia with chloroprocaine, as well as prolonged paralysis with succinylcholine, which is also metabolized by pseudocholinesterase [13].

Pseudocholinesterase levels are reduced by approximately 24 percent during pregnancy, and by 33 percent on the third postpartum day, and return to normal over the first two to six weeks after delivery [14]. The clinical relevance of this decrease is unclear [15], and pregnant patients do not usually have a prolonged response to succinylcholine.

The amide LAs undergo N-dealkylation by hepatic enzymes. Conditions that reduce enzymatic function or hepatic blood flow (eg, renal, hepatic, or cardiac disease) may prolong LA clearance, and therefore increase the duration of block and serum levels. In such patients, doses of LA should be reduced for repeat or continuous administration.

ALLERGIC REACTIONS — Most idiosyncratic reactions to LAs are nonallergic in nature, but may be labelled as allergy. Symptoms of absorption or inadvertent injection of epinephrine or LA, vasovagal reactions, or anxiety related symptoms can all mimic allergy. It has long been stated that allergic reactions are more common with LAs (such as procaine and benzocaine) that are metabolized to P-aminobenzoic acid (PABA), but formal studies to confirm such assertions are lacking. Allergic contact dermatitis and delayed swelling at the site of LA administration are well established, and are more common with the ester group of LAs. Type 1, immediate hypersensitivity reactions, which can include anaphylaxis, are rare. Data implicating LAs are limited to case reports, which mostly involve reactions to amide LAs. The incidence, diagnosis, and management of allergy to LAs are discussed separately. An algorithm for preprocedural evaluation of patients who report a history LA allergy is provided (algorithm 1). (See "Allergic reactions to local anesthetics" and "Common allergens in allergic contact dermatitis".)

NEUROTOXICITY OF LOCAL ANESTHETICS — While all LAs have been shown to cause neurotoxicity in vitro at clinically relevant concentrations, the relevance of these findings to clinical practice is unclear. In general, the degree of toxicity is correlated with the concentration. Nevertheless, certain LAs used in particular clinical settings demonstrate a much higher degree of toxicity than others [16].

Lidocaine Reports of subarachnoid injection of 5% lidocaine in glucose solution leading to transient neurologic symptoms (TNS; common) or permanent neurologic impairment (very rare) have greatly reduced the use of this solution for ambulatory spinal anesthesia in patients who will undergo surgery in the lithotomy position [17].

Transient neurologic symptoms (TNS) are a constellation of non-permanent symptoms including back pain with radiation to buttocks or legs following spinal anesthesia. The reported incidence of TNS with spinal lidocaine varies from 14 percent to 37 percent [17-19], and is increased with lithotomy positioning, knee arthroscopy, and ambulatory procedures [20]. Bupivacaine, ropivacaine, mepivacaine, chloroprocaine, and tetracaine are associated with a lower incidence of TNS than lidocaine [21].

Subarachnoid 5% lidocaine with dextrose administered via a spinal catheter has been implicated in rare cases of permanent neurologic injury, including cauda equina syndrome, with perineal sensory loss, varying degrees of urinary and/or fecal incontinence, and lower extremity motor weakness [22].

2-ChloroprocaineChloroprocaine fell out of favor for use for epidural and spinal anesthesia following reports of prolonged sensory and motor block and subsequent adhesive arachnoiditis with the accidental spinal administration of large doses [23-25]. Use of a formulation containing a sodium metabisulfite preservative at an acidic pH may have contributed. Newer preservative-free preparations have not demonstrated similar toxicity. Indeed, the preservative-free form is now commonly used for brief spinal anesthetics in ambulatory patients.

Mepivacaine The reported incidence of TNS after spinal anesthesia with mepivacaine likely depends on the concentration used. Based on mostly small studies, the reported incidence of TNS after spinal anesthesia with 4% mepivacaine is 30 to 37 percent [26,27], versus 0 to 7.5 percent with the reduced concentrations (1.5% to 2% mepivacaine) commonly used in most centers [28-30].

COMBINATIONS OF LOCAL ANESTHETICS — The combination of a short (intermediate) acting and long acting LA is often used in clinical practice to speed block onset while maintaining duration of blockade. Results are mixed in clinical trials with some studies demonstrating no difference in onset with a combination versus either anesthetic alone [31] while others report faster speed of onset with the combination than with the long acting agent alone [32]. In general, the combination of LAs may provide a block onset and duration that is intermediate between the longer and shorter acting agents [31,32].

Liposomal bupivacaine may be mixed with aqueous bupivacaine (as long as the bupivacaine dose is ≤50 percent of the liposomal bupivacaine dose) to speed the onset of block, but should not be mixed with other LAs. Restrictions on the combination of liposomal bupivacaine with other LAs are discussed below. (See 'Sustained release bupivacaine' below.)

CLINICAL USES

Neuraxial anesthesia

Spinal anesthesia — For single-shot spinal anesthesia, LAs and adjuvant medications must be chosen to achieve the required spinal level and duration of anesthesia. The most important determinants of the extent of sensory block (ie, dermatomal spread) are the baricity and (with hypobaric and hyperbaric solutions) the patient's position after injection of the anesthetic solution (table 2). Increased LA dose increases the duration and the likelihood of a successful block. Baricity and other aspects of the choice of local anesthetics for spinal anesthesia are discussed separately. (See "Spinal anesthesia: Technique", section on 'Choice of spinal drugs'.)

Epidural anesthesia — Multiple variables affect the dermatomal spread and duration of epidural anesthesia. The volume and total LA dose are the two most important drug related factors that influence the dermatomal extent and density of block. The concentrations of commonly used LAs, onset times, duration of action, block height, and recommended top up intervals are shown in tables (table 3 and table 4). (See "Epidural and combined spinal-epidural anesthesia: Techniques", section on 'Choice of epidural drugs'.)

Peripheral nerve block — For peripheral nerve block, the LA and its volume and concentration are chosen according to the goal of the block (ie, surgical anesthesia and/or postoperative analgesia), degree of motor block, toxicity, and the desired duration of the block (table 1). These issues are discussed separately. (See "Overview of peripheral nerve blocks", section on 'Drugs' and "Upper extremity nerve blocks: Techniques", section on 'Drug choices'.)

Intravenous regional anesthesia — In the United States, lidocaine is used most commonly for intravenous regional anesthesia (IVRA). (See "Upper extremity nerve blocks: Techniques", section on 'Intravenous regional anesthesia (Bier block)'.)

Prilocaine is not available for intravenous use in the United States, but is used commonly for IVRA elsewhere. Prilocaine is less likely to cause central nervous system side effects with tourniquet deflation than lidocaine [33], but its application for regional anesthetics requiring larger doses (eg, epidural) is limited by its tendency to cause methemoglobinemia. The development of methemoglobinemia is a dose-dependent phenomenon and a consequence of the metabolism of prilocaine to the intermediate ortho-toluidine [34]. Treatment of methemoglobinemia with methylene blue (1 mg/kg IV) provides a prompt therapeutic effect, but repeat treatment may be required. (See "Methemoglobinemia".)

Infiltration — Subcutaneous and tissue infiltration of LA is discussed separately (table 5). (See "Subcutaneous infiltration of local anesthetics", section on 'Methods to decrease injection pain'.)

Topical anesthetics

Skin Topical anesthetics on the skin are primarily used in children, and are discussed separately. (See "Clinical use of topical anesthetics in children".)

Mucous membranes A number of preparations of LAs are available for topical anesthesia of the upper airway (ie, oropharynx and vocal cords), the trachea, and nasal passages. For anesthesia, topical anesthesia is most commonly used for awake laryngoscopy and intubation. LAs are available as ointments, gels, and solutions for nebulization, spray, and direct application.

Available preparations that are used in anesthesia include the following:

Lidocaine Lidocaine is available in a number of topical preparations, including 2% and 4% solutions, 2% and 4% gels, and 5% ointment, in addition to creams and patches that are used outside of anesthesia. When applied to mucous membranes, lidocaine provides onset of anesthesia within several minutes, and a variable duration of action of at least 30 minutes [35].

Maximal dosing limits for topical lidocaine should be followed (4.5 mg/kg, not to exceed 300 mg per dose), as LA systemic toxicity (LAST) can rarely occur, especially when the drug is applied to mucosal membranes in repeated or high doses. Lidocaine used for oropharyngeal anesthesia is absorbed through mucous membranes, and from the gastrointestinal tract when swallowed. There are multiple case reports of seizures and cardiac arrest with high doses of oral viscous lidocaine in adults and children. (See "Local anesthetic systemic toxicity", section on 'Routes of local anesthetic administration'.)

Benzocaine Benzocaine is a rapidly acting LA compound without an amine that can be protonated (therefore it is obligatorily uncharged) at physiologic pH. Its actions and kinetics are ideally suited for topical anesthesia of mucous membranes. (See 'Speed of onset' above and 'Mechanism of action of local anesthetics' above.)

Benzocaine is available as a gel, liquid, ointment, and spray. The 20% spray is most commonly used for airway anesthesia. The dose of benzocaine spray administered is difficult to determine; the recommended maximum dose is 200 mg, which is delivered after a brief administration. Benzocaine is absorbed rapidly, especially if mucosa is not intact. Benzocaine administered for endoscopy has been associated with severe degrees of methemoglobinemia. For this reason, many institutions have replaced benzocaine with lidocaine for topical anesthesia [36,37].

CocaineTopical cocaine is unique in its ability to provide both topical anesthesia and vasoconstriction, which is particularly advantageous when used for procedures on highly vascularized mucosae in the nose, mouth, and throat. Cocaine is available as a 4 percent solution, and provides rapid onset of action and duration of action of 30 to 60 minutes. Given its abuse potential, cocaine has largely been replaced by combinations of other LAs with vasoconstrictors such as tolazoline, phenylephrine, or epinephrine.

Cornea and conjunctiva Topical local anesthesia may be used for eye surgery. This is discussed in detail separately. (See "Anesthesia for elective eye surgery", section on 'Topical anesthesia'.)

Systemic local anesthetic administration — Unique among LAs, lidocaine may be administered intravenously, as a bolus or infusion, for a variety of indications. Most clinicians will be familiar with the use of lidocaine for life threatening ventricular arrhythmias. Intravenous lidocaine may be administered to reduce the pain associated with injection of propofol, and as an adjunct during induction of anesthesia, to blunt the sympathetic response to airway manipulation. (See "General anesthesia: Intravenous induction agents", section on 'Lidocaine'.)

Lidocaine has also been used as an intraoperative and postoperative intravenous infusion to improve analgesia following a variety of surgical procedures. (See "Nonopioid pharmacotherapy for acute pain in adults", section on 'Intravenous lidocaine'.)

SUSTAINED RELEASE BUPIVACAINE

Liposomal bupivacaine — Liposomal bupivacaine is a sustained-release formulation that consists of bupivacaine in an aqueous core encased in multiple phospholipid bilayers [38]. The liposomes are suspended in saline, with a pH of 5.8 to 7.4, and are available in a 20 mL single-use vial, with a bupivacaine concentration of 1.3%. The maximal allowable dose of liposomal bupivacaine is 266 mg by tissue infiltration (ie, one 20 mL vial) and 133 mg for interscalene block. For children 6 to 17 years old the recommended dose for infiltration is up to 4 mg/kg, maximum 266 mg. Liposomal bupivacaine should only be administered as a single dose.

When liposomal bupivacaine is injected subcutaneously, the maximum plasma concentration is dose dependent [39]. The plasma concentration of bupivacaine exhibits an initial peak within one hour after administration, related to a small amount of extra-liposomal bupivacaine in the preparation, followed by a second peak 10 to 36 hours later. The maximal concentration, time to maximal concentration, and duration of detectable plasma bupivacaine vary widely depending on the injection site [40-42]. At a dose of 266 mg liposomal bupivacaine, plasma bupivacaine can be detectable as long as 72 hours after injection [39].

To avoid altering the release of bupivacaine, the manufacturer's recommendations for infiltration should be followed [43]:

Liposomal bupivacaine may be diluted with normal saline or Lactated Ringer's solution up to 1:14 by volume.

Liposomal bupivacaine should not be mixed with other LAs, except for aqueous bupivacaine.

Liposomal bupivacaine may be mixed in the same syringe as aqueous bupivacaine or administered immediately after a dose of aqueous bupivacaine as long as the bupivacaine dose is ≤50 percent of the liposomal bupivacaine dose.

Liposomal bupivacaine should be administered no sooner than 20 minutes after injection of lidocaine, to avoid immediate release of bupivacaine from the liposome.

Avoid additional use of local anesthetics within 96 hours following administration of liposomal bupivacaine.

Liposomal bupivacaine is approved by the US Food and Drug Administration (FDA) for local infiltration at the surgical site for patients ≥6 years of age, and it is used by surgeons for tissue infiltration prior to wound closure (eg, for periarticular infiltration after joint arthroplasty). It is also approved for field block (including transversus abdominis plane [TAP] block, which is defined as a field block by the FDA), interscalene block, adductor canal block, and popliteal block, all for postsurgical pain [44]. The drug manufacturer does not recommend the use of liposomal bupivacaine for other regional, epidural or intrathecal blocks [43].

Limited evidence suggests that liposomal bupivacaine injected for local infiltration may improve postoperative analgesia compared with saline, but liposomal bupivacaine is not clearly superior to aqueous bupivacaine [45-48]. Similarly, whereas the use of liposomal bupivacaine for peripheral nerve block is increasingly reported, benefits compared with aqueous bupivacaine have not been clearly demonstrated [49-52] and existing studies have not compared equivalent milligram doses of the two drugs. Liposomal bupivacaine is significantly more expensive than aqueous bupivacaine.

A 2021 meta-analysis of nine randomized trials that compared liposomal bupivacaine with non-liposomal bupivacaine for peripheral nerve blocks found that liposomal bupivacaine improved the area under the curve of pain scores from 24 to 72 hours by a clinically unimportant amount (1.0 cm/hour [95% CI 0.5-1.6], on a scale of 0 to 10 cm) [49]. Opioid consumption, time to first analgesic request, and opioid-related side effects were similar in patients who received either drug.

Another 2021 meta-analysis of 23 randomized trials that compared liposomal bupivacaine with non-liposomal bupivacaine for local anesthesia, infiltration, or peripheral nerve block found that liposomal bupivacaine resulted in statistically significant but clinically irrelevant reductions in postoperative pain scores and opioid consumption at 24 hours [50]. The mean difference in pain scores was -0.37 (95% CI -0.56 to -0.19) on a numerical rating scale of 0 to 10; mean 24-hour morphine consumption was reduced by 0.85 mg (96% CI 0.82-0.89 mg), favoring liposomal bupivacaine.

A review of 76 randomized trials concluded that there was no clear evidence in support of the use of liposomal bupivacaine rather than non-liposomal bupivacaine for either peripheral nerve block or local infiltration [51].

The cardiac safety profile for liposomal bupivacaine is similar to that of aqueous bupivacaine [53]. (See "Local anesthetic systemic toxicity", section on 'Amide local anesthetics'.)

Novel formulations — Several formulations of extended-release bupivacaine. Clinical experience with each of them is limited, and further study is required before recommending routine use.

In 2021 a novel sustained-release formulation of bupivacaine (Posimir) was FDA approved for injection into the subacromial space under direct arthroscopic visualization [54]. The dose is 660 mg (5 mL vial) and unlike liposomal bupivacaine, it should not be diluted or mixed with other drugs or solutions.

A bupivacaine collagen implant is now available for postoperative analgesia following open inguinal hernia repair. The recommended dose is 300 mg (three 100 mg implants placed in the wound prior to closure) [55]. Like Posimir, FDA approval was given based on clinical trials demonstrating improved post-operative analgesia versus placebo.

In 2021 an extended release combination bupivacaine-meloxicam (Zynrelef) was FDA approved and is available for topical application into the wound for foot and ankle, small to medium open abdominal, and lower extremity joint arthroplasty surgery [56]. The mixed solution is applied to tissues below the level of the skin, after final wound irrigation. The maximum recommended dose for TKA is 14 mL (bupivacaine 400 mg/meloxicam 12 mg). Zynrelef carries an FDA boxed warning for cardiovascular and gastrointestinal toxicities related to meloxicam, which is a nonsteroidal anti-inflammatory drug (NSAID).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Local and regional anesthesia" and "Society guideline links: Local anesthetic systemic toxicity".)

SUMMARY AND RECOMMENDATIONS

Classification of local anesthetics – The chemical structure of commonly used local anesthetics (LAs) consists of an aromatic ring and a tertiary amine, linked by either a carboxylic ester or an amide bond. The amino ester group of LAs includes chloroprocaine, tetracaine, and procaine. The amino amide group includes lidocaine, bupivacaine, ropivacaine, mepivacaine, and outside the United States, levobupivacaine. (See 'Basic structure/classes' above.)

Metabolism of an LA depends on its chemical structure. Ester LAs are hydrolyzed by plasma cholinesterase, and amide LAs are metabolized via N-dealkylation by hepatic enzymes. (See 'Metabolism of local anesthetics' above.)

Pharmacodynamics – LA pharmacodynamics are determined by the physicochemical properties of the drug, and the specific way in which the drug is used (table 1 and table 2).

Potency of an LA is strongly associated with lipid solubility.

The speed of onset of LA conduction block associates with the physicochemical properties of the specific drug, the concentration of the solution, and the site of injection. In general, the time to onset increases with increasing lipid solubility, and more rapid onset is expected when the solution contains a greater fraction of nonionized molecules. (See 'Speed of onset' above.)

-Onset of block is almost immediate with subcutaneous or tissue infiltration and with intrathecal injection. Onset is delayed if LA must diffuse through tissue to reach the target nerves.

-LA solutions may be alkalinized to speed onset, by increasing the fraction of un-ionized LA molecules.

Duration of action of LA is determined in part by lipophilicity, but varies widely by site of injection and other drug characteristics. (See 'Duration of action' above.)

Serum levels – Serum levels of LA can be the result of systemic absorption from block sites, or inadvertent intravascular injection. Maximum allowable doses can be used as a starting point for deciding on a dose, but are not evidence based. (See 'Maximum allowable doses' above.)

Spinal anesthesia – For spinal anesthesia, the LA must be chosen to achieve the required spinal level and duration of anesthesia (table 2). The most important determinants of the extent of sensory block are the baricity and (with hypobaric and hyperbaric solutions) the patient's position after injection of the anesthetic solution. (See 'Spinal anesthesia' above.)

Transient neurologic symptoms (TNS) have been associated with the use of lidocaine for spinal anesthesia, particularly for patients undergoing surgery in the lithotomy position. Most other LAs are associated with a lower risk of TNS. (See 'Neurotoxicity of local anesthetics' above.)

Epidural anesthesia – For epidural anesthesia, the volume and total LA dose are the two most important drug related factors that influence the dermatomal extent and density of block (table 4). (See 'Epidural anesthesia' above.)

Peripheral nerve blocks – For peripheral nerve block, the LA and its volume and concentration are chosen according to the goal of the block (ie, surgical anesthesia and/or postoperative analgesia), degree of motor block, toxicity, and the desired duration of the block (table 1). (See 'Peripheral nerve block' above.)

Benefits of liposomal bupivacaine over aqueous bupivacaine have not been clearly demonstrated. (See 'Sustained release bupivacaine' above.)

Intravenous regional anesthesia – For intravenous regional anesthesia, lidocaine is the LA used most commonly in the United States, whereas prilocaine is used elsewhere. (See 'Intravenous regional anesthesia' above and "Upper extremity nerve blocks: Techniques", section on 'Intravenous regional anesthesia (Bier block)'.)

Topical anesthesia – Topical anesthesia is most commonly used to anesthetize the upper airway, nasal passages, and trachea, for awake laryngoscopy and intubation. Multiple preparations of lidocaine are available for topical anesthesia. LA toxicity can occur with the use of topical LA, especially when the drug is applied in repeated or high doses. (See 'Topical anesthetics' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Butterworth, IV, MD (deceased), who contributed to earlier versions of this topic review.

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Topic 14929 Version 29.0

References

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