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

IntroductionAlthough 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. MethodsThis 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 also evaluated 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). P0.802), 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  AllocationEnrollment Assessed for eligibility (n=84)Excluded (n=0)¨   Not meeting inclusion criteria (n=0)¨   Declined to participate (n=0)¨   Other reasons (n=0)Randomized (n=84)Analysed (n=27) ¨ Excluded from analysis (n=0)Analysed (n=28) ¨ Excluded from analysis (n=0)Analysed (n=28) ¨ Excluded from analysis (n=0)AnalysisAnalysisAnalysisLost to follow-up (n= 0)Discontinued intervention (n=0) Lost to follow-up (n= 0)Discontinued intervention (n=0)Lost to follow-up (n=0)Discontinued intervention (due to surgical complications leading to open surgery) (n=1)  Follow-UpFollow-UpFollow-Up¨ Group C: Received Acetaminophen + Metoclopramide (n=28)¨ Did not receive allocated intervention (n=0)¨ Group B: Received Acetaminophen + Ondansetron 8mg (n=28)¨ Did not receive allocated intervention (n=0)¨ Group A: Received Acetaminophen + Ondansetron 4mg (n=28)¨ Did not receive allocated intervention (n=0)                                             Figure 1. CONSORT flow diagram of the study calculated at 160.61±241.31, 127.39±206.19, and 137.15±214.23, respectively. Kruskal-Wallis test showed no significant difference among the three groups in terms of PONV mean scores (P=0.812). A summary of the main findings was provided in Table 2.The mean of the interval between the end of surgery and the first analgesia injection were obtained at 2.14±1.18, 1.79±0.74, and 3.76±1.22 h in the A, B and C groups, respectively. Kruskal-Wallis test showed significant difference among the three groups in this regard (P0.999); however, significant differences were observed between the A and B groups (P0.999***a was expressed in frequency (percentage), b mean±standard deviation, c mean±standard deviation with median (1st quarters, 3rd quarters) in the case of a non-normal distribution.* Chi-square                          ** ANOVA                             *** Kruskal-Wallis The mean of pain score at the time of the first analgesia injection were estimated at 6.54±1.07, 6.79±0.83, and 7.04±8.60 in the A, B and C groups, respectively. Kruskal-Wallis test showed no significant difference among  the three groups in this regard (P0.999B vs C P0.999After surgery and before leaving recovery (2)4.64±2.084 (3 , 6.75)Six hours after surgery (3)4.43±1.836 (3 , 6)    acetaminophen + ondansetron 8mg (B)After surgery in recovery (1)4.57±2.063 (3 , 7)1 vs 2p>0.9991 vs 3p= 0.4412 vs 3p>0.999After surgery and before leaving recovery (2)4.89±2.024 (3 , 7)Six hours after surgery (3)5.11±1.576 (3 , 6)    acetaminophen + metoclopramide (C)After surgery in recovery (1)1.59±1.672 (0 , 2)1 vs 2p= 0.2751 vs 3p<0.0012 vs 3p<0.001After surgery and before leaving recovery (2)2.00±1.002 (2 , 3)Six hours after surgery (3)3.11±1.783 (2 , 5)  Tests of Model EffectsTime (Wald Chi-Square: 17.858; P-value<0.001)Group (Wald Chi-Square: 77.874; P-value<0.001)  Pairwise ComparisonsControl vs Intervention 1<0.001Control vs Intervention 2<0.001Intervention 1vs Intervention 2: 0.198 DiscussionAccording to the results of the present study, the patients in the A and B groups who received ondansetron at doses of 4 and 8 mg with acetaminophen, respectively, experienced more pain than the group C who were administered 10 mg of metoclopramide with acetaminophen. Although the group B received a higher dose of ondansetron but had higher mean pain scores than the group A. The results of the study conducted by Ramirez et al. on the interaction and analgesic effect of I.V acetaminophen with 5-HT3 antagonists showed that the pain score in the acetaminophen and ondansetron group was not significantly different from the acetaminophen plus droperidol group, which is a dopamine antagonist similar to metoclopramide. Nevertheless, the administration of morphine in the ondansetron group was 3 times higher, which could indicate the contradictory effect of the 5-HT3 antagonist with acetaminophen (14). In the present study, the time of the first analgesia injection in acetaminophen + ondansetron 8mg (B) group was sooner than acetaminophen + ondansetron 4mg (A) group that could show the contradictory effect of the 5-HT3 antagonist with acetaminophen.Some discrepancy between the results of the mentioned study and the present study can be explained by the different time intervals for assessing the pain scores. Ramirez et al. also investigated this interaction in tonsillectomy among children and suggested the necessity of further studies in other surgeries (14). The findings of other studies indicate a reduction in the analgesic effect of acetaminophen when used concomitantly with 5-HT3 antagonists (7, 15). In the study performed by Koyuncu et al. on patients with abdominal hysterectomy, the postoperative pain scores were higher I those receiving acetaminophen plus ondansetron than those who received acetaminophen alone (7).In some studies, the concomitant use of acetaminophen and 5-HT3 antagonist not only did not reduce the analgesic effect of acetaminophen but also increased its analgesic effect (12, 13). Bhosale et al. reported that the co-administration of ondansetron and paracetamol did not decrease the analgesic effect of paracetamol (13). Based on the results of the above mentioned study, after taking acetaminophen, the concentration of serotonin will be increased, which is one of the mechanisms that acetaminophen inserted its analgesic property, however, 5-HT3 antagonists, such as ondansetron, can block it; nonetheless, their investigation has concluded differently when examined in clinical studies.This differences in the results can be attributed to two reasons; firstly, the mentioned study was performed on patients with local anesthesia and secondly, a small sample size (n=20) may be the effect of other analgesic mechanisms of acetaminophen other than increased serotonin. Furthermore, the findings of  the studies by Bhosale et al. and Tiippana et al. have reported the independent analgesic effects of 5-HT3 antagonist (13,17).Another similar study was performed by Akhondi et al. on patients who underwent upper extremity fracture surgery, and the results revealed that the concomitant use of Apotel (I.V Acetaminophen) and ondansetron could reduce pain more than the administration of Apotel alone. One of the reasons for this difference in the results of their research with those of other studies could be related to the different types of surgery and methods of medication injection. In the present study, the medications were given to the patients in the forms of bolus and infusions for 30 min, but in the mentioned study, 4 ml/h of Apotel and ondansetron (4 mg ondansetron + 2 g Apotel + 100 ml normal saline) was infused during 25 h using a patient-controlled analgesia pump (12).The results of the mentioned study also indicated that the difference between the doses of pethidine administered as an analgesic after the surgery was not significant in the control and intervention groups, which was inconsistent with the assumption that Apotel with ondansetron leads to more analgesia than Apotel alone. In the present study, although the dose of ondansetron was increased from 4 mg to 8 mg and the mean pain scores were lower in patients receiving a lower dose of ondansetron, the results of the Kruskal-Wallis test showed no statistically significant differences. Nevertheless, in the acetaminophen + metoclopramide (C) group, metoclopramide not only controlled PONV (none of the three groups showed a statistically significant difference in PONV score regardless of the intervention), but also reduced pain more than the other medication administered in the other two groups.Regarding the higher analgesic effect of acetaminophen in the presence of metoclopramide in the acetaminophen + metoclopramide (C) group, it can be stated that in addition to the fact that this increase might be due to the lack of blocking effect of acetaminophen on increasing serotonin compared to ondansetron, a reduction in pain could also be due to the analgesic effects of metoclopramide. Various studies have been performed to investigate the anal