Comparing the Impact of Metoclopramide versus Ondansetron on Pain Reduction Caused by Etomidate Injection in Patients under General Anesthesia

Abstract

Background:

Etomidate is a short-acting intravenous anesthetic commonly used for induction of general anesthesia and sedation. Preventing pain caused by etomidate injection can improve patient comfort and broaden its clinical use. This study compared the effects of metoclopramide and ondansetron on etomidate injection-related pain in patients undergoing general anesthesia.

Materials and Methods:

In this randomized clinical trial conducted at Al-Zahra Hospital, Isfahan, from 2021 to 2022, 90 patients were randomly assigned to three groups (n = 30 each): metoclopramide (Group A), ondansetron (Group B), and normal saline (Group C, control). After drug administration, 0.3 mg etomidate was injected, followed by 1 mL of 2% lidocaine. Pain intensity during etomidate injection was recorded. Hemodynamic parameters—including blood pressure, heart rate, and arterial oxygen saturation (SaO₂)—were measured at 5, 10, 15, 30, 45, and 60 minutes, and upon discharge from recovery. Duration of surgery and recovery were also documented.

Results:

The control group exhibited a higher mean pain score than the intervention groups. Pain intensity differed significantly between the metoclopramide and control groups (P = 0.001), but not between ondansetron and control (P = 0.762) or between metoclopramide and ondansetron (P = 0.675). Both metoclopramide and ondansetron effectively reduced etomidate injection pain without significant differences in hemodynamic stability or recovery duration.

Conclusion:

Both metoclopramide and ondansetron attenuate pain associated with etomidate injection during induction of general anesthesia, with no clear superiority of one drug over the other. Their comparable efficacy supports either as an appropriate option for preventing etomidate-related pain.

INTRODUCTION

Etomidate is a short-acting intravenous anesthetic used to produce general anesthesia and drowsiness. It is frequently used for brief surgical operations, including electroconvulsive therapy (ECT) and high-risk surgery, as well as dislocated joints, conization, curettage, and dilatation. This medication maintains hemodynamic stability, minimum respiratory difference, brain protection, speedy recovery after a single dosage, and minimal effects on the circulatory and respiratory systems. However, etomidate anesthesia is associated with several adverse effects—including myoclonus, injection-site pain, and postoperative nausea and vomiting—and its formulation in propylene glycol may provoke pain by activating nociceptive TRPA1 and TRPV1 ion channels in sensory neurons.[1,2,3] As a consequence, if the discomfort it produces is prevented, the benefits of etomidate injection can be extensively exploited in procedures. The impact of serotonin receptors or 5-hydroxytryptamine receptors (5-HT3, 5-HT4, etc.) on pain threshold has been studied. These receptors are found in both the peripheral and central nervous systems. It is possible to activate these receptors to produce both excitatory and inhibitory effects. These receptors are activated by the natural ligand serotonin.[4] Ondansetron and methoclopramide are two of these 5-hydroxytryptamine receptor antagonists.

Metoclopramide is a safe medicine with few side effects that has been used to treat and lessen pain in several trials. The antidopaminergic drug methoclopramide also has antiserotonergic effects. Both the digestive system and the central nervous system are impacted. Even though this medication’s ability to relieve pain has been the subject of several investigations, a precise mechanism is still unknown.[5,6] According to the study, when compared to fentanyl and ketamine and ketamine alone, using metoclopramide and ketamine together after surgery reduces pain for patients and has no negative effects on major postoperative complications.[5,7] It was demonstrated in other trials by Heidari-Tabaee-Zavareh et al. that intravenous metoclopramide can lessen postoperative pain, which may be a greater analgesic benefit of this medication. However, it did not interfere with the anesthesia, and it decreased the difficulties of postoperative nausea and vomiting in addition to the requirement for extra postoperative pain relievers.[8,9] According to research by Sajedi et al.,[10] meperidine and chlorpromazine were both superior to meperidine at relieving headaches following eye surgery. Comparing these medications’ abilities to treat pain and prevent repeated headaches revealed that chlorpromazine has the greatest results. Also, injection of 5 or 10 mg metoclopramide is more effective than a placebo or metoclopramide 2.5 mg in minimizing the discomfort associated with receiving a propofol injection, according to research by Fujii et al.[11] Another research on the impact of adding metoclopramide to lidocaine by Shabanian et al.[12] found that adding metoclopramide to lidocaine decreased postoperative pain.

Ondansetron is a 5-HT3 receptor antagonist that has been used to treat and reduce pain in a number of trials. According to the findings of a study, ondansetron injection significantly reduced the discomfort of etomidate injection.[13] Other trials, including a meta-analysis, found that ondansetron injection considerably decreased the discomfort of propofol injection. Ondansetron is also beneficial for reducing postoperative nausea and vomiting.[14,15] Another research evaluated the effects of lidocaine and ondansetron on propofol pain relief. The results revealed that using lidocaine instead of ondansetron minimized the discomfort of propofol injection.[16]

Despite the fact that several studies have explored the efficacy of metoclopramide or ondansetron in relieving pain, none of these studies have compared the effects of these two medicines. As a result, this study compared the effects of metoclopramide and ondansetron on pain reduction caused by etomidate injection in patients under general anesthesia at Al-Zahra Hospital in Isfahan, Iran.

MATERIALS AND METHODS

This double-blinded randomized clinical trial was performed during the period of 2021–2022 in Al-Zahra Hospital affiliated with Isfahan University of Medical Sciences. Three 30-person groups (90 persons) were randomly selected using Random Allocation software. Patients who were eligible for elective surgery and required general anesthesia, with inclusion criteria, were enrolled in this study. Patients aged 18 to 65 years old with American Society Anesthesia (ASA) I and II and candidates for elective surgery needing general anesthesia with etomidate were eligible. The non-inclusion criteria included patients who had previously received metoclopramide, ondansetron, and etomidate and had complications and allergies. Exclusion criteria were: occurrence of drug sensitivity, change in anesthetic process.

Before patient recruitment, the researchers explained the design, objectives, and stages of the study, as well as the pain scoring system to the subjects. They were ensured that their information would be kept confidential and analyzed with codes and without names. Those willing to participate in the study were asked to read and sign the written informed consent. A basic form of randomization was used, in which eligible patients were assigned to groups A, B, and C depending on their arrival time, and this procedure was repeated until the number of persons in each group reached 30. The drugs were prepared by an assistant, in opaque syringes and the anesthesiologist who injected the drugs and scored the pain was unaware of the drug type. The first group (A) was given 10 mg of metoclopramide and then 5 cc of normal saline 10 minutes later; the second group (B) was given 8 mg of ondansetron and then 5 cc of normal saline 10 minutes later; and the third group (C) was given 2 cc of normal saline and then 5 cc of normal saline intravenously as the control group. For each group, 1 cc of lidocaine 2% corresponding to 20 mg was injected, followed by 0.3 mg etomidate administered at a rate of 1 cc per second, and pain intensity was measured. Blood pressure, heart rate, and arterial oxygen saturation (SaO₂) were measured before drug administration, before anesthesia induction, and after anesthesia induction at minutes 5, 10, 15, 30, 45, and 60, and finally at the end of the recovery period. In addition, the length of operation and recuperation were documented for each of the three groups. In this research, data were collected by completing the demographic questionnaire (age, gender, weight, height, and body mass index [BMI]) of the researcher’s standard checklist. The researcher-made standard checklist: This checklist includes measures of blood pressure, heart rate, and SaO₂ before drug administration, before anesthesia induction, and after anesthesia induction at 5, 10, and 15 minutes and then at 30, 45, and 60 minutes and it was set when exiting recovery.

In this checklist, the pain intensity caused by the injection of etomidate was scored based on a 4-point Likert scale (no pain, mild pain, moderate pain, and severe pain). The number of pain caused by etomidate injection was also scored from 0 (no pain) to 10 (worst imaginable pain) using the visual analog scale (VAS) and their information was recorded. The researcher-made standard checklist was given to 8 medical faculty members and after collecting their comments, the necessary modifications were applied to the tool based on the feedback obtained. Its reliability was reported to be 95% using Cronbach’s alpha method. SPSS 26 (IBM Corp., Armonk, NY, USA) software was used to examine the data.

RESULTS

In this study, we evaluated 90 patients with a mean age of 40.23 ± 6.49 years and gender distribution of 36 women (40%) and 54 men (60%), and a weight of 5.43 ± 73.7. No significant difference exists in gender distribution, age, and weight in the three groups (P > 0.05) [Figure 1].

Figure 1.

CONSORT flow diagram

The results [Table 1] revealed no difference in the average blood pressure score between the three groups before medication administration, before anesthetic induction, after anesthesia induction, 5, 10, 15, 30, 45, and 60 minutes after anesthesia induction, and upon leaving recovery (P > 0.05). Furthermore, no significant difference in average recovery time was found across the three groups (P > 0.05) [Table 1].

Table 1.

Comparison of systolic blood pressure in the studied times and recovery time between the three groups

Variable		Time		Group A (M±SD)		Group B (M±SD)		Group C (M±SD)		Statistical test of analysis of variance with repeated observations
										F		P
Systolic blood pressure		before prescribing the drug		89.76±7.07		88.1±6.65		87.06±5.11		1.387		0.255
		Before induction of anesthesia		89.36±5.39		88.33±6.26		86.5±6.29		1.758		0.178
		After induction of anesthesia		86.5±5.28		86.66±5.88		88.83±6.82		1.397		0.253
		5 minutes after induction of anesthesia		86.23±5.02		84.96±6.57		87.56±6.95		1.301		0.278
		10 minutes after induction of anesthesia		84.53±5.63		85.3±7.3		86.76±6.66		0.895		0.413
		15 minutes after induction of anesthesia		83.13±4.85		84.4±7.92		84.9±4.96		0.673		0.513
		30 minutes after induction of anesthesia		83.1±4.83		83.9±6.5		85.06±3.76		1.102		0.337
		45 minutes after induction of anesthesia		84.53±5.11		85.1±6.28		86.63±3.93		1.309		0.275
		60 minutes after induction of anesthesia		89.96±8.08		88.63±6.5		90.96±3.49		1.532		0.222
		When exiting recovery		98.3±4.44		97.33±7.39		98.6±7.29		0.309		0.735
Recovery time		Recovery time		64.5±7.35		62.03±12.95		65.39±6.66		1.178		0.313

Scheffe’s post hoc test revealed a difference in the average heart rate score following anesthetic induction between groups A and C. Other comparisons do not vary based on Scheffe’s test (P > 0.05) since the significance level attained is greater than 0.05 [Table 2].

Table 2.

Comparison of heart rate in the studied times among the three groups using Scheffe’s post hoc test

Variable		Time		Post hoc test		Mean difference		P		95% Confidence interval
										Lower bound		Upper bound
heart rate		After induction of anesthesia		Group A with Group B		5.2		0.236		−12.7		2.3
				Group A with Group C		8.7		0.019		−16.3		−1.2
				Group B with Group C		3.5		0.504		−3.9		11.1
		10 minutes after induction of anesthesia		Group A with Group B		3.5		0.147		−11.2		1.2
				Group A with Group C		7.3		0.016		−13.6		−1.1
				Group B with Group C		2.4		0.634		−8.6		3.8
		15 minutes after induction of anesthesia		Group A with Group B		3.5		0.314		−9.2		2.2
				Group A with Group C		6.2		0.029		−12.1		−0.52
				Group B with Group C		2.7		0.499		−8.4		3.01
		45 minutes after induction of anesthesia		Group A with Group B		1.5		0.745		−6.5		3.4
				Group A with Group C		5.1		0.040		−10.1		−0.19
				Group B with Group C		3.6		0.197		−8.6		1.3
		60 minutes after induction of anesthesia		Group A with Group B		1.2		0.803		−5.8		3.3
				Group A with Group C		4.8		0.040		−9.4		0.17
				Group B with Group C		3.5		0.165		−1.06		8.1

The post hoc examination of Scheffe’s test revealed a difference in the mean SaO₂ score before medication administration between groups A, B, and C (P < 0.01). There was a difference in the average SaO₂ score before induction of anesthesia between groups A, B, and C (P < 0.05). There was a difference in the average SaO₂ value following anesthetic induction between groups A and B (P < 0.05). The average SaO₂ level 5 minutes after anesthetic induction differs between groups A and B (P < 0.05). The average SaO₂ level upon exiting recovery differs between groups A and B, as well as between groups B and C (P < 0.01). There was a difference in the average SaO₂ value when exiting recovery between groups A and C (P < 0.05). Other comparisons do not vary based on Scheffe’s test (P > 0.05) since the significance level attained is greater than 0.05 [Table 3]

Table 3.

Comparison of arterial oxygen saturation (SaO₂) in the studied times among the three groups using Scheffe’s post hoc test

Time		Post hoc test		Mean difference		P		95% Confidence interval
								Lower bound		Upper bound
Before prescribing the drug		Group A with Group B		10.03		0.001		−1.6		0.44
		Group A with Group C		0.96		0.001		−1.5		−0.38
		Group B with Group C		0.06		0.961		−0.51		0.65
Before induction of anesthesia		Group A with Group B		1.03		0.026		1.9−		0.09−
		Group A with Group C		1		0.033		1.9−		0.09−
		Group B with Group C		0.03		0.996		0.9−		0.96
After induction of anesthesia		Group A with Group B		1.1		0.026		−2.09		0.1−
		Group A with Group C		0.56		0.367		−1.5		0.42
		Group B with Group C		0.53		0.411		−1.5		0.45
5 minutes after induction of anesthesia		Group A with Group B		0.96		0.018		−1.7		−0.13
		Group A with Group C		0.53		0.283		−1.3		0.29
		Group B with Group C		0.43		0.433		−0.39		1.2
60 minutes after induction of anesthesia		Group A with Group B		0.63		0.097		−1.3		0.08
		Group A with Group C		0.06		0.974		−0.65		0.78
		Group B with Group C		0.70		0.059		−1.4		0.01
When exiting recovery		Group A with Group B		1		0.001		−1.6		−0.37
		Group A with Group C		7		0.024		0.07		1.3
		Group B with Group C		1.7		0.001		1.07		2.3

The post hoc analysis of Scheffe’s test revealed a difference in the average length of operation between groups A, B, and C (P < 0.05) [Table 4]. However, there was no difference in the average length of operation between groups B and C (P > 0.05). The aforementioned results reveal a difference in average pain intensity between groups A and C, as well as between groups B and C (P < 0.01), while no difference occurred between groups A and B (P > 0.05).

Table 4.

Comparison of the average duration of surgery and pain intensity among three groups using Scheffe’s post hoc test

Time		Post hoc test		Mean difference		P		95% confidence interval
								Lower bound		Upper bound
Duration of surgery		Group A with Group B		23.1		0.011		4.4		41.5
		Group A with Group C		28.5		0.001		9.9		47.05
		Group B with Group C		5.5		0.762		−24.1		13.05
Intensity of pain		Group A with Group B		0.26		0.675		−0.48		1.01
		Group A with Group C		2.1		0.001		1.3		2.8
		Group B with Group C		2.4		0.001		1.6		3.1

DISCUSSION

This research compared the effects of metoclopramide and ondansetron on pain relief following etomidate injection in individuals under general anesthesia. Based on the visual analog scale (VAS), the results revealed a significant difference in the average pain intensity generated by etomidate injection in three groups receiving metoclopramide, ondansetron, and normal saline (as a placebo). As a result, the group receiving normal saline had a greater average than the other two groups. In addition, the post hoc analysis of Scheffe’s test revealed a difference in average pain intensity between the groups receiving metoclopramide and the normal saline (placebo), and between the ondansetron group and the group receiving normal saline (placebo), but no significant difference was found between the two groups receiving metoclopramide and ondansetron. These findings demonstrated that ondansetron and metoclopramide can both lessen the discomfort induced by etomidate injection, but neither has an advantage over the other. As a result, Azimaraghi et al.,[17] in the only published study, investigated the effectiveness of ondansetron in reducing pain caused by etomidate injection and found that administering ondansetron before etomidate injection significantly reduces injection pain, and the findings of this study are consistent with the findings of the current study.

Several studies have demonstrated that ondansetron binds to opioid receptors in the human body and has agonist action on these receptors, which lessens the pain induced by etomidate injection by activating these receptors.[17] The impact of ondansetron injection on pain reduction induced by rocuronium and propofol has also been investigated in studies, all of which emphasize the usefulness of ondansetron in decreasing pain caused by anesthetic injections such as propofol and rocuronium.[18] In a research titled “Comparing the impact of lidocaine and ondansetron on pain reduction caused by propofol injection,” Ayub et al.[19] discovered that using lidocaine instead of ondansetron lessens the discomfort of propofol injection. Khorasanizadeh et al.[20] investigated the combination of ondansetron and aprepitant in reducing nausea and vomiting caused by etomidate injection compared to the combination of metoclopramide and dexamethasone and concluded that the combination of ondansetron is stronger than metoclopramide in reducing nausea and vomiting caused by etomidate injection. Other medications, such as lidocaine and magnesium sulfate, have been examined to lessen the pain induced by etomidate injection; however the reduction in the usage of magnesium sulfate was greater than the reduction in the use of lidocaine.[21]

The most typically utilized medications are lidocaine or fentanyl, both of which have local anesthetic and sedative characteristics. Ondansetron was similarly effective in avoiding pain produced by propofol injection as tramadol, sustained the analgesic effect of ondansetron, and was superior to tramadol in preventing postoperative nausea and vomiting.[17]

Recent studies have evaluated various agents, including metoclopramide, for attenuating pain caused by propofol injection, and demonstrated that metoclopramide effectively decreases injection pain without significant adverse effects,[22] which is consistent with the findings of the current study. The effect of metoclopramide injection on pain reduction caused by etomidate injection has not been studied so far, but its effectiveness on postoperative pain reduction has been determined in various studies, so that in the studies conducted by Heydari Tabai Zavareh et al., it was shown that the use of intravenous metoclopramide can reduce postoperative pain, which can suggest the better analgesic effects of this medicine. However, it did not interfere with the anesthetic, and it minimized the difficulties of postoperative nausea and vomiting, as well as the requirement for extra postoperative pain relief medicine.[8,9] In addition, Sajedi et al.[10] discovered that chlorpromazine and metoclopramide were more efficient than meperidine in alleviating headache following eye surgery in a research. A study done by Fuji et al.[11] revealed that metoclopramide injection is beneficial in minimizing the discomfort of propofol infusion. Shabanian et al.[12] did a research and discovered that combining metoclopramide with lidocaine decreased postoperative pain. The effectiveness of ondansetron and metoclopramide on physiological indicators, SaO₂, and recovery time were also measured in this study, and the results revealed no difference between the three groups in the average blood pressure score before medication, before, during, and after anesthesia induction, and when leaving recovery, as well as the average duration of recovery. However, there was a difference in the average heart rate score during induction of anesthesia and 10, 15, 45, and 60 minutes after induction of anesthesia between the groups receiving metoclopramide and the groups receiving normal saline. Before medication delivery, there was no change in the average SaO₂ score between the groups receiving metoclopramide, ondansetron, and normal saline. There was no difference in the average score of SaO₂ immediately and 5 minutes after induction of anesthesia and when leaving the recovery between the three groups receiving metoclopramide, ondansetron, and normal saline, and the results showed that ondansetron and metoclopramide have no preference over each other in terms of blood pressure control and recovery time, but metoclopramide was more effective than ondansetron in controlling heart rate and SaO₂ in cert. Given the importance of postoperative pain reduction, it is preferable to conduct additional studies comparing ondansetron and metoclopramide in reducing pain caused by etomidate injection in various surgeries and across all age groups in order to provide patients with a rich source of information to more effectively control pain caused by drug injection during anesthesia.

CONCLUSION

The results of this study demonstrate that metoclopramide and ondansetron are effective in reducing pain caused by etomidate injection under general anesthesia, although neither of these two medications has an advantage over the other in terms of pain control.

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of Isfahan University of Medical Sciences with code: IR.MUI.MED. REC.1399.521, registered with ID: IRCT20160307026950N32 in the Iranian Clinical Trials Center (IRCT).

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.