1 Service d'Anesthésie Réanimation Chirurgicale 2, 2 Laboratoire Optimisation Biopharmaceutique par modulation des passages transmembranaire and 3 Laboratoire GRETAC, University of Rennes 1, Rennes, France
* Corresponding author: Service d'Anesthésie Réanimation 2, CHRU de Rennes, Hôpital Hôtel Dieu, 2 rue de l'Hôtel Dieu, 35000 Rennes, France. E-mail: jean-pierre.estebe{at}chu-rennes.fr
Accepted for publication June 8, 2004.
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Abstract |
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Method. We performed ipsilateral sciatic nerve block on the inflamed hind paw with bupivacaine-loaded microspheres suspended in dexamethasone (bupivacaine 12.5 mg) and with amitriptyline (6.25 and 12.5 mg) as ultralong-acting local anaesthetics. Bupivacaine (1.25 mg) was used as long-acting local anaesthetic and saline was used as a control. The sixth group received amitriptyline 6.25 mg intraperitoneally (n=10 for each group).
Results. The duration of ipsilateral nerve block was 2 h for bupivacaine, 7 h for amitriptyline 6.25 mg, 11 h for amitriptyline 12.5 mg and 21 h for bupivacaine-loaded microspheres in suspension with dexamethasone. Whereas contralateral hyperalgesia was not observed during block produced by bupivacaine-loaded microspheres, contralateral hyperalgesia was observed with sciatic nerve block using amitriptyline.
Conclusions. Because of the differential effect observed on the contralateral side, the mechanism underlying the prolongation of ipsilateral block with amitriptyline may not result only from a prolonged Na+ channel blockade but might be explained by a local toxic effect or lack of systemic actions.
Keywords: anaesthetics local, bupivacaine ; anaesthetics local, bupivacaine-loaded microspheres ; analgesics, non-opioid ; model, rat ; pain, mechanism
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Introduction |
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On the other hand, when used for sciatic nerve block, amitriptyline, a tricyclic antidepressant, appears to be a more potent Na+ channel blocker than bupivacaine.4 Furthermore, it has been reported that amitriptyline and derivatives prolong sciatic block.45 However, no information about the contralateral effect is available for amitriptyline in an inflammatory model.
Thus, the aim of the present study, in an inflammatory carrageenan rat model, was to compare the effect on the contralateral non-inflamed hind paw of two experimental approaches for prolongation of nerve blockade (i.e. bupivacaine-loaded microspheres suspended in dexamethasone and amitriptyline).
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Materials and methods |
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Experiments were performed on male SpragueDawley rats weighing 270320 g and purchased from Janvier Farm (Le Genest-Saint-Isle, France). The local Animal Research Committee approved the study. Inflammation was induced by injection of carrageenan 1%, 0.2 ml, subcutaneously in the plantar area of the right hind paw under brief general anaesthesia (halothane 23%). The circumference of the paw was measured with a thread to the nearest millimetre at the metatarsal level before and after.3 The threshold of response to increasing pressure (i.e. change in withdrawal threshold) was measured with the use of an Analgesy Meter (Ugo Basile, Milan, Italy). Ipsilateral and contralateral hyperalgesia were determined by positioning the paw under a pressure pad, the probe tip (diameter 1 mm) being applied to the dorsal, lateral and external parts of the paw, avoiding the territory innervated by the saphenous nerve. The choice of a cut-off value of 600 mm Hg was necessary to limit injury of the paw.3 After training animals in the pressure test, the baseline values for paw withdrawal were recorded. An observer who was unaware of the experimental groupings performed the evaluations.
One hour after carrageenan infiltration, the sciatic nerve was identified using a nerve stimulator under general anaesthesia (halothane 23%).8 Briefly, landmarks were easily picked out by means of palpation (i.e. greater trochanter and sciatic notch of the pelvis). Under aseptic conditions, blocks were performed using electrical stimulation. When muscle twitches of the hind paw were elicited with 0.5 mA impulses, and after the blood aspiration test had been found to be negative, 0.5 ml of drug was injected. Nerve twitches disappeared immediately at the onset of injection of the solution, and reappeared when the intensity of nerve stimulation was increased. Injections were performed via an insulated needle; inner diameter of the needle was 0.7 mm for solutions (bupivacaine, saline and amitriptyline) and 1.3 mm for bupivacaine-loaded microspheres suspended in dexamethasone. Two minutes after the end of anaesthesia, the sciatic block was evaluated by the rat's ability to hop and to place weight on its hind leg. The animals were assigned randomly to one of six groups (n=10 for each group). The control group (group 1) received sciatic saline injection. In the second group (group 2), bupivacaine 1.25 mg solution was used for sciatic nerve block. Bupivacaine was chosen for long action from a previous study.1 In the third and fourth groups, sciatic blocks were performed with amitriptyline 6.25 mg (group A6.25) and 12.5 mg (group A12.5). In the fifth group, bupivacaine 12.5 mg was injected as bupivacaine-loaded microspheres in suspension with dexamethasone. Groups 3, 4 and 5 were considered as ultralong-acting local anaesthetic groups. Group 6 received amitriptyline 6.25 mg intraperitoneally (group 6).
Sample size was calculated on the basis of a previous study using the same model.1 The main endpoint for efficacy was the lack of contralateral hyperalgesia after administration of bupivacaine-loaded microspheres. The test was designed to allow the detection of a difference between groups on the main endpoint with 95% confidence, the type I error (two-sided) being set to 5%. Inclusion of at least n=10 in each group was required. Data were analysed using analysis of variance followed by the unpaired Student's t test with Bonferroni correction for parametric data. The MannWhitney U and KruskalWallis tests were used for non-parametric data. Statistical significance was defined as P<0.05.
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Results |
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In the saline injection control group (group 1), mean withdrawal threshold of the right infiltrated paw (ipsilateral hyperalgesia) decreased significantly from 1 h after carrageenan infiltration (P<0.005) up to 24 h (P<0.05) (Fig. 1). For the left paw (contralateral hyperalgesia), the decrease in mean withdrawal threshold was significant after carrageenan infiltration from 2 h (P<0.03) up to 24 h (P<0.05) (Fig. 2).
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Compared with group 2, when dexamethasone and bupivacaine-loaded microspheres were injected, the average duration of neural blockade was significantly prolonged [2 (1) h vs 21 (2) h; P<0.0001] (Fig. 1). Before sciatic nerve block, there was a significant decrease in withdrawal threshold (P=0.002), which disappeared after the block. Contralateral hyperalgesia was never observed in animals injected with dexamethasone and bupivacaine-loaded microspheres (Fig. 2).
No motor block was recorded after intraperitoneal administration of amitriptyline (group 6) and there was no difference compared with group 1. Before sciatic injection of amitriptyline (groups 4 and 5), there was a significant decrease in withdrawal threshold in the infiltrated right hind paw (Fig. 1). Motor block was observed in each animal after sciatic amitriptyline administration. The average duration of neural blockade was 7 (0.5) and 11 (1) h for amitriptyline 6.25 and 12.5 mg, respectively. After recovery, there was no significant difference compared with the baseline for group 4. However, a significant residual analgesic effect was recorded for group 5 at 22 h (P<0.05), but not at 24 h (Fig. 1). Contralateral hyperalgesia was observed continuously during and after ipsilateral sciatic amitriptyline block (Fig. 2) (P=0.0002).
All rats recovered motor function completely and showed no signs of neurobehavioral impairment after saline (group 1), local anaesthetic (groups 2 and 3) or amitriptyline injection (groups 4 and 5).
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Discussion |
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A dose-dependent duration of motor block observed with amitriptyline is similar to those observed after peripheral administration in a non-inflammatory model.459 This effect is unlikely to result from a systemic mechanism because amitriptyline does not exhibit any effect when injected intraperitoneally. The peripheral ipsilateral analgesic effect of amitriptyline is consistent with a previous study in which amitriptyline was injected subcutaneously.9 Amitriptyline seems to have no analgesic effect after intraperitoneal, spinal or intrathecal1011 administration in rats, although tricyclic antidepressants have long been used orally to treat chronic pain with some beneficial effects.11 A lack of effect of amitriptyline after oral administration in humans has been reported recently.12 In this placebo-controlled trial with an active placebo (i.e. placebo inducing similar adverse effects), amitriptyline used orally was not effective in reducing chronic pain in patients with spinal cord injury.12
With bupivacaine (either as solution or as bupivacaine-loaded microspheres suspended in dexamethasone), our data on motor block duration are in agreement with previous studies using the same carrageenan inflammatory animal model.137
In this inflammatory rat model it has been demonstrated that contralateral hyperalgesia does not occur during neural blockade obtained with bupivacaine. As described previously,1 when the duration of neural block is too short, ipsilateral hyperalgesia reappears. When the block is prolonged for more than 4 h with local anaesthetics (i.e. repeat injection of bupivacaine through a catheter or with bupivacaine-loaded microspheres acting as ultralong-acting local anaesthetic),1313 ipsilateral hyperalgesia does not appear. The present study shows similar results when the block is significantly prolonged with dexamethasone added to bupivacaine-loaded microspheres.714 It was reported previously that dexamethasone injected alone near the sciatic nerve had no clinical effect.7
Few studies have evaluated the occurrence of contralateral hyperalgesia. It has been reported recently that ipsilateral hyperalgesia is reduced during bupivacaine block.1 When the block is prolonged for more than 4 h, the hyperalgesia phenomenon (i.e. contralateral and ipsilateral) is not observed after block recovery.1 However, the mechanisms of prevention of hyperalgesia with bupivacaine are not clearly defined and the role of local anaesthetics in hyperalgesia through their action on peripheral nerve input remains unclear. It is interesting to note that a significant analgesic effect was reported recently when bupivacaine was administered contralateral to the inflammation, but not with systemic administration (i.e. intraperitoneal).15 This effect was reduced after sciatic nerve ligation ipsilateral to bupivacaine administration or after intrathecal saline administration. Similar results were reported with lidocaine injected subcutaneously contralateral to chronic constriction of the sciatic nerve.16 Collectively, these results suggested an effect of local anaesthetics on spinal hyperactivity, allowing a contralateral analgesic effect. However, local anaesthetics may also act systemically, as suggested by lidocaine administration in neuropathic pain.17 Indeed, in a neuropathic rat model an analgesic effect has been reported after intravenous administration of local anaesthetics, but not with amitriptyline.18
While amitriptyline led to a significantly prolonged block, there was no contralateral effect. Compared with bupivacaine, it was reported that amitriptyline seems to be a more potent blocker of neuronal Na+ channels4 and presents more potent antioxidant properties.19 The present data suggest that the mechanism of the analgesic effect of amitriptyline seems to be different from those of local anaesthetics, given the observed differences in contralateral hyperalgesia.
Knowledge of the difference in their mechanism of action might be of interest in the understanding of inflammatory pain phenomena. Although amitriptyline blocks Na+ channels, the long duration of action might not result from prolonged Na+ channel blockade. Indeed, amitriptyline and derivatives have been shown to induce severe axonal degeneration.5 Toxicity has been suggested in the case of amitriptyline application to the skin2022 and on human polymorphonuclear neutrophils.23 Hence, the long duration of action could be related to a dose-related neurotoxic effect, as reported recently;24 this in turn would explain the lack of a contralateral effect in our experiment. Recently, despite recovery of the motor block, it was shown that Wallerian degeneration occurred in the subperineural space that was closest to extraneurally administered amitriptyline. With higher doses, the number of degenerating fibres was increased, as was their spatial distribution.24 The prolongation of block observed with amitriptyline should be interpreted cautiously, with the suggestion that neurotoxic injury may be part of the mechanism for the delayed recovery. If confirmed by further studies, a simple evaluation of the contralateral effect could be helpful in clinically evaluating newer local anaesthetic drugs and could allow discrimination of a local anaesthetic effect from a neurotoxic effect. For clinical evaluation, sciatic nerve injection with nerve stimulation seems to be more effective than the classical approach usually used (i.e. based only on landmarks). Although it has not been demonstrated, nerve stimulation probably avoids nerve lesion during puncture.
Despite block prolongation by bupivacaine and amitriptyline, amitriptyline does not exhibit any analgesic effect on contralateral hyperalgesia in inflammatory pain.
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References |
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