Medical and Dental Consultantsí Association of Nigeria
Home - About us - Editorial board - Search - Ahead of print - Current issue - Archives - Submit article - Instructions - Subscribe - Advertise - Contacts - Login 
  Users Online: 5738   Home Print this page Email this page Small font sizeDefault font sizeIncrease font size
 

  Table of Contents 
ORIGINAL ARTICLE
Year : 2022  |  Volume : 25  |  Issue : 7  |  Page : 1149-1157

The reversing effect of ondansetron on bupivacaine-induced sciatic nerve block


1 Department of Anesthesiology and Intensive Car, Selcuk University Medical Faculty, Konya, Turkey
2 Department of Pharmacology, Selcuk University Medical Faculty, Konya, Turkey
3 Department of Anatomy, Lokman Hekim University Medical Faculty, Ankara, Turkey
4 Department of Anesthesiology and Intensive Care, Selcuk University Medical Faculty, Konya, Turkey; 4Cleveland Clinic Anesthesiology Institute Outcomes Research Consortium, Cleveland, Ohio, United States of America

Date of Submission09-Sep-2021
Date of Acceptance01-Jun-2022
Date of Web Publication20-Jul-2022

Correspondence Address:
Dr. O Onal
Cleveland Clinic Anesthesiology Institute Outcomes Research Consortium, Cleveland, Ohio, United States of America. Selcuk University Medical Faculty, Department of Anesthesiology and Intensive Care, Konya

Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_1804_21

Rights and Permissions
   Abstract 


Background and Aims: This experimental study was designed to test the hypothesis that ondansetron, a selective 5-HT3 receptor antagonist, would decrease the duration of motor, sensory, and proprioception blockade in a dose-dependent fashion in a bupivacaine-induced sciatic nerve blockade. Materials and Methods: Forty-nine male Wistar Albino rats who underwent unilateral sciatic nerve block were divided into seven groups with an equal number in each group. Group B: only perineural block (PB), Group BO200: PB and perineural 200 μg ondansetron, Group BO400: PB and perineural 400 μg ondansetron, Group BO800: PB and perineural 800 μg ondansetron, Group BO800IP: PB and intraperitoneal 800 μg ondansetron, Group O800: only perineural 800 μg ondansetron, Group S: sham-operated. The rats' motor, sensory, and proprioception functions were evaluated by a blinded investigator every 10 min until they returned to normal function. The recovery times of the motor, sensory, and proprioception functions were recorded and compared. All sciatic nerves were removed and examined by electron microscopy for neurotoxic signs. Results: In which sciatic nerve block was formed with bupivacaine, the duration of the motor, sensory, and proprioception functions blockade was decreased, and the duration to return to normal functions was significantly shortened at Group BO800 (p < 0.05). According to electron microscopy results, perineural 200 μg, 400 μg, and 800 μg ondansetron were not neurotoxic. Conclusion: This is the first study showing that perineural ondansetron administration (800 μg dose) reverses the effect of the local anesthetics and shortens the duration of the motor, sensory, and proprioception functions blockade.

Keywords: Rat, ondansetron, sciatic nerve, transmission electron microscopy


How to cite this article:
Saltali A O, Apiliogullari S, Bagci S, Sargon M F, Celik J B, Onal O. The reversing effect of ondansetron on bupivacaine-induced sciatic nerve block. Niger J Clin Pract 2022;25:1149-57

How to cite this URL:
Saltali A O, Apiliogullari S, Bagci S, Sargon M F, Celik J B, Onal O. The reversing effect of ondansetron on bupivacaine-induced sciatic nerve block. Niger J Clin Pract [serial online] 2022 [cited 2022 Aug 15];25:1149-57. Available from: https://www.njcponline.com/text.asp?2022/25/7/1149/351460




   Background Top


Local anesthetics (LA) are the basic drugs for regional anesthesia and local anesthesia applications. With the application of LA agent to various parts of the body, nerve conduction is temporarily blocked depending on the dose, volume, concentration, and application site.[1] Thus, sympathetic, sensory, and motor block is formed. However, the continuation of tissue anesthesia despite the completion of the procedure becomes a disadvantage in some cases, may lead to complications,[2] and increase the duration and cost of hospital stay.[3],[4] In case of accidental high dose intravenous (IV) administration of LA, it may also cause cardiac arrest resistance to resuscitation.

The lack of specific fast-acting antagonists that can be used in such situations is a major problem.[1] In addition, the prolongation of the effect of LAs beyond the desired after dental procedures causes difficulties in speaking and eating, tongue and lip injuries, saliva flowing from the mouth, difficulties in business and social life, and additional costs.[2] Therefore, there is a need to define reliable agents with antagonist effects that enable LA to be eliminated quickly. Until now, some medications have been suggested that can reverse the effect of LA, but no definitive result has been obtained.[5],[6],[7]

Ondansetron is the first selective 5-HT3 (5-hydroxy tryptamine 3) receptor antagonist, introduced into clinical use in 1990.[8] Although Ondansetron is an U.S. Food & Drug Administration (FDA) approved drug for use in the treatment of nausea and vomiting, its effectiveness in different diseases such as irritable bowel syndrome, schizophrenia, anxiety, cognitive function, substance abuse, and addiction, bulimia, pruritus, obsessive convulsive disorder, the pain syndromes has been investigated.[9],[10],[11],[12] Furthermore, ondansetron has been shown to inhibit the analgesic effects of tramadol, a type of opioid, and increase its postoperative use.[13],[14],[15],[16] Therefore, its effects on regional anesthesia have been recently investigated.[17],[18],[19],[20],[21],[22],[23] In addition, conflicting results have been reported regarding whether ondansetron,[24] enhances,[20],[21],[22],[23] decreases,[25] or does not alter the effect of LAs.[21] Our previous thermal pain model study showed that the duration of soft tissue sensory block induced by LA in the rat paw was shortened with ondansetron applied to the same site.[26] However, there are no studies in the literature investigating the effect of perineurally administered ondansetron on regional anesthesia induced by perineurally administered bupivacaine. We preferred bupivacaine as a local anesthetic agent, because there are many studies on the effectiveness of bupivacaine as an anesthetic agent to control pain in the post-operative period. The most important reason for using bupivacaine in our study is that in addition to reducing postoperative pain, it is frequently used in long-term invasive procedures and oral surgery procedures.[27],[28] In the study, bupivacaine dose was applied as 0.2 milliliter (ml) of 0.5%, similar to the study by Brummet et al.,[29] in the formation of sciatic nerve block.

We aimed to investigate the effect of ondansetron on the motor block, sensory block, and proprioception block function caused by bupivacaine in the sciatic nerve block and whether it has an antagonizing effect on local anesthesia.

Procedure

Ethical approval was obtained for our study from the local ethics committee of Selcuk University Experimental Medicine Application and Research Center (SUDAM) animal experiments (Reference number: 20146).

Inclusion criteria

Forty-nine Wistar Albino male rats raised in Selcuk University Experimental Medicine Application and Research Center (SUDAM) Animal Experiments Laboratory. All rats weighted an average of 300-400 grams and had normal motor function, were included in the study. Each of the rats was placed in a separate cage. The light arrangement was made in the environment where the animals were sheltered, with 12 hours of light and 12 hours of darkness. All animal research ethical conditions demanded by Selcuk University Experimental Medicine Application and Research Center (SUDAM) Animal Experiments Local Ethics Committee were taken into account in the care and use of the rats used in the study.

Exclusion criteria

Accidental damage or rupture of the sciatic nerve during the removal of the sciatic nerve, death of the rat before the removal of the sciatic nerve, no motor blockade even if LA is applied, infection around the sciatic nerve before the sciatic nerve is removed.

Preparation of study drugs

During the study, Bupivacaine (0.5% Marcanu vial, Astra Zeneca, Luleburgaz, Turkey) and ondansetron (Zofran, GlaxoSmithKline, Italy) were used. We adjusted the dose of ondansetron used in the study groups not to exceed 3 mg/kg.[30] We decided to examine the effect of three doses of ondansetron (200 μg, 400 μg, and 800 μg). We standardized the doses of all study drugs so that the volume was equal to 0.4 ml. For this, 0.9% saline (SF) was added as needed.

Experimental model

Anesthesia induction for surgical procedures was performed with 5% isoflurane (Isoflurane-USP Adeka Drug and Chemical Products Industry Trade Corporation, MINRAD Inc. Circle Bethlehem PA, 18017 USA) and 3L/min-1 oxygen inhalation (in glass bell jar). Anesthesia was maintained with 2% isoflurane and 3L/min-1 oxygen inhalation. After shaving the hip and thigh areas, the feet were determined in the supine position. The sciatic nerve area was cleaned with 10% povidone-iodine (ISOSOL, Center Lab. Istanbul, Turkey). Then, the thigh skin and subcutaneous tissue were cut with a lateral incision, the muscle and superficial fascia were separated, and the sciatic nerve was exposed. The sciatic nerve was stimulated in 0.5 mA using a 22-gauge insulated nerve block needle accompanied by a peripheral nerve stimulator (StimuplexR, B. Braun, Melsungen AG, Germany). When a motor response was obtained, the sciatic nerve was confirmed to be intact.[31]

Study groups and interventions

Forty-nine Wistar Albino rats were randomly divided into seven groups, with seven rats with normal motor activity in each group.

Group B (n = 7, only bupivacaine group): 0.2 ml of 0.5% bupivacaine was administered to the proximal sciatic nerve bifurcation under the fascia surrounding the nerve and to the perineural region of rats. A non-absorbable marker suture was placed in the biceps femoris muscle at the level where the study drug was administered. The applied suture was not directly touched the nerve. 0.5 mA stimulation was applied to the sciatic nerve using a peripheral nerve stimulator at the 10th min after LA application. It was thought that sciatic nerve block occurred when the motor response associated with the sciatic nerve could not be obtained.

Group BO200 (n = 7, bupivacaine and perineural 200 μg ondansetron group): 0.2 ml of 0.5% bupivacaine was administered to the proximal sciatic nerve bifurcation, under the fascia surrounding the nerve, and to the perineural region of rats. A non-absorbable marker suture was placed in the biceps femoris muscle at the level where the study drug was administered. The applied suture was not directly touched the nerve. 0.5 mA stimulation was applied to the sciatic nerve using a peripheral nerve stimulator at the 10th min after LA application. It was thought that the sciatic nerve block occurred when the motor response associated with the sciatic nerve could not be obtained. 200 μg 0.4 ml-1 ondansetron was administered perineurally 10 min after bupivacaine administration.

Group BO400 (n = 7, bupivacaine and perineural 400 μg ondansetron group): 0.2 ml of 0.5% bupivacaine was administered to the proximal sciatic nerve bifurcation, under the fascia surrounding the nerve, and to the perineural region of rats. A non-absorbable marker suture was placed in the biceps femoris muscle at the level where the study drug was administered. The applied suture was not directly touched the nerve. 0.5 mA stimulation was applied to the sciatic nerve using a peripheral nerve stimulator at the 10th min after LA application. It was thought that the sciatic nerve block occurred when the motor response associated with the sciatic nerve could not be obtained. 400 μg 0.4 ml-1 ondansetron was administered perineurally 10 min after bupivacaine administration.

Group BO800 (n = 7, bupivacaine and perineural 800 μg ondansetron group): 0.2 ml of 0.5% bupivacaine was administered to the proximal sciatic nerve bifurcation, under the fascia surrounding the nerve, and to the perineural region of rats. A non-absorbable marker suture was placed in the biceps femoris muscle at the level where the study drug was administered. The applied suture was not directly touched the nerve. 0.5 mA stimulation was applied to the sciatic nerve using a peripheral nerve stimulator at the 10th min after LA application. It was thought that the sciatic nerve block occurred when the motor response associated with the sciatic nerve could not be obtained. 800 μg 0.4 ml-1 ondansetron was administered perineurally 10 min after bupivacaine administration.

Group BO800IP (n = 7, bupivacaine, and intraperitoneal (IP) 800 μg ondansetron group): This administration group was planned to determine the systemic effect of ondansetron. 0.2 ml of 0.5% bupivacaine was administered to the proximal sciatic nerve bifurcation, under the fascia surrounding the nerve, and to the perineural region of rats. A non-absorbable marker suture was placed in the biceps femoris muscle at the level where the study drug was administered. The applied suture was not directly touched the nerve. 0.5 mA stimulation was applied to the sciatic nerve using a peripheral nerve stimulator at the 10th min after LA application. It was thought that the sciatic nerve block occurred when the motor response associated with the sciatic nerve could not be obtained. 800 μg. 0.4 ml-1 ondansetron was administered intraperitoneally 10 min after bupivacaine administration.

Group O800 (n = 7, perineural 800 μg ondansetron group): 800 μg 0.4 ml-1 ondansetron was administered to the proximal sciatic nerve bifurcation, under the fascia surrounding the nerve, and to the perineural region of the rats. A non-absorbable marker suture was placed in the biceps femoris muscle at the same level as the study drug was administered. The applied suture was not directly touched the nerve. 0.5 mA stimulation was applied to the sciatic nerve using a peripheral nerve stimulator at the 10th min after LA application. The motor response associated with the sciatic nerve was checked and recorded as present or absent.

Group S (n = 7, sham operation group): The proximal sciatic nerve bifurcation of the rats was opened with the same surgical technique. The nerve was stimulated with a peripheral nerve stimulator. A non-absorbable marker suture was placed in the biceps femoris muscle at the level of stimulation. The applied suture was not directly touched the nerve. 0.5 mA stimulation was applied to the sciatic nerve using a peripheral nerve stimulator at the 10th min. The motor response associated with the sciatic nerve was checked and recorded as present or absent. Information on the groups and the applied transactions are presented in [Table 1].
Table 1: Flowchart of the study method separately according to the study groups

Click here to view


The superficial muscle layer of the rats in all groups in the explored operation area was closed with 5-0 silk and the skin with 3-0 silk. Isoflurane was then capped, and mice were awakened. All rats included in the study were evaluated using methods applied in similar studies every 10 min until their motor function, sensory function, and proprioception functions returned to normal. In addition, 48 hours later, the rats were anesthetized with the same technique, the sutures were reopened, and an approximately 0.4 cm long sciatic nerve was removed to evaluate the possible neurotoxicity in the nerves by electron microscopy.


   Measurements Top


Evaluation of motor function

Motor function of the hind limb was evaluated every 10 min on a 4-point scale[32] until the motor block returned completely.[29],[31],[32],[33]

  • 0 = Normal motor function (foot in normal dorsiflexion, toes open, walking),
  • 1 = Foot in normal dorsiflexion, toes curled, walking,
  • 2 = Foot slightly dorsiflexed, toes curled, walking,
  • 3 = Full loss of dorsiflexion in the foot, toes bent, walking.


The score was accepted as 0 in normal motor function and 1 in blocked motor function (1-2-3 values were considered blocked and evaluated in the 1 category). After the motor block (evaluated as 1), the time until the normal motor function returns (the time from 1 to 0) was recorded as the motor function recovery time. We used minutes as the unit of time for recording recovery times.

Evaluation of sensory function

To assess the complete disappearance of the sensory block in the hind limb, the foot withdrawal reflex was assessed by giving a painful stimulus every 10 min.[29],[34],[35] The painful stimulus was created by applying pressure with forceps on the foot-lateral metatarsal.[35] Pressure application was limited to a maximum of 1 s to prevent tissue damage. The following scale was used to evaluate the return of sensory blocks. 0 = Strong foot withdrawal response to compression (normal sensory function), 1 = Moderate foot withdrawal response, 2 = Mild foot withdrawal response, 3 = No response to compression (full sensory block).[29],[34] While evaluating the sensory block, score 0 was accepted as a normal sensory response, and score 1 was accepted as a sensory block. (1-2-3 values were considered as blocked and evaluated in the 1 category). After the sensory block (evaluated as 1), the time until the normal sensory function returns (the time from 1 to 0) was recorded as the sensory function recovery time. We used minutes as the unit of time for recording recovery times.

Evaluation of proprioception function

A tactile placement test evaluated proprioceptive response in the posterior limb until the block disappeared completely. The toes of the rat were stretched on a supporting base. The rat's ability to return the toes to normal position (extension) was evaluated as a normal proprioceptive response, and inability to return to normal position as an abnormal proprioceptive response.[36] After holding the proprioception block, the time is taken for complete recovery of normal proprioceptive function was recorded. We used minutes as the unit of time for recording recovery times.

Transmissive electron microscopy analysis

To evaluate the possible neurotoxicity in the sciatic nerve, the rats were anesthetized with the same anesthetic agents 48 hours after the experimental procedures. The sutures were reopened, and a sample of the sciatic nerve, approximately 0.4 cm in length, was removed from the central marker suture. The sciatic nerves of the experimental groups were compared under the electron microscope using the ultrastructural grading system.[37] In myelinated axons, separation of myelin layers (score value: 1), interruption in myelin layers (score value: 2), and honeycomb appearance (score value: 3) were not observed.[37] The rats were sacrificed by the cervical dislocation method after their sciatic nerves were removed for examination.

Statistical analysis

First, the mean and standard deviation values of the groups were calculated. The Kruskal-Wallis H test was used to compare the recovery times of motor, sensory, and proprioceptive functions between the groups. In cases of differentiation, the Kruskal–Wallis test was used between which groups the differentiation occurred, the corrected p value (Bonferroni correction) according to the number of groups was calculated by the program (SPSS 22.0). p < 0.05 was taken as the statistical significance level.


   Results Top


There was no change in motor function with nerve stimulator in Group S and Group O800 (10 min after ondansetron). There were no changes in motor, sensory and proprioceptive functions compared to the beginning in the follow-up after the surgical area was closed. This was interpreted as perineural administration of 800 μg ondansetron had any LA effect. These two groups were not statistically compared with the other five groups treated with bupivacaine but were evaluated for neurotoxicity.

Motor function recovery time of Group B, Group BO200, Group BO400, Group BO800, and group BO800ip was 95.57 (± 10.34), 95.71 (± 7.29), 87.14 (± 12.92), 67.42 (± 2.37), 97.85 (± 22.93), respectively [Table 2]. Kruskal–Wallis Test Value (X2 (4)) was calculated as 17.886 (p < 0.05) for motor function recovery time.
Table 2: Comparison of the motor function recovery time between groups

Click here to view


The sensory function recovery time average of Groups B, BO200, BO400, BO800 and BO800ip were 91.28 (± 8.03), 90.28 (± 5.96), 89.85 (± 12.32), 67.42 (± 2.37), 97.85 (± 22.93), respectively [Table 3]. Kruskal–Wallis Test Value (X2 (4)) was calculated as 16.444 (p < 0.05) for sensory function recovery time.
Table 3: Comparison of the sensory function recovery time between groups

Click here to view


Groups B, BO200, BO400, BO800, and BO800ip's average recovery time of proprioceptive functions were 90.71 (± 8.90), 80.42 (± 23.37), 63.42 (± 30.48), 48.42 (± 8.20), 85.57 (± 23.42), respectively [Table 4]. Kruskal–Wallis Test Value (X2 (4)) was calculated as 13.115 (p < 0.05) for proprioceptive function recovery time.
Table 4: Comparison of the proprioception function recovery time between groups

Click here to view


Motor function recovery time comparisons between groups according to Bonferroni corrected p values was showed that the motor function recovery time of group BO800 was significantly lower than the B, BO200, and BO800ip groups (p = 0.004, P = 0.003, P = 0.021, respectively) [Table 2]. Sensory function recovery time comparisons between groups according to Bonferroni corrected p values was showed that the sensory function recovery time of group BO800 was statistically significantly lower than the B, BO200, BO400, and BO800ip groups (p = 0.009, P = 0.014, P = 0.017, P = 0.015 respectively) [Table 3]. The recovery time of proprioceptive function in Group BO800 group was significantly lower only than Group B (p = 0.008).

Transmission electron microscopy analysis evaluation findings

All myelinated axons (small, medium, and large diameter) examined were ultrastructurally normal.[35] In some groups, there were slight and tiny separations in the myelin layers. Since the same finding was also found in the control group, it was understood that it occurred due to the time spent during tissue exploration and delayed fixation. All unmyelinated axons examined were ultrastructurally normal. All the Schwan cells examined were ultrastructurally normal. All perineurium examined were ultrastructurally normal. Electron microscopy image of the ondansetron applied sciatic nerve sample is presented in [Figure 1].
Figure 1: Electron microscopy images of the groups. Electron micrographs showing ultrastructurally normal myelinated axons and unmyelinated axons. Electron microscopy images of the groups are presented in the group order from left to right. a: Myelin sheath, b: Unmyelinated axons, c: Schwann cell, p: Perineurium

Click here to view



   Discussion Top


This study aimed to investigate the effect of ondansetron on the motor, sensory, and proprioception block function caused by bupivacaine in the sciatic nerve block and whether it antagonizes local anesthesia. The study is an experimental type of study conducted on rats. In terms of structure and function similarity to humans, the mammalian group is frequently preferred in experimental studies. Mainly, rats are frequently used as experimental animals in many physiological and pharmacological studies in terms of rapid reproduction, practical use in the experimental application phase, and easy care.[38] Our study results showed that the duration of motor, sensory, and proprioception blocks created by using bupivacaine (800 μg) in the sciatic nerve was shortened with locally applied ondansetron. To our knowledge, to date, no active substance has been reported or reported to have an antagonistic effect against LA agents. However, Phentolamine Mesylate (FM) (Oraverse, Septodont Inc, Louisville, United States) is one of the agents that can shorten the duration of action of LA preparations containing adrenaline, which have been commercially available in recent years.[39] However, FM is a non-selective alpha-adrenergic blocker[40] and has a vasodilator effect.[41] In fact, FM is not an LA antagonist as it acts by indirectly reversing the effect of adrenaline added to it. With FM, the duration of LA action decreases from 155 min to 70 min[42],[43] while the feeling of pain completely returns at an average of 90 min.[44] However, FM does not influence blocks produced by LA agents that do not contain adrenaline.[45] Another drug used in dentistry to shorten the LA effect is hydralazine hydrochloride (HCl). However, the efficacy of hydralazine hydrochloride in combined anesthesia with epinephrine has been tested in related study like FM.[7] There are also studies in the literature on the reversal of magnesium sulfate and insulin by shortening the duration of local anesthesia.[5],[6] Hung et al.[5] suggested that the effect of magnesium sulfate is independent of the local anesthetic receptor within the Na+ channel. However, in this study, the mechanism suggested shortening the block time induced by amide-type LA agents by magnesium sulfate were that instead of a complete antagonism, magnesium sulfate causes local vasodilation of the tissues in the perineural injection site, accelerates the systemic intake of LA agents, and shortens the block time.[7] Another study by Kim and Seok found that short-acting insulin shortened the local anesthetic effect of lidocaine and bupivacaine in rats.[6] However, the experimental method used in their study was the application of drugs to the isolated nerve that is not possible and meaningful in clinical practice. With their experimental method, the LA agent and insulin dose could not be calculated precisely since a fixed volume is not applied to tissues. And also, due to the block onset time depends on the formulation applied, it was impossible to prevent the passage of different doses of the drug to the tissues, which is different durations have occurred. Therefore, there is a need to define new drugs that can shorten the effect of LA even more and have an adrenaline-independent effect especially.

In an experimental study using the thermal pain model by Apiliogullari et al.[26] the effect of systemically and locally applied ondansetron on the antinociceptive component of the LA effect induced by articaine was investigated. Local ondansetron was applied to the site where articaine was applied, and the LA-induced antinociceptive effect and local analgesic effect were significantly shortened. In contrast to this study, ondansetron was applied to the periphery in our study. In addition, another difference between the two studies is that long-acting bupivacaine without epinephrine was used in our study. With our study, it was shown for the first time in the literature that locally administered ondansetron shortened the duration of motor block and proprioception block due to LA agents in a dose-dependent manner.

In another experimental study by Bravo-Hernández et al.,[46] the role of peripheral and spinal 5-HT3 receptors on formalin-induced secondary allodynia and hyperalgesia was investigated. After administering formalin to both paws, acute nociceptive behavior followed by long-term secondary mechanical allodynia and hyperalgesia occurred. It was observed that peripheral and ipsilateral administration of 5-HT and m-CPBG 10 min before formalin administration increased secondary allodynia and hyperalgesia in both paws. It was observed that m-CPBG applied spinally before formalin administration increased secondary hyperalgesia but not allodynia. In addition, it has been shown that ondansetron administered spinally and peripherally ipsilaterally before formalin administration prevents secondary mechanical allodynia and hyperalgesia. It has been shown that the peripheral pronociceptive effects of 5-HT and m-CPBG are inhibited by peripheral ondansetron and the effects of spinally administered m-CPBG are prevented by spinally administered ondansetron. In addition, it was shown that ondansetron administered spinally six days after formalin administration eliminated formalin-induced secondary mechanical allodynia and hyperalgesia. With this result, it was thought that 5-HT5-HT3 receptors had a role in the development of formalin-induced secondary allodynia and hyperalgesia.[46] The possible reasons why the results of this study differ from the results of our study may be that the effect mechanisms of LA agent and formalin on analgesia and hyperalgesia are different, ondansetron also has a local analgesic effect in the periphery, or the mechanism of action of ondansetron changes depending on the LA agent type in the environment.

In a study conducted on neurons isolated from rat brain, ondansetron was shown to block Na channels in a dose-dependent manner[24]; therefore it was suggested to have similar properties to LAs. In a study conducted to verify this result in vivo, the LA effects of ondansetron were investigated using the tail-flick test.[24] In this study, the response of ondansetron applied to the subcutaneous tail region to thermal pain in rats was examined, and it was shown that ondansetron prolonged the tail-wagging time in a dose-dependent manner; that is, it affected similar to that of LA agents, even 15 times more potent than lidocaine.[24] However, it should be noted that the effect evaluated by this study was a sensory block and local analgesic effect. In our study, while investigating whether all 200 μg, 400 μg, and 800 μg ondansetron doses have neurotoxic effects, it was investigated whether only 800 μg dose had both LA and neurotoxic effects. Ye et al.[24] created local anesthesia with subcutaneous injection of 200 μg ondansetron into the tail; in our study, the absence of motor block or sensory block even at a dose of 800 μg was caused by the difference in the application site or the possibility of a different distribution of 5-HT receptor types in these regions or different stimuli (thermal, mechanical). Our study suggested that the dose of 800 μg decrease in LA effect with ondansetron administration after LA administration may be due to a competition between ondansetron and bupivacaine. However, electrophysiological studies are needed to reveal this effect fully.

This study has some limitations. The LA effect of ondansetron was investigated by administering to the sciatic nerve at a dose of 200, 400, 800 μg with the perineural application, and at a dose of only 800 μg with the intraperitoneal application. Investigating this effect by studying different pain models at different doses and different application areas will enable us to reach more objective results. The amide derivative bupivacaine was used as an LA effective agent. However, as is known, interactions of amide- and ester-type LAs with 5-HT3 receptors are different.[47] To generalize the results, both amide- and ester-type LA-active agents should be compared.


   Conclusion Top


As a result of our study, when ondansetron is applied locally at a dose of 800 μg to the area where the local anesthetic agent is applied, ondansetron has an antagonizing effect on the local anesthesia. However, when ondansetron is administered systemically, it does not have an antagonizing effect. According to electron microscopy analysis results, the neurotoxic effect of perineural bupivacaine and ondansetron application could not be demonstrated. To increase the level of evidence of our study, we need to plan new studies in vivo and in vitro. We believe that both our study and other studies on this subject may guide the clinical use of LA-effective agents and ondansetron.

Financial support and sponsorship

This study was conducted within the scope of the first researcher's doctoral thesis. Financial support such as medicine and laboratory fees in the research process was supported by the decision of Selcuk University Scientific Research Projects (BAP) commission with project number 15102019.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Trevor AJ, Katzung BG, Masters SB, Akkan AG. Katzung and Trevor Pharmacology Examination and Review. 8th ed. Ankara: Detail Printing; 2010.  Back to cited text no. 1
    
2.
Malamed S. Local anesthesia reversal. Dent Today 2010;29:65-6.  Back to cited text no. 2
    
3.
Duman A, Apilioğulları S, Tekin A, Bodur S. Comparison of selective spinal anesthesia and local infiltration anesthesia under monitored anesthesia care techniques in patients undergoing anorectal day surgery. Nobel Med 2011;7:61-6.  Back to cited text no. 3
    
4.
Lacasse MA, Roy JD, Forget J, Vandenbroucke F, Seal RF, Beaulieu D, et al. Comparison of bupivacaine and 2-chloroprocaine for spinal anesthesia for outpatient surgery: A double-blind randomized trial. Can J Anesth 2011;58:384-91.  Back to cited text no. 4
    
5.
Hung YC, Chen CY, Lirk P, Wang CF, Cheng JK, Chen CC, et al. Magnesium sulfate diminishes the effects of amide local anesthetics in rat sciatic nerve block. Reg Anesth Pain Med 2007;32:288-95.  Back to cited text no. 5
    
6.
Kim JM, Seok CH. Reversing effect of insulin on local anesthetics-induced sciatic nerve block in rats. BioMed Res Int 2019. doi: 10.1155/2019/4252349.  Back to cited text no. 6
    
7.
Fakheran Esfahani O, Pouraboutaleb MF, Khorami B. Effect of hydralazine on duration of soft tissue local anesthesia following dental treatment: A randomized clinical trial. Gen Dent 2015;63:39-42.  Back to cited text no. 7
    
8.
Kayaalp SO. Medical Pharmacology in Terms of Rational Treatment. 12. Printing, Ankara, Feryal Printing; 2009.  Back to cited text no. 8
    
9.
Faerber L, Drechsler S, Ladenburger S, Gschaidmeier H, Fischer W. The neuronal 5- HT 3 receptor network after 20 years of research-evolving concepts in management of pain and inflammation. Eur J Pharma 2007;560:1-8.  Back to cited text no. 9
    
10.
Thompson AJ, Lummis SC. The 5-HT3 receptor as a therapeutic target. Exp Op Ther Targ 2007;11:527-40.  Back to cited text no. 10
    
11.
Machu TK. Therapeutics of 5-HT 3 receptor antagonists: Current uses and future directions. Pharma Thera 2011;130:338-47.  Back to cited text no. 11
    
12.
Lennertz L, Wagner M, Grabe HJ, Franke PE, Guttenthaler V, Rampacher F, et al. 5-HT3 receptor influences the washing phenotype and visual organization in obsessive-compulsive disorder supporting 5-HT3 receptor antagonists as novel treatment option. Eur Neuropsychopharma 2014;24:86-94.  Back to cited text no. 12
    
13.
De Witte JL, Schoenmaekers B, Sesler DI, Deloof T. The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron. Anesth Analg 2001;92:1319-21.  Back to cited text no. 13
    
14.
Arcioni R, Della Rocca M, Romano S, Romano R, Pietropaoli P, Gasparetto A. Ondansetron inhibits the analgesic effects of tramadol: A possible 5-HT (3) spinal receptor involvement in acute pain in humans. Anesth Analg 2002;94:1553-7.  Back to cited text no. 14
    
15.
Mannion S, O'Callaghan S, Murphy D, Shorten G. Tramadol as adjunct to psoas compartment block with levobupivacaine 0.5%: A randomized double-blinded study. Br J Anesth 2005;94:352-6.  Back to cited text no. 15
    
16.
Vale C, Oliveira F, Assunção J, Fontes-Ribeiro C, Pereira F. Co-administration of ondansetron decreases the analgesic efficacy of tramadol in humans. Pharma 2011;88:182-7.  Back to cited text no. 16
    
17.
Kelsaka E, Baris S, Kefeli H, Mehel A, Karakaya D, Kocamanoglu S. Comparison of ondansetron and lidocaine in preventing of rocuronium injection pain. J Exp Clin Med 2002;19:163-7.  Back to cited text no. 17
    
18.
Kelsaka E, Barıs S, Tepe S, Sarıhasan B, Sener B, Tur A. Comparison of ondansetron and lidocaine in preventing of propofol injection pain. J Exp Clin Med 2002;19:263-7.  Back to cited text no. 18
    
19.
Fassoulaki A, Melemeni A, Zotou M, Sarantopoulos C. Systemic ondansetron antagonizes the sensory block produced by intrathecal lidocaine. Anesth Analg 2005;100:1817-21.  Back to cited text no. 19
    
20.
Farouk S. Ondansetron added to lidocaine for intravenous regional anesthesia. Eur J Anaesth 2009;26:1032-6.  Back to cited text no. 20
    
21.
Paraskeva A, Chatziara V, Siafaka I, Zotou M, Fassoulaki A. Ropivacaine spinal anesthesia is not antagonized by ondansetron pre-treatment. Anesth Analg 2009;109:1684-7.  Back to cited text no. 21
    
22.
Samra T, Bala I, Chopra K, Podder S. Effect of intravenous ondansetron on sensory and motor block after spinal anesthesia with hyperbaric bupivacaine. Anesth Int Care 2011;39:65-8.  Back to cited text no. 22
    
23.
Honarmand A, Safavi M, Adineh-Mehr L. Effect of adding 8 milligrams ondansetron to lidocaine for Bier's block on post-operative pain. Adv Biomed Res 2013;2:52.  Back to cited text no. 23
    
24.
Ye JH, Mui WC, Ren J, Hunt TE, Wu WH, Zbuzek VK. Ondansetron exhibits the properties of a local anaesthetic. Anest Analg 1997;85:1116-21.  Back to cited text no. 24
    
25.
Selcuk A, Pala Y, Taspinar V, Donmez NF, Dikmen B. The effect of systemic ondansetron on subarachnoid block. J Turk Anesth Int Care Soc 2009;37:297-303.  Back to cited text no. 25
    
26.
Apiliogullari S, Ileri Z, Onal O, Taylan SB, Saltali AO, Bariskaner H, et al. The reversal effect of ondansetron on local anesthesia in the thermal pain model of rats. The 12th Congress of the Eur Assoc for Clin Pharma and Therap (EACPT 2015), 27-30 June 2015 in Madrid, Spain.  Back to cited text no. 26
    
27.
Singh S, Sohi KS. A comparative study of the efficacy of bupivacaine versus lignocaine local anesthetic agent in preventing post-operative pain in single sitting endodontic treatment. J Adv Med Dent Sci Res 2019;7:85-7.  Back to cited text no. 27
    
28.
Fisher SE, Frame JW, Rout PG, McEntegart DJ. Factors affecting the onset and severity of pain following the surgical removal of unilateral impacted mandibular third molar teeth. Br Dent J 1988;164:351-4.  Back to cited text no. 28
    
29.
Brummett CM, Norat MA, Palmisano JM, Lydic R. Perineural administration of dexmedetomidine in combination with bupivacaine enhances sensory and motor blockade in sciatic nerve block without inducing neurotoxicity in rat. Anaesth 2008;109:502-11.  Back to cited text no. 29
    
30.
Rahmadi M, Su'aida N, Yustisari P, Agung Dewaandika W, Oktavia Hanaratri E, Andarsari MR, et al. Gastroprotective effect of fluvoxamine and ondansetron on stress-induced gastric ulcers in mice. J Basic Clin Physiol Pharmacol 2021;32:485-90.  Back to cited text no. 30
    
31.
Grant GJ, VermeuIen K, Zakowski MI, Sutin KM, Ramanathan S, Langerman L, et al. A rat sciatic nerve model for independent assessment of sensory and motor block induced by local anaesthetics. Anesth Analg 1992;75:889-94.  Back to cited text no. 31
    
32.
Dyhre H, Soderberg L, Bjorkman S, Carlsson C. Local anaesthetics in lipid-depot formulations neurotoxicity in relation to duration of effect in a rat model. Reg Anesth Pain Med 2006;31:401–8.  Back to cited text no. 32
    
33.
Ali Erdogan M, Polat A, Yucel A, Aydogan MS, Parlakpinar H, Tekin S, et al. Effects of perineural administration of dexmedetomidine in combination with levobupivacaine in a rat sciatic nerve block. Cur Ther Res 2013;74:74-8.  Back to cited text no. 33
    
34.
Kau YC, Hung YC, Zizza AM, Zurakowski D, Greco WR, Wang GK, et al. Efficacy of lidocaine or bupivacaine combined with ephedrine in rat sciatic nerve block. Reg Anesth Pain Med 2006;31:14-8.  Back to cited text no. 34
    
35.
Carnaval TG, Sampaio RM, Lanfredi CB, Borsatti MA, Adde CA. Effects of opioids on local anesthesia in the rat: A codeine and tramadol study. Braz Oral Res 2013;27:455-62.  Back to cited text no. 35
    
36.
Thalhammer J, Vladimirova M, Bershadsky B, Strichartz G. Neurologic evaluation of the rat during sciatic nerve block with lidocaine. Anesthesiology 1995;82:1013-25.  Back to cited text no. 36
    
37.
Turkoglu OF, Eroglu H, Okutan O, Tun MK, Bodur E, Sargon MF, et al. A comparative study of treatment for brain edema: Magnesium sulphate versus dexamethasone sodium phosphate. J Clin Neurosci 2008;15:60-5.  Back to cited text no. 37
    
38.
Iannaccone PM, Jacob HJ. Rats!. Dis Model Mech 2009;2:206-10.  Back to cited text no. 38
    
39.
Yagiela J. What's new with phentolamine mesylate: A reversal agent for local anesthesia? SAAD Digest 2011;27:3-7.  Back to cited text no. 39
    
40.
Boynes S, Riley A, Milbee S, Bastin M, Price M, Ladson A. Evaluating complications of local anesthesia administration and reversal with phentolamine mesylate in a portable pediatric dental clinic. Gen Dent 2013;61:70-6.  Back to cited text no. 40
    
41.
Vinnakota DN, Kamatham R. Safety profile of phentolamine mesylate as reversal agent of pulpal and soft tissue dental anesthesia: A systematic review and meta-analysis. Quint Int 2019;50:568-76.  Back to cited text no. 41
    
42.
Hersh EV, Moore PA, Papas AS, Goodson JM, Navalta LA, Rogy S, et al. Reversal of soft tissue local anesthesia with phentolamine mesylate in adolescents and adults. The J Am Dent Assoc 2008;139:1080-93.  Back to cited text no. 42
    
43.
Laviola M, McGavin S, Freer G, Plancich G, Woodbury SC, Marinkovich S, et al. Randomized study of phentolamine mesylate for reversal of local anesthesia. J Den Res 2008;87:635-9.  Back to cited text no. 43
    
44.
Al-Khafaji HHJ, Abass MK, Al-Ameedee AH. Unaddressed local anesthesia reversal action of phentolamine mesylate after plain mepivacaine. Eurasia J Biosci 2020;14:3883-88.  Back to cited text no. 44
    
45.
Prasanna J. OraVerse: Reverses numbness after dental procedures. J Max Oral Sur 2012;11:212-9.  Back to cited text no. 45
    
46.
Bravo-Hernández M, Cervantes-Durán C, Pineda-Farias JB, Barragán-Iglesias P, López-Sánchez P, Granados-Soto V. Role of peripheral and spinal 5-HT 3 receptors in development and maintenance of formalin-induced long-term secondary allodynia and hyperalgesia. Pharma Bioch Beh 2012;101:246-57.  Back to cited text no. 46
    
47.
Ueta K, Suzuki T, Sugimoto M, Uchida I, Mashimo T. Local anesthetics have different mechanisms and sites of action at recombinant 5-HT 3 receptors. Reg Anest Pain Med 2007;32:462-70.  Back to cited text no. 47
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
  
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
    Abstract
   Background
   Measurements
   Results
   Discussion
   Conclusion
    References
    Article Figures
    Article Tables

 Article Access Statistics
    Viewed120    
    Printed4    
    Emailed0    
    PDF Downloaded24    
    Comments [Add]    

Recommend this journal