| Summary: | 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.
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