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Central and peripheral analgesic properties of local anesthetics : effects of lidocaine on thalamic neurons and efficacy of ropivacaine in femoral 3-in-1 nerve blockade

University of British Columbia

This thesis is dedicated to the pharmacology & therapeutics of local anesthetics, with a specific focus on their analgesic properties. In the first section, laboratory studies emphasize central mechanisms of the prototype agent, lidocaine, whereas clinical studies in the second section investigate the analgesic efficacy of the recently introduced aminoamide, ropivacaine, when administered peripherally for nerve blockade in knee surgery. The specific objective of the laboratory studies was to define the concentrationdependent effects of lidocaine on the membrane properties and excitability of neurons in the ventral posterior lateral thalamic nucleus (VPL), a major somatosensory and nociceptive relay station that plays a central role in pain states. Lidocaine produces central analgesia and sedation when present in the systemic circulation at low concentrations, and evidence implicates VPL neurons in these actions. Differential interference contrast infrared (DIC-IR) videomicroscopy-guided whole-cell patch clamp techniques were used to record from VPL neurons in rat brain slice preparations. Low, analgesic lidocaine concentrations (10 μM) significantly decreased neuronal input resistance (ft), which shunted action potentials, increased current thresholds, and reduced tonic firing. The effects were not associated with the classic signs of Na⁺ conductance blockade. The GABAA receptor antagonist, bicuculline, had no effect on the lidocaine-induced shunt. Higher lidocaine concentrations (> 300 uM; clinically CNS-toxic) did not decrease Ri but reversibly unmasked high threshold Ca²⁺ spikes (HTSs), susceptible to blockade by Cd²⁺. Extracellular QX-314, a quaternary lidocaine analogue, increased rather than decreased Ri. Similarly, neither procainamide nor bupivacaine reduced Ri. In summary, these studies identified novel actions of lidocaine in the thalamus, distinct from the classic effects on NA⁺ conductance. Low concentrations produced a shunting type of inhibition, likely a result of interaction with an intracellular target that does not involve GABAA receptors. These findings serve as an attractive and plausible mechanism for the systemic analgesic and sedative actions of lidocaine in vivo and may provide a basis for the development of novel, selective, and effective agents for the treatment of acute and chronic pain. The observation of an unmasking of high threshold Ca²⁺ spikes is in contrast to previous studies in other tissues showing that lidocaine blocks Ca²⁺ conductances, and is of potential significance for the mechanisms of local anesthetic CNS toxicity. The purpose of the clinical studies was to test if postoperative pain control in patients undergoing arthroscopic anterior cruciate ligament reconstruction (ACLR) under general anesthesia is improved by addition of a preincisional femoral 3-in-l block with ropivacaine 0.2% to standard intra-articular instillation at the end of surgery. In a prospective, randomized, controlled, double-blind trial (RCT), 44 patients scheduled for inpatient ACLR were studied. Prior to surgery, the treatment group (» = 22) received a femoral 3-in-l block with 40 ml of ropivacaine 0.2%, augmented by additional periincisional infiltrations (20 ml) at the end of the procedure. The control group [n — 22) received saline 0.9% instead of ropivacaine. All patients received an intra-articular instillation with 30 ml of ropivacaine 0.2% at the end of surgery. The primary efficacy variable was 24 h morphine consumption postoperatively standardized by weight, administered intravenously via a patient-controlled analgesia (PCA) pump. There was no significant difference between both groups in the primary efficacy variable. No difference was found in visual analog scale pain scores, adverse events, or vital signs. More patients in the treatment group did not require any morphine than in the control group, but this difference was not statistically significant. In conclusion, the clinical studies demonstrated no significant effect in an RCT of a femoral 3-in-l block with ropivacaine 0.2% on postoperative analgesic consumption, compared to intra-articular instillation alone, in patients undergoing ACLR under general anesthesia.

Thesis/Dissertation

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2009-09-26

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http://hdl.handle.net/2429/13230

Pharmacology

University of British Columbia

UBCV

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