The pharmaceutical properties of these formulations compare favorably with those of other depot preparations. The high-percentage ones showed the longest duration of action yet reported for sciatic nerve block in rats. The possibility of using a high-concentration local anesthetic depot formulation as an alternative to ethanol or phenol for long-term nerve blocks in chronic pain merits further investigation.

Equimolar doses of the investigated local anaesthetics exerted similar durations of sensory blockade in a peripheral nerve block model in the rat.

The findings suggest that depot formulations of local anesthetics with advantageous pharmaceutical and pharmacologic properties can be prepared by use of bupivacaine as the active component and natural lipids as carriers. A favorable balance between effects and toxicity may conceivably be obtained. After supplemental testing in more sensitive models for toxicity, such formulations could be candidates for clinical trials.

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The aim of this study was to develop an in-vitro release method suitable for injectable slow-release lipid formulations of local anaesthetics (or other drugs). We also aimed that the results of the in-vitro measurements should have a clear relationship to duration of action in-vivo. Six formulations of bupivacaine base in medium-chain triglyceride-glyceryl dilaurate mixtures were developed. A new apparatus was constructed for determination of their in-vitro release profiles. A bulbous glass tube was fixed inside a standard glass bottle, which was then filled with release medium. A stirring magnet was enclosed in the perforated polypropylene cylinder holding the glass tube. The stirring created a continuous, rotating downward flow of medium inside the tube, which kept the lipid phase, introduced by means of a syringe, suspended as a single, free drop. Release profiles were obtained by sampling of the release medium for up to 72 h and analysis by gas-liquid chromatography. The duration of action in-vivo of the respective formulations was tested by the hot-plate method in rats. The release profiles of bupivacaine in-vitro were mono-exponential for four formulations and bi-exponential for the other two. There was a positive correlation between the proportion of glyceryl dilaurate in the formulation and the slow half-life of release of bupivacaine. All formulations showed prolonged duration of action in-vivo, median values within the range 4.5-12 h, as compared with a 2-h effect of bupivacaine hydrochloride solution. A comparison of in-vitro release curves and durations of action in-vivo suggested that to maintain nerve blockade in-vivo the formulations must release bupivacaine at a rate of approximately 350 microg h(-1) under the in-vitro conditions. To conclude, we designed and tested a novel apparatus for measuring release of a local anaesthetic (or other drug) from a fluid or semi-solid formulation in-vitro. Release rates obtained in-vitro by means of this technique may be used to guide the development of formulations with suitable durations of action in-vivo. The apparatus is, however, as yet a prototype. Rigorous evaluation of performance should be carried out on devices built to specific standards according to their intended application.

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 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.

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