Lidocaine

Mechanism of Action

Similar to other local anesthetics, lidocaine acts on voltage-gated sodium channels on the internal surface of nerve cell membranes. The uncharged form of lidocaine diffuses through neural sheaths into the axoplasm, where it ionizes by combining with hydrogen ions. The resulting cation binds reversibly to sodium channels from the inside, stabilizing them in the open and inactivated state and thereby preventing nerve depolarization. Lidocaine is a weak base with a dissociation constant (pKa) of 7.7. Approximately 25% of lidocaine molecules are neutrally charged at a physiological pH of 7.4 and can diffuse into nerve cells, contributing to lidocaine’s more rapid onset of action compared with other local anesthetics that have higher pKa values.[14]

Lidocaine's efficacy is reduced at sites of inflammation; this reduction may result from acidosis decreasing the proportion of neutral lidocaine molecules, accelerated reduction in local lidocaine concentration due to increased blood flow, or increased production of inflammatory mediators, such as peroxynitrite, which act directly on sodium channels.[15] Lidocaine's function as an N-methyl-D-aspartate (NMDA) antagonist offers potential benefits for patients with difficult-to-control pain, such as mixed nociceptive-neuropathic pain and central sensitization.[10] In cardiac myocytes, lidocaine slows the rise of the cardiac action potential during phase 0, thereby increasing the effective threshold potential. Increased blood levels of lidocaine can affect cardiac output, total peripheral resistance, and mean arterial pressure, likely due to its direct depressant effects on the cardiovascular system.

Pharmacokinetics

Absorption: An IV bolus of lidocaine has a very rapid onset of action, occurring within approximately 45 to 90 seconds. Lidocaine ointment provides local, topical anesthesia with an onset of action between 3 and 5 minutes. Absorption of lidocaine following topical application to mucous membranes varies with application site, concentration, duration, and dosage.

Distribution: Lidocaine is 60% to 80% protein-bound to albumin and α1-acid glycoprotein in plasma, resulting in a medium duration of action compared with other local anesthetic agents. This drug is less lipid-soluble than other agents, limiting its overall potency. The volume of distribution of a single IV bolus of lidocaine is approximately 0.8 to 2.8 L/kg.

Metabolism: The hepatic enzymes CYP1A2 and CYP3A4 metabolize lidocaine into active and inactive molecules. The active metabolites of lidocaine are monoethylglycylxylidide (MEGX) and glycylxylidide (GX).[16]

Elimination: The half-life of lidocaine is approximately 1.5 to 2 hours and may be prolonged in patients with congestive heart failure or hepatic impairment. Approximately 90% of lidocaine is excreted in urine.

Administration

Available Dosage Forms and Strengths

Lidocaine is available in various formulations, including solutions, aqueous gels, and ointments of various strengths. Additionally, lidocaine may be combined with epinephrine or other local anesthetics (eg, prilocaine). Lidocaine is also a component of other products, including medicated plasters designed to treat chronic postherpetic neuralgia. Different routes of administration require specific lidocaine preparations.

• Diluted solutions of 0.05% to 0.1% may be injected subcutaneously in large volumes to provide tumescent local anesthesia. This technique results in swelling and firmness of the site, which may benefit certain surgical procedures.
• Preservative-free solutions of 0.25% to 0.5% are used for IV regional anesthesia (Bier block).
• Solutions of 1% to 2% are used for epidural anesthesia and regional nerve blocks.
• IV preparations of lidocaine available for antiarrhythmic use.
• Aqueous lidocaine gels of 1% to 2%  are used to topicalize and lubricate the urethra before procedures such as Foley catheterization. Lidocaine gels are also available in combination with antiseptics such as chlorhexidine.
• Solutions of 4% are used for topical anesthesia of accessible airway mucous membranes, including those of the mouth, pharynx, and respiratory tract. These solutions may be applied by gargling, spraying, or atomization.
• Solutions of 10% are applied topically for airway anesthesia using a metered-dose atomizer.
• Ointments typically contain 5% lidocaine mixed with hydrocortisone and are applied topically to mucous membranes such as the skin or rectum.
• An eutectic mixture of lidocaine and prilocaine (EMLA) combines the local anesthetics prilocaine and lidocaine. EMLA effectively penetrates the skin to provide local cutaneous anesthesia and is commonly used to avoid the pain associated with needle punctures.
• The aqueous preparations are available in concentrations of 0.5%, 1%, and 2%, with or without epinephrine (1:200,000 epinephrine). Dentistry sometimes uses formulations containing epinephrine at concentrations of 1:100,000 or higher. These preparations are available with or without preservatives, depending on the intended route of administration.

Adult Dosage

Lidocaine dosing depends on the route of administration (intravenous, perineural, or topical), the site of administration, and the use of adjuvants such as epinephrine.

• Doses used for infiltrative or regional anesthesia vary by site, purpose, and desired duration of the nerve block. The FDA-approved label states a maximum dose of 4.5 mg/kg (maximum 300 mg) for plain formulations and 7 mg/kg (maximum 500 mg) when used with epinephrine. When lidocaine is used for epidural or caudal anesthesia, the maximum dose should not be repeated more frequently than every 90 minutes.
• When lidocaine is administered to obtund airway reflexes, the recommended dose is 1 to 2 mg/kg, administered 2 to 5 minutes before intubation.
• For cardiac dysrhythmias, the initial dose is 1 to 1.5 mg/kg administered intravenously, optionally followed by an infusion as clinically indicated.[4]
• As an adjuvant IV treatment for acute pain, a 2020 consensus statement recommended a loading dose of no more than 1.5 mg/kg over 10 minutes, followed by an infusion of no more than 1.5 mg/kg/h for no longer than 24 hours, with close monitoring for clinical response and signs of toxicity.[17] 

The ASA panel noted the absence of definitive evidence regarding the optimal dosing of lidocaine. However, based on clinical experience, the ASA recommends administering an induction dose of 1.5 mg/kg, followed by an intraoperative infusion of 2 mg/kg/h, for patients undergoing open or laparoscopic abdominal surgery.[8] For awake intubation, effective topical application and adequate airway anesthesia must be ensured. The maximum dose of lidocaine should not exceed 9 mg/kg of lean body weight. To minimize the risk of laryngospasm, clinicians should consider nebulized lidocaine and lower concentrations.[9]

Specific Patient Populations

Hepatic impairment: A lower maintenance infusion rate should be administered, with close monitoring for signs of toxicity. According to the American Association for the Study of Liver Diseases guidelines, a patch can be used for pain relief in patients with decompensated cirrhosis; however, it should be used with caution.[18][19]

Renal impairment:  A lower maintenance infusion rate should be administered, with close monitoring for signs of toxicity. Dosage adjustments are generally unnecessary for patients with renal impairment, as topical and local lidocaine demonstrate limited absorption.

Pregnancy considerations: Lidocaine is thought to cross the placenta by passive diffusion. According to the American College of Obstetricians and Gynecologists (ACOG), local anesthesia for the treatment of oral conditions, including lidocaine with or without epinephrine, is considered safe during pregnancy.[20] The maximum recommended dose of lidocaine is 4.5 mg/kg (300 mg) for plain formulations and 7 mg/kg (500 mg) when used with epinephrine.[21] A pregnant woman should not be denied or have medically necessary surgery postponed due to pregnancy, as such delays may negatively impact both the mother and fetus. Elective procedures should generally be deferred until after delivery. Current evidence indicates that in utero exposure to anesthetic or sedative drugs does not appear to adversely affect fetal brain development. Additionally, animal studies have not shown adverse effects from limited exposures lasting less than 3 hours.

Breastfeeding considerations: Lidocaine concentrations in breast milk are low following continuous IV infusion, epidural administration, or high-dose local anesthesia, placing breastfeeding infants at minimal risk of exposure. Therefore, lidocaine is unlikely to cause adverse effects in breastfed infants, and no special precautions are necessary. Concerns regarding lidocaine's potential interference with breastfeeding, particularly when used with other anesthetics and analgesics, are debated due to variability in study designs and methodologies. With adequate breastfeeding support, epidural lidocaine combined with opioids typically has a minimal impact on breastfeeding success, although labor pain medication may delay the onset of lactation.[22]

Pediatric patients: Neonates have immature metabolic clearance mechanisms, which increase the risk of drug and metabolite accumulation. Additionally, the α1-acid glycoprotein levels in neonates and infants are lower, with concentrations at birth approximately half those observed in adults. This results in a higher unbound fraction of lidocaine, an extended elimination half-life, and an increased risk of accumulation, particularly with continuous infusions.[23] 

Topical lidocaine must be dosed carefully in pediatric patients to prevent overdose. The maximum dose is based on weight or age for otherwise healthy children older than 3 years. In infants and children younger than 3 years, no more than 1.2 mL of the 2% solution should be applied, with at least a 3-hour interval between doses and a maximum of 4 doses within 12 hours.

Systemic lidocaine infusions are well established for managing postoperative acute pain in pediatric patients but are less validated for other types of pediatric pain. Lidocaine’s NMDA antagonist properties may benefit difficult-to-control pain, including mixed nociceptive-neuropathic pain and central sensitization. Dosing for these indications typically includes a 1.5 mg/kg bolus followed by a 1 mg/kg/h infusion, with higher doses used in pediatric oncology settings. Additional studies are needed to better define the safety and efficacy of lidocaine infusions in children and to refine dosing recommendations for different pain conditions. Further research is also required to determine the importance of monitoring plasma concentrations during continuous infusion.[24]

Older patients: Local anesthesia should be prioritized for surgical procedures in older adults. The lowest effective volume and concentration should be administered to minimize the risk of systemic toxicity. For lidocaine, the recommended concentration is 1% (10 mg/mL), and dosing should not exceed standard weight-based limits of 4.5 mg/kg. This approach provides effective local anesthesia for many surgical procedures while reducing the risk of postoperative complications.[25]

Adverse Effects

Most adverse reactions associated with lidocaine occur when plasma concentrations reach toxic levels. Lidocaine enters the intravascular compartment most rapidly when administered into the intercostal space, followed by the caudal, epidural, brachial plexus, femoral, and subcutaneous spaces. The maximum safe dose per kilogram of body weight may range from 3 to 7 mg/kg for formulations containing epinephrine, although other doses have been reported. Smaller doses can still result in adverse effects and toxicity if administered intravenously. Lidocaine is considered to be more neurotoxic than other local anesthetics, especially when high concentrations are applied directly to nervous tissue. Use of highly concentrated lidocaine (2.5% to 5%) for spinal anesthesia has been associated with a higher incidence of transient radicular irritation syndrome, which is a painful but self-limiting condition affecting the calves, thighs, and buttocks.[26]

Drug-Drug Interactions

• Concomitant administration of lidocaine and propranolol significantly increases serum lidocaine concentrations.
• Caution is advised when administering lidocaine hydrochloride to patients with digitalis toxicity or atrioventricular block.
• Lidocaine is a substrate of CYP1A2, CYP2B6, and CYP2D6 and exerts an inhibitory effect on CYP1A2. Caution is advised when coadministering lidocaine with fluvoxamine.[27][28]
• Patients may be at increased risk of developing methemoglobinemia when local anesthetics (eg, lidocaine) are coadministered with other drugs, including nitrates, nitric oxide, hydroxyurea, dapsone, sulfonamides, chloroquine, phenobarbital, and phenytoin.[29] Methemoglobinemia may also result from lidocaine metabolism to O-toluidine.[30] This metabolite is more likely to accumulate at very high doses but may also occur at lower doses in patients taking other medications that can precipitate methemoglobinemia or in those with hemoglobinopathies or other causes of anemia.

Contraindications

Lidocaine is contraindicated in patients with a known severe adverse reaction to lidocaine or other amide-type local anesthetics. Anaphylactic reactions to lidocaine are rare but possible. Methemoglobinemia may occur in patients with hemoglobinopathies or other causes of anemia. Lidocaine should not be used as an antiarrhythmic agent when the dysrhythmia is suspected to be secondary to local anesthetic toxicity.

Lidocaine should also be avoided in patients with conditions such as Wolff-Parkinson-White syndrome, Adam-Stokes syndrome, as well as in those with advanced sinoatrial, atrioventricular, or intraventricular conduction block, unless a functional artificial pacemaker is present. Additionally, certain premixed injectable formulations may contain dextrose derived from corn and are therefore contraindicated in patients with known hypersensitivity to corn or corn-related products.

Box Warnings (Lidocaine Viscous)

Life-threatening events in young children: Severe adverse events, including seizures, cardiopulmonary arrest, and death, have been reported in children younger than 3 years due to improper use of lidocaine viscous 2%. This drug should not be administered for teething pain and should be used in this age group only when no safer alternatives are available.[31] Strict adherence to dosing guidelines and secure storage practices are essential to mitigate risks. This FDA-issued boxed warning applies specifically to these circumstances and does not extend to all lidocaine formulations, such as IV lidocaine.

Warning and Precautions

Injectable anesthetic: Careful administration techniques should be employed to prevent unintended intravascular injection. Preparations containing antimicrobial preservatives are not suitable for spinal or epidural anesthesia. Certain formulations include sodium metabisulfite, which should be avoided in individuals with known sulfite hypersensitivity. 

Previous studies have reported that lidocaine suppresses premature ventricular complexes and nonsustained ventricular tachycardia, which were thought to precede VF or pVT. However, recent findings have linked prophylactic lidocaine administration to suppress premature ventricular complexes with higher mortality following acute myocardial infarction, likely due to increased asystole and bradyarrhythmias, leading to abandonment of routine prophylactic use. Observational studies indicate that while lidocaine reduces VF/pVT recurrence after the return of spontaneous circulation, it does not improve survival and has no benefit for patients with nonshockable rhythms.[5]

Postmarketing reports have described chondrolysis, primarily involving the shoulder joint, following continuous intra-articular infusion of local anesthetics, with some cases requiring arthroplasty or shoulder replacement.

Benzyl alcohol is no longer commonly used as a preservative in standard lidocaine injection formulations; however, exposure may still occur through certain topical products, combination formulations, or bacteriostatic diluents.

Monitoring

Lidocaine has a narrow therapeutic index, and plasma-level monitoring may be necessary in patients with hepatic impairment who require prolonged infusions. Ideal or lean body weight may be used for dose calculations during continuous infusions to reduce the risk of toxicity, although practices vary and should align with institutional protocols. Infusion rates are typically titrated according to clinical response and patient health status.[17] Vital signs and electrocardiographic activity should be continuously monitored during systemic lidocaine administration. Clinicians should use validated tools such as the Short-Form McGill Pain Questionnaire (SF-MPQ) and the Visual Analog Scale (VAS)  to assess analgesic response when lidocaine is used for pain management.[32][17]

Lidocaine preparations containing epinephrine can produce significant cardiovascular effects even when administered in small amounts; therefore, hemodynamic monitoring is essential before and during the use of vasopressor-containing solutions, particularly in patients with underlying cardiovascular concerns.[33]

Toxicity

Signs and Symptoms of Overdose

Signs and symptoms of mild toxicity become apparent at plasma levels greater than 5 μg/mL, with initial symptoms including slurred speech, tinnitus, circumoral paresthesia, and lightheadedness. At plasma levels of approximately 8 to 10 μg/mL, patients may experience seizures or loss of consciousness. At concentrations of approximately 15 μg/mL, myocardial and central nervous system depression become more pronounced, potentially progressing to cardiac arrhythmias, respiratory arrest, and cardiac arrest at concentrations exceeding 20 μg/mL.[33] Animal studies suggest that the dose of lidocaine required to cause cardiovascular collapse (CC) is 7.1 ± 1.1 times higher than the dose required to induce CNS effects.[34] This so-called "CC/CNS ratio" is significantly higher than that observed with other local anesthetic agents; for example, bupivacaine has a CC/CNS ratio of approximately 2:1. In conscious patients experiencing toxic dosing, lidocaine may be less likely than other local anesthetics to progress rapidly from neurological effects to complete cardiovascular collapse. By contrast, neurological signs and symptoms may be masked in patients receiving concurrent sedation or general anesthesia; consequently, cardiovascular instability or arrhythmias may represent the initial manifestations of toxicity.[35]

Management of Overdose

Lidocaine administration should be discontinued immediately if toxicity or overdose is suspected. During cardiorespiratory collapse, airway management and ventilatory support should be prioritized to prevent the development of respiratory acidosis, which may exacerbate toxicity and potentiate negative chronotropic and inotropic effects of lidocaine.[36] Vital function support, including oxygen, IV fluids, and inotropes, should be initiated as needed. IV lipid emulsion is indicated as rescue treatment in the standard management of local anesthetic systemic toxicity, particularly in cases of refractory cardiovascular collapse.[37]

Enhancing Healthcare Team Outcomes

All interprofessional healthcare team members, including clinicians, nurses, and pharmacists, should be familiar with lidocaine toxicity and management. Lidocaine may cause significant pain during the initial injection because it stimulates nociceptors before exerting its effects on sodium channels; this pain can be reduced by buffering the lidocaine with small volumes of sodium bicarbonate shortly before use, thereby making the solution less acidic.[38] Injection pain can also be reduced by warming the solution to body temperature, administering the injection slowly, using narrow cannulas, and inserting the needle perpendicular to the skin.[39] 

Patients receiving IV lidocaine infusions should be considered high risk; a 2020 consensus statement recommended that, when these infusions are administered outside the operating room or postanesthesia care unit, patients should be managed in a high-dependency or intermediate care unit (IMC) with continuous monitoring. The infusion should be administered through a separate, dedicated cannula using a tamper-proof pump.[17] 

Clinicians are responsible for appropriate patient selection, accurate dose calculation, and adherence to guideline-based administration techniques. Nurses play a critical role in continuous monitoring of vital signs and electrocardiographic activity, early recognition of neurologic or cardiovascular toxicity, and prompt escalation of care. Pharmacists contribute by verifying dosing, assessing drug-drug interactions, and recommending dose adjustments in special populations, including older adults, pediatric patients, and patients with hepatic impairment. Clear communication, preparedness with resuscitation equipment, and adherence to safety protocols are essential for enhancing patient outcomes and minimizing complications associated with lidocaine use.