Mechanisms of analgesia of intravenous lidocaine

Abstracts

JUSTIFICATIVA E OBJETIVOS: A lidocaína é utilizada por via venosa desde a década de 1960 para diversas finalidades. Seu mecanismo de ação multimodal foi o objetivo principal dessa revisão. CONTEÚDO: Foram revisados mecanismos de ação divergentes do clássico bloqueio do canal de Na+, a ação diferencial da lidocaína venosa na sensibilização central, sua ação analgésica e citoprotetora, assim como as diferentes doses da lidocaína utilizadas por via venosa. CONCLUSÕES: A ação analgésica final da lidocaína por via venosa reflete seu aspecto multifatorial de ação. Em relação à sensibilização central, sugere-se uma ação anti-hiperalgésica periférica da lidocaína na dor somática e central na dor neuropática, com resultante bloqueio da hiperexcitabilidade central. A dose por via venosa não deve exceder a concentração plasmática tóxica de 5 µg.mL-1, sendo consideradas seguras doses inferiores 5 mg.kg-1, administradas lentamente (30 minutos), com monitoração.

ANALGESIA; ANALGESIA; ANALGESIA

REVIEW ARTICLE

Gabriela Rocha Lauretti

Professora Livre-Docente da FMRP/USP; Chefe da Disciplina de Anestesia e Chefe da Clínica para o Tratamento da Dor do Hospital das Clínicas, FMRP/USP

Correspondence to

SUMMARY

BACKGROUND AND OBJECTIVES: Intravenous lidocaine has been used for several indications since the decade of 1960. Its multimodal mechanism of action was the objective of this review.

CONTENTS: Mechanisms of action that diverge from the classical Na⁺ channel blockade, the differential action of intravenous lidocaine in central sensitization, and the analgesic and cytoprotective actions, as well as the different doses of intravenous lidocaine were reviewed.

CONCLUSIONS: The final analgesic action of intravenous lidocaine is a reflection of its multifactorial action. It has been suggested that its central sensitization is secondary to a peripheral anti-hyperalgic action on somatic pain and central on neuropathic pain, which result on the blockade of central hyperexcitability. The intravenous dose should not exceed the toxic plasma concentration of 5 µg.mL^-1; doses smaller than 5 mg.kg^-1, administered slowly (30 minutes), under monitoring, are considered safe.

Key Words: ANALGESIA: lidocaine, mechanisms of action, intravenous.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La lidocaína se utiliza por vía venosa desde la década de 60 para diversas finalidades. Su mecanismo de acción multimodal fue el objetivo principal de esta revisión.

CONTENIDO: Se revisaron mecanismos de acción divergentes del clásico bloqueo del canal de Na⁺, la acción diferencial de la lidocaína venosa en la sensibilización central, su acción analgésica y citoprotectora, como también las diferentes dosis de la lidocaína utilizadas por vía venosa.

CONCLUSIONES: La acción analgésica final de la lidocaína por vía venosa refleja su aspecto multifactorial de acción. Con relación a la sensibilización central, se sugiere una acción antihiperalgésica periférica de la lidocaína en el dolor somático y central en el dolor neuropático, con el resultante bloqueo de la hiperexcitabilidad central. La dosis de por vía venosa no debe exceder la concentración plasmática tóxica de 5 µg.mL^-1, siendo consideradas seguras dosis inferiores 5 mg.kg^-1, administradas lentamente (30 minutos), con monitorización.

INTRODUCTION

Lidocaine, a local anesthetic, has been used intravenously, since the decade of 1960, for several indications such as improvement of the acoustic function ¹, regional blocks, antiarrhythmic, analgesic on neuropathic and central pain ², and as adjuvant on postoperative pain, including postoperative pain refractory to opioids ³. Recently, its mechanism of action has been studied in more details, emphasizing its multimodal aspect, which was the main objective of this review.

Classical action of lidocaine on peripheral and central Na⁺ channels

Transmission of the peripheral nociceptive stimulus depends on the presence of voltage-gated Na⁺ channels. Two types of channels are expressed on peripheral sensitive neurons (NaV 1.8 and NaV 1.9), while the third type can be found in sensitive neurons of the sympathetic nervous system (NaV 1.7). A subtype of embryonic Na⁺ channel (NaV 1.3) has been described in damaged peripheral neurons, and it is associated with neuropathic pain and increase in excitability ⁴, since peripheral hyperexcitability is partly caused by an accumulation of Na⁺ channels on the site of damage ⁵. The development of postoperative central hyperalgesia can be reduced by blocking Na⁺ channels resistant to tetrodotoxin on nerve endings of mechanonociceptors, particularly sensitive to low doses of lidocaine, in the spinal cord and dorsal root ganglion ⁶.

Common allosteric mechanism of action on Na⁺ channels

Intravenous lidocaine (and consequently its active metabolite, monoethylglycinexylidide) interacts with peripheral and central voltage-gated Na⁺ channels, in the intracellular side of the cell membrane. It has more affinity for the opened ionic channel, which occurs during depolarization. The preferential location of the local anesthetic when it penetrates the phospholipid bilayer is determined by its hydrophobic and esteric properties. The location of lidocaine (non-polar) in the cell membrane reduced the resting period of the membrane and temporary chemical changes, indicating a specific orientation of the aromatic ring and less rotational freedom of the molecule in the membrane. On the other hand, bupivacaine increased the resting period of the membrane and temporary chemical changes due to its entrance in a perpendicular orientation to the one described previously ⁸. The action of lidocaine in the Na⁺ channel results from its allosteric coupling in the third and fourth segments of the third domain of the Na⁺ channel (Na⁺ channels in the heart have four domains), inhibiting completely the movement of the channel ⁹.

High concentrations of lidocaine can cause disruption of the cellular membrane secondary to the detergent properties of local anesthetics, analogous to surfactants, causing irreversible neural lesion¹⁰. It is interesting that lidocaine has a concentration-dependent antimicrobial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans ¹¹, and Streptococcus pneumoniae ¹², which might be secondary to the surfactant effect of lidocaine or suppression of the human leukocyte antigen type DR on monocyte surface mCD14 ¹³.

Differential action of intravenous lidocaine on central sensitization, depends on the affected tissue

Intravenous lidocaine affects peripheral and central nerve endings. Data in the literature indicate that central sensitization, resulting from tissue damage, would be minimized by intravenous lidocaine in different levels of the nervous system (peripheral and central), depending on the tissue damaged. For example, incision of rat skin (skin is an example of somatic tissue) resulted in a decrease of the receptive field of peripheral nociceptive stimuli and did not reduce the response of spinal wide-dynamic-range neurons to this stimulus ¹⁴, suggesting a peripheral anti-hyperalgic action of lidocaine in this model of pain ¹⁴. As for acute neuropathic pain secondary to spinal cord trauma, it was blocked by the intravenous administration of lidocaine, through the action of this drug on Na⁺ channels and blockade of the central hyperexcitability ¹⁵. The central neurotoxicity of high doses of lidocaine seems to affect cells of the dorsal ganglion of the spinal cord, and it is mediated by the specific activation of the p38 mitogen-activated protein kinase, but not by the extracellular signals of terminal protein kinases resulting from the c-jun system ¹⁶.

Analgesic action of intravenous lidocaine. Participation of mechanisms of action divergent from the classic Na⁺ channel blockade

When lidocaine is administered intravenously, the concentration of the neurotransmitter acetylcholine increases in the cerebrospinal fluid (CSF), which would exacerbate the inhibitory descending pain pathways resulting in analgesia ¹⁷ probably by binding to muscarinic receptors M3 ¹⁸, inhibition of glycine receptors ¹⁹, and release of endogenous opioids ^20,21 leading to the final analgesic effect.

Besides the mechanisms of action described, when lidocaine reaches the spinal cord, it reduces directly or indirectly the post-synaptic depolarization mediated by N-methyl-D-aspartate and neurokinin receptors ²². Topical application of lidocaine before bilateral dorsal rhizotomy in L₄ and L₅ decreased the spinal release of excitatory amino acids with reduction of allodynia in the animal model. The authors suggested the routine administration of lidocaine in the spinal nerves or on the surface of the spinal cord during surgeries involving manipulation of nerve tissue (laminectomy, herniated disks, decompression) ²³.

However, contrary to bupivacaine, the intravenous administration of lidocaine prior to the nociceptive stimulus did not reduce the expression of the spinal Fos gene involved in the development of central hyperalgesia ²⁴. It was described that the intravenous administration of 8 mg of ondansetron, a serotonergic 5HT3 antagonist, blocked the sensorial effect (but not motor) of spinal lidocaine, but the mechanism of action is unknown ²⁵.

Intravenous lidocaine reduces the inflammatory response to tissue ischemia and attenuates the tissue damage induced by endothelial and vascular cytokines through a mechanism involving the release of adenosine triphosphate and K⁺ channels ²⁶. The administration to culture of cells from the hippocampus 10 minutes after neuronal ischemia reduced the rate of cell death caused by oxygen deprivation and glucose ²⁷. Toxic doses can result in tonic-clonic ²⁸ seizures that are prevented by the prior administration of intravenous ketamine ²⁸, an antagonist of the N-methyl-D-aspartate receptor complex. It is speculated that administration of lidocaine would reduce the synthesis of tromboxane A2 (a mediator of myocardial ischemia, vasoconstriction, and thrombosis) by the direct interaction with the function of the cell membrane ²⁹.

Different doses of intravenous lidocaine

Although body weight is routinely used to determine the dose of the local anesthetic to be administered, a correlation between bodyweight and maximal plasma concentration does not exist ³⁰, making the dose calculated in mg.kg^-1 arbitrary. However, since the dose recommended by manufacturers of local anesthetics is lower than the toxic doses, one apparently works on a safe level. Nevertheless, one should be aware that plasma concentrations of lidocaine and its active metabolite, monoethylglycinexylidide, have different pharmacokinetic profiles when administered in the animal anesthetized with isoflurane and in the awaken animal. In the anesthetized animal, the volume of the central compartment, clearance and elimination half-life of lidocaine are smaller than in the awaken animal, resulting in higher plasma concentrations of lidocaine in the anesthetized animal ³¹. The administration of high doses of intravenous lidocaine to a patient being anesthetized with sevoflurane and under bispectral index (BIS) monitoring caused a fall of BIS to zero for 15 minutes, indicating an interaction between both anesthetics ³². One should also be careful on adjusting the dose of lidocaine for intravenous administration in patients with renal failure who are not undergoing hemodialysis ³³, and in those with cardiopathies ³⁴.

Lidocaine toxicity is more likely to manifest when its plasma concentration reaches 5 µg.mL^{-1 35}. Doses between 1 and 2 mg.kg^-1, administered as bolus followed or not by continuous infusion of 1.5 mg.kg^-1.h^-1, which correspond to plasma concentrations of 2 µg.mL^{-1 17}, are considered small. The toxic dose seems to change in patients with terminal diseases ³⁶. The intravenous administration of low doses of lidocaine was effective in the management of headaches refractory to conventional oral treatment ³⁷. Even the intraperitoneal administration of lidocaine (12.5 mg.h^-1) reduced postoperative opioid consumption in patients undergoing abdominal hysterectomy ³⁸, and it was also used, as a bolus, before anesthesia to prevent the ischemic tourniquet pain during intravenous regional anesthesia ³⁹.

Patients undergoing laparoscopic colectomy received intravenous lidocaine (bolus injection of 1.5 mg.kg^-1 during induction, followed by continuous infusion of 2 mg.kg^-1.h^-1 intraoperatively, and 1.33 mg.kg^-1.h^-1 in the first postoperative hours) while the control group received intravenous NS. This model demonstrated the benefits of lidocaine: reduction in the perioperative consumption of opioids, reduction in fatigue, improved intestinal function, and hospital discharge in 48 hours, while the control group was discharged in 72 hours ⁴⁰. In another study, intravenous lidocaine (2 mg.kg^-1 administered in 5 minutes, followed by 3 mg.kg^-1.min^-1 for 10 minutes) reduced airways resistance by 26% in patients with asthma who were intubated when compared with the control group, whose patients received NS, that showed a 38% increase in airways resistance above initial values ⁴¹, suggesting a local anesthetic action.

In cases of pain secondary to a lesion in the central nervous system, intravenous lidocaine (up to 5 mg.kg^-1) resulted in anti-allodynic and anti-hyperalgesic effects ⁴², suggesting an action on the central nervous system. Analgesia produced by the intravenous administration of lidocaine seldom persists when the infusion is discontinued ⁴³, and it should be restricted to patients with chronic neuropathic pain that are unable to ingest oral medications, in order to diagnose neuropathic pain and as a response test to oral sodium channel blockers ^43,44. Among 22 patients with peripheral neuropathies who received intravenous lidocaine (5 mg.kg^-1 in 30 minutes), those with mechanical allodynia demonstrated analgesia ⁴⁵. In a patient with neuropathic pain, the intravenous infusion of lidocaine required approximately 5 minutes to achieve maximal analgesia (time difference between ED50 and ED90 = 5.3 min) ⁴⁶. The analgesic effect increased abruptly once a specific plasma concentration was reached (0.62 µg.mL^-1), demonstrating that the analgesic effect of lidocaine does not follow a dose-effect curve, but it seems to suddenly block the painful stimulus ⁴⁶. The sodium channel blocker, mexiletine, can be administered orally to patients responsive to lidocaine ⁵, but one should pay attention to the adverse effects and the dose should be increased gradually.

The subcutaneous administration of 35 mg.kg^-1 of lidocaine (equivalent to 116 mL.min^-1) for abdominal liposuction was evaluated at regular intervals for 20 hours during the postoperative period. Plasma concentrations varied from 2.3 to 3.3 mg.mL^-1 between the 5^th and 17^th hours ³⁸, remaining within safe limits.

CONCLUSIONS

The final analgesic action of intravenous lidocaine reflects the multifactorial aspect of its action, resulting from the interaction with Na⁺ channels, and direct or indirect interaction with different receptors and nociceptive transmission pathways:

1. Muscarinic antagonist

2. Glycine inhibitor

3. Reduction in the production of excitatory amino acids

4. Reduction in the production of thromboxane A2

5. Release of endogenous opioids

6. Reduction in neurokinins

7. Release of adenosine triphosphate

As for central sensitization, it has been suggested a peripheral anti-hyperalgesic effect of lidocaine on somatic pain, and central effect on neuropathic pain, with the consequent blockade of central hyperexcitability. The intravenous dose of lidocaine should not exceed the toxic plasma concentration of 5 µg.mL^-1, and doses below 5 mg.kg^-1, administered slowly (30 minutes), under monitoring, are considered safe.

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Mechanisms of analgesia of intravenous lidocaine

Mecanismos involucrados en la analgesia de la lidocaína por vía venosa

Publication Dates

• Publication in this collection
  15 Sept 2008
• Date of issue
  June 2008

History

• Received
  01 Mar 2007
• Accepted
  19 Feb 2008