Inclusion of lignocaine base into a polar lipid formulation--in vitro release, duration of peripheral nerve block and arterial blood concentrations in the rat.

BACKGROUND: Slow-release formulations of local anaesthetics may produce nerve blocks of long duration. The present study aimed at investigating the in vitro and in vivo properties of a polar lipid formulation for slow release of lignocaine and the effects on nerve block duration by inclusion of dexamethasone into the system. METHODS: In vitro release of lignocaine from the lipid formulation was studied in a US Pharmacopoeia rotating apparatus. Sciatic nerve blocks were induced in rats by 0.1 ml of test formulations containing lignocaine HCl 20 mg. ml-1 in aqueous solution, lignocaine base 20, 100 or 200 mg. ml-1 in lipid formulation or the last formulation with dexamethasone 0.05, 0.5 or 5 mg. ml-1. The durations of sensory and motor block and the arterial blood concentrations of lignocaine were investigated. RESULTS: In vitro there was a sustained release of lignocaine from the lipid formulation, with 50% release at around 48 h. In vivo lignocaine base 20 mg. ml-1 in lipid formulation produced sciatic nerve blocks of significantly shorter duration than lignocaine HCl 20 mg. ml-1 in aqueous solution, while lignocaine base 100 and 200 mg. ml-1 in lipid formulation produced blocks lasting two and three times longer, respectively, than the lignocaine HCl solution. Addition of dexamethasone did not affect the duration of nerve block. Following administration of lignocaine base 200 mg. ml-1 in lipid formulation, as compared to lignocaine HCl 20 mg. ml-1 in aqueous solution, the maximal blood concentration of lignocaine was only three times higher in spite of the ten-fold difference in dose, and the mean terminal half-life was three times longer, reflecting the slow release from the formulation. CONCLUSIONS: Our findings indicate that lignocaine base in polar lipids acts as a slow-release preparation of local anaesthetic both in vitro and in vivo.

The duration of action of bupivacaine, levobupivacaine, ropivacaine and pethidine in peripheral nerve block in the rat.

BACKGROUND: There is a current interest in local anaesthetic drugs/formulations exhibiting long durations of sensory block and minor motor-blocking effects. OBJECTIVES: To compare the duration of sensory and motor blockade in peripheral nerve blocks induced by the new agents ropivacaine and levobupivacaine, with that of racemic bupivacaine and pethidine. METHODS: Groups of 8 male Sprague-Dawley rats were subjected to infraorbital (IONB) or sciatic nerve block (SNB) employing 0.2 ml of differently concentrated solutions of bupivacaine, levobupivacaine, ropivacaine or pethidine. The sensory blocking effect in IONB is expressed as (i) the time to elicitation of an abdominal jerk by electrical stimulation at arbitrarily chosen (threshold) intensities (IONB degree 3, 5, 8 and 10), and as (ii) the area under the curve (AUC, threshold intensities vs time). The duration of motor block in SNB is given as the time from injection to regained ability to walk and grip normally with the toes. Comparisons of the dose-effect relationships for the investigated agents were made by analysis of covariance. RESULTS: In IONB the log (dose)-log (effect) lines for bupivacaine, levobupivacaine and ropivacaine did not deviate from parallelism. The duration of sensory block induced by equimolar doses of these agents was similar, although bupivacaine exerted more pronounced effects than levobupivacaine (AUC by 25%, P=0.001; IONB degree 3 by 14%, P=0.03). In SNB only the log (dose)-log (duration) lines for bupivacaine vs levobupivacaine were found not to deviate from parallelism, both agents exerting similar durations of action. The motor-blocking effects of ropivacaine showed an inverse dose-duration relationship (P=0.019). CONCLUSIONS: Equimolar doses of the investigated local anaesthetics exerted similar durations of sensory blockade in a peripheral nerve block model in the rat.

Effects of pH and buffer capacity modulation on the analgesic efficacy of lignocaine and pethidine solutions.

BACKGROUND: Objectives were to study the effects of variations in the pH and the buffer capacity of solutions of lignocaine or pethidine on their analgesic efficacy in peripheral nerve block. METHODS: Infraorbital nerve blocks (IONB) were induced in rats during light pentobarbitone anaesthesia employing 0.2 ml of test solutions containing 10 mg center dot ml-1 of lignocaine or pethidine dissolved in normal saline, 50 mmol and 150 mmol tris-hydroxymethylaminomethane (THAM) hydrochloride (THAM center dot HCl) of pH 4.8 and 4.5, respectively, or 100 mmol THAM + THAM center dot HCl of pH 7.4. The pH of solutions in saline was varied from 3.0 to 9.3 by adding HCl or NaHCO3. The analgesic efficacy is expressed as the interval from injection to elicitation of a minimal response to electric stimulation at various intensities (threshold intensities) within the blocked area (IONB 3 to 10), and in terms of the area under the curve (AUC, threshold intensities vs. time). RESULTS: When dissolved in saline, pH 7.4, pethidine exerted more pronounced effects than lignocaine [AUC by 3.5 times (P<0.001), IONB 3 to 10 by 2.7 (P<0.05) to 3.6 (P<0.001) times]. Variations of the pH of solutions did not affect their analgesic efficacy. Lignocaine exerted more pronounced local analgesic effects when mixed with 150 mmol THAM center dot HCl than when mixed with saline (pH 7.4), but manifested even more pronounced effects when dissolved in THAM + THAM center dot HCl [AUC by 3.7 times (P<0.001), IONB 3 to 10 by 2.7 (P<0.01) to 3.8 (P<0.001) times]. When dissolved in THAM + THAM center dot HCl, the analgesic efficacy of pethidine increased by 2.0 to 2.8 times (P<0.001), as compared to a solution in saline at the same pH. CONCLUSIONS: It is concluded that variations in the pH of solutions of lignocaine or pethidine in saline does not affect the analgesic efficacy of the drugs, presumably due to the low buffer capacity of the medium, whereas when dissolved in THAM + THAM center dot HCl, their effect is enhanced.

Assessment of sensory block in epidural anaesthesia by electric stimulation.

The onset of sensory block in lumbar epidural anesthesia was investigated in 26 patients, aged 18 to 84 years, employing the loss of discrimination to cold and pinprick, as well as by determining threshold electric stimulation (threshold intensities). A standard dose of 2% mepivacaine with adrenaline, 5 micrograms.ml-1, (0.1 ml per cm body height) was given and the patients' ability to discriminate stimuli within dermatomes T8, T10, T12, L2, L4 and S1 was investigated at five min intervals for 30 min after injection. From the results of the study it is concluded that i) The interval to peak analgesic efficacy of the anaesthetic solution used is < 30 min when assessments are based on the patients' ability to discriminate cold or pinprick but > 30 min when determinations of threshold intensities are employed. ii) Cold discrimination is lost earlier than discrimination to pinprick and at lower threshold intensities. iii) Threshold intensities describe the time course of onset of sensory block more precisely than results of testing by cold or pinprick. iv) The onset of sensory block was found to be positively correlated to the age of patients in the following respects: a) Threshold intensities during early onset in all investigated dermatomes except L2. b) Intensity of block in T8, T10, and S1 at the end of the study period. c) Time to loss of discrimination to cold and pinprick in T12, L2 and S1, and d) Threshold intensities at loss of discrimination to cold and pinprick. We propose that determinations of threshold intensities offer distinct advantages over conventional testing by cold and pinprick discrimination, especially when detailed analyses of the sensory blocking effects of local anaesthetic drugs are being investigated.