The Effect of Adding Ondansetron and Metoclopramide to Intravenous Acetaminophen on Pain Control and Post-operative Nausea and Vomiting: A Randomized Double-blind Clinical Trial

Although laparoscopic surgery causes less postoperative pain than open surgery, however, the pain at the site of the laparoscopic port incision and in the shoulder and upper abdomen are the main complaints. Moreover, since postoperative nausea and vomiting (PONV) is the other complaints of these patients, it is important to adopt measures to address this issue (1-5).Today, acetaminophen is one of the most widely used analgesics due to its efficacy, safety, low side effects, and rare drug interactions (5, 6). Acetaminophen has different mechanism of actions that some of them have not been identified yet. It controls pain by preventing the production of prostaglandin E2, indirectly activating the cannabinoid receptor type 1, inhibiting the nitric oxide system by involving N-methyl-D-aspartate and substance P, and directly by stimulating descending serotonergic pathways that hinder pain signals transmitted by the spinal cord. Serotonin 5-Hydroxytryptamine (5-HT3) receptor antagonists, such as ondansetron, are at the front line of PONV treatment (7, 8). Furthermore, use of intravenous acetaminophen can also reduce PONV and the rate of antiemetic consumption (9-12). PONV is a common complication with a prevalence rate of 20-30% (3, 10). Ondansetron is the selective 5-HT3 antagonist which is effective in the prevention of PONV particularly if administered prior to the onset (3). In laparoscopic cholecystectomy, ondansetron administration can reduce the incidence of PONV in the first 4 h after the surgery (1). Ondansetron, in addition to triggering zone chemoreceptor in the medulla oblongata, affects the 5-HT3 receptor in the spinal cord on the pathway that modulates pain transmission signals. Some studies proposed that since ondansetron has antagonistic effects on 5ht3 receptors, it can reduce analgesic effects of acetaminophen. Therefore,ondansetron may be present at the 5-HT3 receptor of acetaminophen antagonist since the two medications have opposite effects on the 5-HT3 pathway (7).However, other studies have not concluded that co-administration of 5ht3 antagonists such as ondansetron and tropisetron could reduce the analgesic effects of acetaminophen. Moreover, review of literature showed one study which claimed direct analgesic effects for 5-HT3 antagonists (7, 12-17).Metoclopramide is another medication used to control PONV, and some studies reported the analgesic effects of this medication (18-22). Khazaei et al. and Karacabey et al. examined the effect of metoclopramide on migraine headaches and confirmed the results of previous studies regarding the positive effect of metoclopramide in reducing such headaches (19, 20). Ceyhan and colleagues conducted an experimental study on male rats and reported that metoclopramide could reduce incisional pain (22).Contrary to the laboratory results, the findings of some clinical studies have indicated that ondansetron did not reduce or even increased the analgesic effect of acetaminophen; however, the results of some studies have reported the blockage or reduction of this effect. According to our researches, there was no study on analgesic effect of co-administration of metoclopramide and acetaminophen and comparing its analgesic effect with ondansetron; therefore, this study was performed aimed to evaluate the effect of adding ondansetron and metoclopramide to intravenous acetaminophen on pain control and postoperative nausea and vomiting of patients undergoing laparoscopic cholecystectomy.

This double-blind clinical trial study with a parallel design was conducted in 2019 on patients undergoing laparoscopic cholecystectomy in the central operating room of Ghaem Hospital in Mashhad, Iran. According to the study by Koyunco et al. (7), the sample size was estimated to be 25 patients in each group by confidence level of 95% and power of 80%; finally, considering the possibility of 10% drop, 28 patients were considered in each group The study population consisted of all patients undergoing laparoscopic cholecystectomy. Participants were selected by Convenience Sampling method and entered the study after obtaining the written informed consent. The subjects were randomly allocated to three groups using the selection of sealed envelopes by the researcher. The first group (group A) received 1 g of intravenous acetaminophen by infusion 30 minutes before the end of surgery plus 4mg of ondansetron at the end of procedure. The second group (group B) was administered 1 g of intravenous acetaminophen by infusion 30 minutes before the end of surgery plus 8 mg of ondansetron at the end of procedure. The third group (group C) took 1 g of intravenous acetaminophen by infusion 30 minutes before the end of surgery plus 10 mg of metoclopramide at the end of procedure. Postoperative pain was measured as a primary outcome using the Numeric Rating Scale (NRS) after transferring the patient to the recovery room when patients' consciousness returned, before leaving the recovery room and 6 h after the operation in the ward. According to this scale, patients were asked to score their pain from a score of 0= no pain to 10= the most pain they have ever experienced. The validity and reliability of this scale have been investigated in various studies (23,24). Analgesic drug (other than acetaminophen) was injected for patients who had NRS score of ˃ 4.Demographic data, including age, weight, gender, and the duration of surgery were also recorded. The severity of nausea and vomiting before leaving the recovery was assessed by the PONV scale, which was developed by Wengritzky et al., who alsoevaluated its validity and reliability. In this 4-item scale, the highest score of items one or two is multiplied by the scores of items three and four to render the PONV score in the first 6 h after surgery (25).The inclusion criteria were: class I and II ASA age of 18-64 years, ability to communicate, no drug addiction, no analgesic administration in the last 24 h, no ondansetron or metoclopramide intake in the last 24 h, no chronic pain, and no history of sensitivity to acetaminophen, ondansetron, and metoclopramide.The exclusion criteria were: unusual and severe side effects of anesthesia, such as a severe drop (more than 50% of the baseline) in systolic blood pressure and heart rate that doesn’t respond to initial treatment, surgical complications which turned the procedure into an open surgery or despite managing the surgery with the closed approach, the operation lasted for more than 50% of the average of other operations, and the incidence of PONV, which required treatment with any of the medications in the family of 5-hydroxytryptamine inhibitors.All participants were completely monitored. General anesthesia was induced with propofol 2.5 mg/kg, atracurium 0.5 mg/kg, fentanyl 2 mcg/kg, and midazolam 20 mcg/kg. Maintenance of anesthesia was continued with propofol at a dose of 100-200 mcg/kg/min and remifentanil at a dose of 0.2-0.3 mcg/kg/min. The laparoscopic procedure and employed equipment were identical for all patients.In addition to the patients and the statistical analyzer, the person completing the NRS and PONV scales was also blinded to the groups.  Kolmogorov-Smirnov test was applied to assess the normal distribution of quantitative variables. Qualitative variables were expressed in the form of frequency and percentage, quantitative variables in the form of mean (standard deviation), or with median (1st and 3rd quarters) in the case of a non-normal distribution. Chi-square and Fisher's exact test were used to evaluate the equality of proportions of qualitative variables among the three groups. Analysis of variance was used to compare the mean of quantitative normal variables in the three groups. The marginal model of generalized estimate equations (GEE) was used for intragroup and intergroup comparisons. Bonferroni's post hoc test was used for pairwise comparisons. Data was analyzed using SPSS software (version 25.0). P< 0.05 was considered statistically significant.

Ethical considerations:

This research was approved by the Ethics Committee of Mashhad University of Medical Sciences, Mashhad, Iran (Ir.mums.medical.rec.1397.593) and registered in the Iranian Registry of Clinical Trials (IRCT20160516027925N4). Informed consent was obtained from the patients before entering the study. All the conditions, the possibility of study withdrawal and how to access the results were explained to the participants orally and in written form. The data of this study can be obtained by sending an email request to the corresponding author while maintaining the confidentiality of the patients' information.

A total of 84 individuals participated in this study, among them 1 case in the third group  was excluded due to surgical complications leading to open surgery (Figure 1). In the acetaminophen + ondansetron 4mg (group A), acetaminophen + ondansetron 8mg (group B), and acetaminophen + metoclopramide (group C), 77.8%, 75.0%, and 74.1% of the patients were female, respectively. According to the Analysis of variance, Chi-square and Kruskal Wallis tests, all three groups were homogeneous in terms of gender (P=0.947), age (P>0.802), weight (P=0.724), and the duration of surgery (P>0.99). The summary of demographic information and the duration of surgery were presented in Table 1.The patients' PONV mean scores in the acetaminophen + ondansetron 4mg (group A), acetaminophen + ondansetron 8mg (group B), and acetaminophen + metoclopramide (group C) groups were