Which of the following local anesthetics is the most neurotoxic?

October 7, 2025 •

5 min read

Case reports and clinical studies have shown that some local anesthetics carry a higher risk of neurotoxicity than others, especially when administered intrathecally. This inherent risk is a critical consideration for practitioners choosing the appropriate agent and technique to answer the question: which of the following local anesthetics is the most neurotoxic?

Quick Summary

This article evaluates the comparative neurotoxicity of common local anesthetics, focusing on factors influencing neural injury. It compares agents like lidocaine and bupivacaine, explores cellular mechanisms, and discusses patient and procedural risks, emphasizing best practices for safe administration.

Key Points

Lidocaine has a historically higher neurotoxicity risk in certain applications, notably intrathecal (spinal) anesthesia, where it has been linked to Transient Neurologic Symptoms (TNS) and, in the past, Cauda Equina Syndrome (CES).
Neurotoxicity is dose- and concentration-dependent, meaning the risk increases with higher doses and concentrations of any local anesthetic.
Prolonged exposure amplifies risk, as seen with continuous infusion techniques, which increases the likelihood of nerve damage.
Injection technique is critical, with intrafascicular injection carrying the highest risk of direct nerve trauma and high-concentration exposure. Ultrasound guidance significantly reduces this risk.
Patient-specific risk factors exist, including pre-existing neuropathies (e.g., diabetes) and compromised vascular health, which increase vulnerability to local anesthetic-induced nerve injury.
Bupivacaine carries a lower neurotoxicity risk than lidocaine at equipotent doses but has a higher potential for severe cardiotoxicity if accidentally injected intravascularly.
Intravenous lipid emulsion therapy is the recommended treatment for severe local anesthetic systemic toxicity (LAST), offering a critical intervention for both central nervous system and cardiovascular events.

The question of which local anesthetic is the most neurotoxic is complex, as toxicity depends on numerous factors beyond the drug itself. While all local anesthetics can exhibit dose- and concentration-dependent neurotoxicity, historical clinical evidence and laboratory studies have consistently singled out lidocaine as having a higher potential for neurotoxicity, particularly in intrathecal (spinal) and continuous infusion applications. Newer agents like ropivacaine were developed with an improved safety profile, though no agent is entirely free of risk.

The Special Case of Lidocaine Neurotoxicity

Lidocaine's reputation for higher neurotoxicity largely stems from its association with two specific conditions following spinal anesthesia: Transient Neurologic Symptoms (TNS) and, historically, Cauda Equina Syndrome (CES).

Transient Neurologic Symptoms (TNS): After spinal anesthesia with high-concentration lidocaine, TNS can manifest as pain or dysesthesia in the buttocks, thighs, and lower extremities. While the symptoms are temporary, they can be severe in some patients. The incidence of TNS with lidocaine is notably higher than with other commonly used agents.
Cauda Equina Syndrome (CES): In the early 1990s, cases of CES, a devastating neurological injury, were reported in patients receiving continuous spinal anesthesia through microcatheters with high concentrations of lidocaine. This led to the withdrawal of these catheters and a general shift away from using high-dose, continuous spinal lidocaine. CES is now exceedingly rare but serves as a stark reminder of the potential for severe neurotoxic effects.

Animal and in vitro studies have further substantiated lidocaine's higher neurotoxic potential compared to equipotent concentrations of bupivacaine. Its mechanism involves cellular damage, including changes in calcium homeostasis and mitochondrial function, which can trigger programmed cell death (apoptosis).

Factors Beyond the Agent Itself

Neurotoxicity is not solely an intrinsic property of the local anesthetic but is influenced by the interaction of the drug with the nervous system under specific conditions. Several critical factors modulate the risk of nerve injury.

Concentration and Dosage: The risk of neurotoxicity is directly proportional to both the concentration and total dose of the local anesthetic. Higher concentrations and large volumes, especially when injected near nerves, can cause direct cytotoxic effects.
Duration of Exposure: Prolonged exposure to local anesthetics, such as with continuous infusion techniques, increases the risk of nerve damage. This is one of the key reasons continuous spinal lidocaine fell out of favor.
Site and Technique of Injection: Intrafascicular injection (injection directly into a nerve bundle) is a significant risk factor for severe nerve injury. This exposes nerve fibers to a much higher local anesthetic concentration than intended. The use of fine-beveled needles and avoiding high-pressure injections are crucial preventative measures.
Patient Factors: Certain pre-existing conditions can increase a patient's susceptibility to neurotoxicity.
- Pre-existing Neuropathies: Conditions like diabetic neuropathy can make nerves more vulnerable to local anesthetic damage.
- Vascular Compromise: Any medical condition affecting microvasculature, such as hypertension or diabetes, can make nerves more susceptible to ischemic injury, which can be exacerbated by local anesthetic vasoconstrictors.

Comparative Neurotoxicity of Common Local Anesthetics

While lidocaine is often cited as a higher-risk agent in specific contexts, a broader comparison is necessary to understand the full landscape of local anesthetic safety.


Local Anesthetic	Class	Onset	Duration	Neurotoxicity Risk (Relative)	Key Risks/Considerations
Lidocaine	Amide	Fast	Intermediate	Higher potential, especially in spinal applications. Associated with TNS.	TNS (Transient Neurologic Symptoms), historical association with CES. Higher risk of CNS excitation followed by depression at toxic systemic levels.
Bupivacaine	Amide	Slower	Long	Lower than lidocaine at equipotent concentrations, but still present.	High risk of cardiovascular toxicity at high systemic levels, making it dangerous for accidental intravascular injection. Resuscitation is more difficult than with lidocaine toxicity.
Ropivacaine	Amide	Slower	Long	Generally considered less neurotoxic and cardiotoxic than bupivacaine.	Similar to bupivacaine but with a higher margin of safety regarding cardiotoxicity. Neurotoxicity still possible, particularly with overuse or in high-risk patients.
Tetracaine	Ester	Slower	Long	Dose-dependent neurotoxicity observed in animal studies.	High systemic plasma levels can cause LAST. Risk is dependent on concentration and exposure time.

Preventing and Managing Local Anesthetic Neurotoxicity

Given that any local anesthetic can be neurotoxic under the right circumstances, preventative measures are paramount. The American Society of Regional Anesthesia and Pain Medicine (ASRA) provides guidelines for minimizing risk.

Prevention Strategies

Use the Lowest Effective Dose: Employing the lowest concentration and volume of local anesthetic necessary for the procedure reduces the risk of reaching toxic levels.
Ultrasound Guidance: Visualizing the needle's trajectory and the location of nerve tissue with ultrasound significantly reduces the chance of inadvertent intrafascicular or intravascular injection.
Incremental Injection and Aspiration: Injecting the anesthetic in small increments while frequently aspirating for blood reduces the risk of a large, unintentional intravascular dose.
Patient Monitoring: Continuous verbal contact and vital sign monitoring are essential to detect the early signs of local anesthetic systemic toxicity (LAST), such as perioral numbness, dizziness, or confusion.

Management of Local Anesthetic Systemic Toxicity (LAST)

In the event of LAST, prompt recognition and treatment are critical. Management involves immediate cessation of the anesthetic and supportive care.

Airway and Respiration: Maintain the airway and provide oxygen, potentially with intubation if CNS or respiratory depression is severe.
Seizure Control: Benzodiazepines are the first-line treatment for seizures caused by LAST due to their minimal cardiac depressant effects.
Lipid Emulsion Therapy: Intravenous lipid emulsion is a highly effective treatment for severe LAST. It is thought to act as a "lipid sink," sequestering the lipophilic local anesthetic from the target organs, including the central nervous system and heart.

Conclusion

In conclusion, while multiple local anesthetics have been studied for their neurotoxic potential, historical evidence and comparative research point toward lidocaine having the highest risk of neurotoxicity, particularly in the context of spinal administration. However, the overall risk is heavily dependent on factors like dose, concentration, duration, injection technique, and patient comorbidities. Modern practice emphasizes stringent preventative measures, such as using ultrasound guidance and incremental dosing, to mitigate these risks across all local anesthetic agents. Understanding these nuances is key to ensuring patient safety and minimizing adverse neurological outcomes.

For more detailed guidance, the American Society of Regional Anesthesia and Pain Medicine (ASRA) provides extensive practice advisories on local anesthetic safety and toxicity.

Frequently Asked Questions

Local anesthetic neurotoxicity refers to the potential of these drugs to cause damage or toxic effects on nerve tissue, which can result in temporary or permanent neurological deficits. It is primarily dependent on the drug's concentration, dose, and exposure time.

Lidocaine has been linked to a higher incidence of Transient Neurologic Symptoms (TNS) and was historically associated with Cauda Equina Syndrome (CES) following specific types of spinal anesthesia. Laboratory studies have shown it can be more damaging to nerve cells than some other local anesthetics at equipotent concentrations.

Yes, the site of injection is a major factor. Inadvertent intrafascicular injection, where the anesthetic is deposited directly into a nerve bundle, exposes nerves to extremely high concentrations, dramatically increasing the risk of injury.

Early signs of systemic toxicity often include perioral tingling, lightheadedness, a metallic taste, tinnitus, dizziness, and visual disturbances. In severe cases, this can progress to CNS excitation (seizures) and then depression (respiratory arrest, coma).

Doctors can minimize risk by using the lowest effective dose, employing ultrasound guidance for blocks, injecting incrementally with frequent aspiration, and carefully monitoring the patient for signs of toxicity.

In terms of neurotoxicity, studies suggest bupivacaine may have a lower risk than lidocaine at equivalent potency, particularly regarding TNS. However, bupivacaine has a higher risk of severe cardiotoxicity if it is accidentally injected into a blood vessel, a critical distinction.

Intravenous lipid emulsion therapy is a modern treatment for severe Local Anesthetic Systemic Toxicity (LAST). It works by creating a 'lipid sink' that draws the anesthetic out of the heart and brain, effectively reversing the toxic effects.