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Background: Adding sodium bicarbonate to lidocaine to enhance its efficacy during peripheral nerve block is controversial. The authors studied the effect of adding sodium bicarbonate to lidocaine with and without epinephrine versus equivalent alkalinization by sodium hydroxide (NaOH) on onset, degree, and duration of peripheral nerve block., Methods: Part I examined alkalinization by sodium bicarbonate versus NaOH to pH 7.8 on 0.5% lidocaine, with and without epinephrine (1:100,000), prepared from crystalline salt. Part II examined 0.5% and 1.0% commercial lidocaine solutions, with and without epinephrine, either unalkalinized or alkalinized with sodium bicarbonate or NaOH. With NaOH, pH was adjusted to 7.8, but with sodium bicarbonate, no pH adjustments were made to simulate clinical conditions., Results: In part I, addition of either NaOH or sodium bicarbonate to 0.5% lidocaine without epinephrine produced a faster onset than did unalkalinized lidocaine, without effecting degree or duration of block. In solutions with epinephrine there were no differences in onset, degree, or duration between lidocaine alkalinized with sodium bicarbonate versus NaOH. In part II, addition of sodium bicarbonate or NaOH to 1.0% commercial lidocaine without epinephrine did not accelerate onset compared with the unalkalinized solution. However, adding sodium bicarbonate decreased the degree and duration of block by 25% and more than 50%, respectively, compared with lidocaine unalkalinized and alkalinized with NaOH. With epinephrine, sodium bicarbonate hastened onset without effecting degree and duration compared with the unalkalinized solution., Conclusions: With 1% commercial lidocaine without epinephrine, sodium bicarbonate decreases the degree and duration of block. However, in solutions with epinephrine, sodium bicarbonate hastens onset, without effecting degree or duration.

Background: N-butyl tetracaine has local anesthetic and neurolytic properties. An injection of this drug at the rat sciatic notch produces rapid onset and nerve impairment lasting > 1 week. This study aimed to elucidate the structure-activity relation of various tetracaine derivatives to design better neurolytic agents., Methods: N-alkyl tetracaine salts (n = 2-6) were synthesized, and their ability to elicit sciatic nerve impairment of sensory and motor functions in vivo was tested in rats. A single dose (0.1 ml at 37 mM) was administered close to the sciatic nerve at the sciatic notch. Regeneration was assessed morphologically in transverse sections of treated nerves. Finally, the drug potency in blocking Na+ currents was studied under voltage-clamp conditions., Results: N-ethyl and N-propyl tetracaine derivatives were non-neurolytic and elicited complete sciatic nerve block lasting 3-7 h. In contrast, N-butyl, N-pentyl, and N-hexyl tetracaine derivatives were strong neurolytic agents and elicited functional impairment of sciatic nerve for > 1 week. All derivatives were strong Na+ channel blockers, more potent than tetracaine if applied intracellularly. External drug application showed marked differences in their wash-in rate: tetracaine > N-hexyl > N-butyl > N-ethyl tetracaine. All derivatives were trapped within the cytoplasm and showed little washout within 7 min., Conclusions: When n-alkylation is 4-6, n-alkyl tetracaine appeared as a strong neurolytic agent. Neurolytic derivatives retained their local anesthetic activity and elicited rapid onset of nerve block after injection. Such derivatives are potential local anesthetic-neurolytic dual agents for chemical lesions of the sciatic nerve.

Background and Objectives: Pregnant patients need less local anesthetic in order to obtain the same quality of functional block as nonpregnant patients. Our goal was to demonstrate a similarly increased functional susceptibility to local anesthetics in the awake pregnant rat during peripheral nerve block and to investigate the pharmacokinetic and/or pharmacodynamic mechanisms responsible for this phenomenon., Methods: Radiolabeled lidocaine uptake was determined in vivo during sciatic nerve block with 0.1 ml of 1% lidocaine in the nerves of nine pregnant and five nonpregnant female rats and six male rats at the return of deep pain sensation, assessed by withdrawal of the hindlimb from a brief squeeze of a digit with serrated forceps. During recovery from complete functional block, the time at which deep pain returned and the amount of lidocaine in the nerve at that time were compared among the three groups of rats. Lidocaine content was also determined in vitro after exposure of ensheathed sciatic nerves from pregnant and nonpregnant rats to a 0.2% lidocaine bath for specified times., Results: Full block of function developed in all groups within 6 minutes of the lidocaine injection and lasted significantly longer in pregnant rats than in nonpregnant and male rats (49.0 +/- 3.3 vs 34.0 +/- 3.1 and 32.0 +/- 1.3 minutes mean +/- SEMI, respectively. At the time of deep pain return, the intraneural lidocaine content of pregnant rats was significantly lower than that of nonpregnant and male rats (2.2 +/- 0.25 vs 3.9 +/- 0.7 and 3.7 +/- 0.6 nmoles/mg of wet nerve, respectively). No difference in lidocaine uptake kinetics between P and NP nerves was observed in vitro., Conclusions: Block of peripheral neural function is prolonged in pregnant rats, and lidocaine content in the nerve is lower at a specific stage of neural block. These results are consistent with a pharmacodynamic mechanism for increased susceptibility to lidocaine neural block during pregnancy.

Background: Neurolytic agents such as phenol (5% to 10%) and absolute alcohol have long been used clinically to destroy the pathogenic nerve regions that manifest pain. Both phenol and alcohol are highly destructive to nerve fibers. However, these agents exert only weak local anesthetic effects and therefore are difficult to administer to alert patients without pain. This report describes a tetracaine derivative that displays both local anesthetic and neurolytic properties. Studies with such a compound may lead to the design of neurolytic agents that are more effective and more easily administered than phenol and alcohol., Methods: A tetracaine derivative, N-butyl tetracaine quaternary ammonium bromide, was synthesized, and its ability to elicit sciatic nerve block of sensory and motor functions in vivo was tested in rats. A single dose of 0.1 ml N-butyl tetracaine at 37 mM was injected into the sciatic notch. Transverse sections of treated sciatic nerves were subsequently examined to determine the neurolytic effect of this drug. Finally, the local anesthetic properties of N-butyl tetracaine were studied in vitro; both tonic inhibition and use-dependent inhibition of Na+ currents in neuronal GH3 cells were characterized under whole-cell voltage-clamp conditions., Results: N-butyl tetracaine at 37 mM (equivalent to 1.11% tetracaine-hydrochloric acid concentration) elicited prolonged sciatic nerve block of the withdrawal response to noxious pinch in rats for more than 2 weeks. The withdrawal response was fully restored after 9 weeks. Parallel to sensory block, motor functions of the hind legs were similarly blocked by this drug. Morphologic examinations 3 and 5 weeks after a single injection of drug revealed degeneration of many sciatic nerve fibers, consistent with the results of functional tests. Finally, N-butyl tetracaine was found to be a potent Na+ channel blocker in vitro. It produced strong tonic and use-dependent inhibition of Na+ currents with a potency comparable to that of tetracaine., Conclusions: A single injection of N-butyl tetracaine produces ultralong sciatic nerve block in rats. This compound possesses both local anesthetic and neurolytic properties and may prove useful as a neurolytic agent in pain management.

Background: During peripheral nerve block, local anesthetic (LA) penetrates within and along the nerve to produce the observed functional deficits. Although much is known about the kinetics and steady-state relation for LA inhibition of impulse activity in vitro in isolated nerve, little is known about the relation between functional loss and intraneural LA content in vivo. This study was undertaken to investigate the relation of functional change to intraneural LA., Methods: A sciatic nerve block was performed in rats with 0.1 ml 1% lidocaine radiolabeled with 14C. The total intraneural uptake of LA was determined at different times after injection, and the distribution of lidocaine along the nerve was assayed at different stages of functional block. Drug content was also compared with equilibrium lidocaine uptake in the isolated rat sciatic nerve., Results: Total intraneural lidocaine in vivo increased to near steady-state in about 3 min, stabilizing at approximately 14.3 nmol/mg wet tissue for about 12 min before decreasing to zero at 70 min after injection. Although intraneural lidocaine was 1.6% of the injected dose during full block, only 0.3% was left when deep pain sensation returned and 0.065% was still detected when functions fully recovered. Despite these large differences in total lidocaine content, the longitudinal distribution remained constant. Intraneural lidocaine concentrations obtained at full block and partial recovery could be achieved in vitro by equilibration in 0.7-0.9 and 0.2-0.3 mM lidocaine, respectively., Conclusions: During peripheral nerve block only a small amount of injected LA penetrates into the nerve. The intraneural content of LA correlates with the depth of functional block.

Background: Quantitative behavioral testing is necessary to establish a reproducible measure of differential functional blockade during regional anesthesia. Methods for assessment of the neurologic status (mental status, posture, gait, proprioception, motor function, autonomic function, and nociception) in veterinary neurology were adapted for the rat and used to monitor functional changes separately during a sciatic nerve block., Methods: Sprague-Dawley rats were acclimated to laboratory routine before the study so that lidocaine (0.1 ml, 1%) could be injected near the sciatic notch without any chemical restraint. The onset, duration, and magnitude of functional losses were monitored. Proprioceptive integrity was evaluated by assessing the response to tactile placing and the hopping response. Extensor postural thrust, a test for postural reactions in small animals, was assessed on a digital balance and found adequate for quantifying motor function. Analgesia was assessed by measuring withdrawal response latencies to noxious thermal stimulation (51 degrees C) and to superficial and deep noxious pinches. Autonomic function was monitored by measuring skin temperature. Contralateral limb function was used as an internal control, and injection of saline was used as an external control in separate, control animals., Results: Onset of postural and gait abnormalities were observed as early as 40 s after injection. On each occasion proprioceptive impairment was detected first, followed by impairment of motor function and nociception. Complete absence of proprioception occurred from 10 to 30 min (n = 9) and of motor function at 30 min after injection (n = 10); both functions were fully recovered by 120 min. A unilateral increase in skin temperature on the foot was detected by 1 min; had reached its maximum change, 5.3 +/- 0.7 degrees C, at 10 min; and had returned to control levels at 60 min after injection (n = 12). Withdrawal response to cutaneous or superficial pain was absent in all ten animals from 5 to 30 min whereas the response to deep pain was absent in all ten animals at 20 min only. The response to noxious stimulation recovered at 90 min. Attention was paid to the temporal relation of the impairment of various functions., Conclusions: Quantitative observations of the onset, offset, and intensity of differential functional impairment or block over time will make it possible to establish the doses and conditions for local anesthetics that result in differential nerve block and will permit comparison of these changes among different drugs and "clinical" protocols.