Evaluation of the addition of tramadol on lidocaine-induced motor block regression time . Experimental study in rats *

BACKGROUND AND OBJECTIVES: Tramadol blocks somatosensory potentials in vitro and may be associated to local anesthetics to improve analgesic quality. This study aimed at evaluating whether tramadol changes lidocaine motor block regression in two different concentrations. METHOD: Male Wistar rats weighing 250 to 300 g were submitted to sciatic nerve block guided by percutaneous nerve stimulation. Animals were distributed in four groups (n = 5 per group): 2% lidocaine (GI), 0.5% lidocaine (GII), 2% lidocaine/1.25 tramadol (GIII), 0.5% lidocaine/1.25 tramadol (GIV). Partial and total motor block regression times were evaluated. RESULTS: Al animals had total motor block when awakening from anesthesia, which has totally regressed during the observation period. Total regression time of 2% lidocaine was 41 ± 1.71 minutes, 0.5% lidocaine was 25.26 ± 0.83 minutes, 2% lidocaine/tramadol was 46.06 ± 0.88 minutes and 0.5% lidocaine/ tramadol was 36.15 ± 1.18 minutes. The association of 0.5% lidocaine and 1.25 mg tramadol was more effective as compared to 0.5% lidocaine alone. Data are presented in mean ± mean standard error (mse), considering significant p < 0.05 using ANOVA followed by Tukey test. CONCLUSION: Tramadol has effects similar to local anesthetics and, when used as adjuvant of lidocaine, prolongs motor block duration in rats.


INTRODUCTION
Tramadol (1-RS, 2RS)-2-[(dimethyl-amine)-methyl]-1-(3 methoxyphenyl)-cyclohexanol hydrochloride is a central action drug sold as a racemic mixture of two enantiomers [(+) and (-) tramadol].The methyl group in the phenolic part of the molecule is responsible for the opioid agonist activity and its affinity for μ receptors is approximately 6 thousand times lower than morphine, 100 times lower than dextropropoxyphene and 10 times lower than codeine 1 .After systemic administration, tramadol is demethylated by the P450 cytochrome system in o-desmethyl-tramadol (M1), active metabolite with agonist activity in  3 .By spinal route, it suppresses spinal cord somatosensory potentials 4 and after perineural injection it induces total motor block 5 .A previous study has described different motor block intensities by perineural tramadol in sciatic nerve of rats, where motor block induced with 5 mg tramadol was similar to motor block induced with 2% lidocaine 5 .
This study aimed at evaluating the possibility of tramadol potentiating duration and intensity of motor block induced by 0.5% and 2% perineural percutaneous lidocaine in the sciatic nerve of rats.Parameter was motor block regression time.
Graph 1 -Lidocaine-induced motor block regression time (in minutes) in sciatic nerve of rats.

DISCUSSION
The administration of anesthetic solutions close to peripheral nerves or neural complexes induces longer anesthesia as compared to neuraxial blocks, depending on physical agent characteristics and the presence or not of vasoconstrictors 7 .
Combinations of local anesthetics and adjuvants, such as epinephrine 8 , ketamine 9 , neostigmine 10 , clonidine 11 opioids and dexmedetomidine 12 aim at prolonging analgesia time, allowing the use of local anesthetics in low concentrations and subsequent decrease of drug noxious effects.
Our study has evaluated duration and total regression of motor block induced by different lidocaine concentrations in mixed peripheral nerve, made up of sensory and motor fibers of different diameters with different sensitivities to local anesthetics.According to our results, it is clear that tramadol added to lidocaine has prolonged motor block duration.Previous studies have reported significant better quality of analgesia with tramadol associated to ropivacaine 13 and intraarticular bupivacaine 14 , as well as with lidocaine for brachial plexus block in orthopedic surgeries in humans 15 ; however, authors have not mentioned motor block duration.Our study has shown that motor block induced with 0.5% lidocaine, but not with 2% lidocaine, was prolonged by the addition of tramadol.Such effect might have been caused by tramadol action on perineural adrenergic fibers, prolonging lidocaine action on sciatic nerve fibers 16 .However, the most likely possibility for such effect is the action of tramadol on the kinetics of sodium channel, where it decreases neural excitability 17 , the mechanism of which is possibly different from lidocaine 16 and not totally clear.In addition, in vivo, tramadol blocks neural somatosensory potentials conduction 17 and has local anesthetic effect as effective as 2% prilocaine 18 .When directly applied on the sciatic nerve, it dose-dependently blocks neural conduction 3 with lower potency as compared to lidocaine 16 , being critical the proximity of neural sheaths for the synergistic effect 19 .We have not found significant increase in total duration of 2% lidocaine effect in this model.However, animals receiving tramadol associated to 2% lidocaine had deep neural block (degree 3) for a longer time as compared to those submitted to 2% lidocaine alone, which could be understood as indirect measurement of motor block intensity.One hypothesis for this phenomenon might have been the participation of tramadol in the early conduction blockade stage, where blockade duration is limited by drug potency.
Clinically, the association of tramadol to loco-regional anesthesia might decrease surgical stress and improve postoperative recovery in humans, due to the physiological advantages of such techniques and to the possibility of early hospital discharge 20 .However, there have been limitations to the technique and the models of our study because it was impossible to measure blockade onset time.

CONCLUSION
Current results allow concluding that tramadol may be used as adjuvant for lidocaine, prolonging motor block recovery time in rats, possibly by mechanisms similar to local anesthetics.
Twenty male Wistar rats weighing 250 to 300 g were placed in pairs in cages with 12-hour light-dark cycles.Water and food were supplied ad libitum.Animals were supplied by the Central Vivarium of the School of Medicine, University block with 2% lidocaine.The second group (GII) received 0.5% lidocaine.The third group (GIII) received 2% lidocaine and 1.25 mg tramadol.The fourth group (GIV) received 0.5% lidocaine associated to 1.25 mg tramadol.Motor block duration and intensity were observed in the four groups.Tramadol concentration was based on a previous study, which has observed the presence of minimum motor block with 2.5% tramadol concentration without changing flinching ability.
of São Paulo (FMUSP) and experiments were carried out in FMUSP's LIM-08, after adaptation to the study environment for 30 minutes.Anesthetic technique: animals were placed in a closed chamber where 4% isoflurane in oxygen was supplied by gauged vaporizer for anesthetic induction -anesthesia was maintained with 1% isoflurane via facial mask to allow sciatic nerve block.Sciatic nerve block: after being anesthetized, right femur greater trochanter was located by palpation and a 2.5 cm needle without bevel (BBraun, Germany) connected to a Stimuplex nerve stimulator (BBraun, Brazil) to locate the sciatic nerve.The needle was introduced at 1 mm from right femoral shaft, in the notch located between greater trochanter and ischial tuberosity and was then directed to the ischium.A ground electrode was fixed to the right ear and the needle was connected to an electric cable which supplied initial current with 0.6 mA intensity able to promote right thigh muscle contraction, which was progressively increased the greater the proximity to the sciatic nerve.Current was decreased to ever with paw inversion; 2 = moderate motor block, animals traction the paw using thigh muscles, but paw is flaccid and does not support the plantar aspect on surface; 3 = total motor block, totally flaccid paw.Experimental design: animals were distributed in four different study groups.The first group (GI) was submitted to sci-atic nerve