Effect of Combined Paracetamol and Dexamethasone on Pain and Postoperative Nausea Vomiting

Effect of Combined Paracetamol and Dexamethasone on Pain and Postoperative Nausea Vomiting Dian Ayu1*, Apita Sekar Widowati2, Mohamad Riza3 Abstract: Background : Pain and Postoperative Nausea and Vomiting (PONV) are surgical side effects. Pain management can use opioids and non-opioids. Opioids have side effects such as nausea, vomiting, pruritus, somnolence, and respiratory depression, so other alternatives are needed to reduce pain. Paracetamol is an analgesic while dexamethasone is antiinflammatory and anti-emetic. This study was to determine whether the combination of paracetamol and dexamethasone was more effective in dealing with pain and PONV after cesarean section than paracetamol. Materials and Methods : This was an experimental study employing post-test only control group design, using two study groups. Group PD (combined paracetamol and dexamethasone) was treated using dexamethasone 8 mg and paracetamol 1 gram intravenously, while the group P (paracetamol) was treated using paracetamol 1 gram intravenously. Data of Pain and PONV were collected using the Wong Baker Faces Scale, Numeric Rating Scale, and a frequency table for PONV at the 4th, 6th, 12th, and 24th hours of postoperative administration. The data were analyzed using Mann Whitney test. Results : The results of this study found that the multimodal administration of combined paracetamol and dexamethasone was better in reducing the pain compared to administration of a paracetamol at 4th, 6th, 12th, and 24thhours of post cesarean section(p <0.05). Multimodal administration of combined paracetamol and dexamethasone was better reduced the incidence of PONV compared tothat of paracetamol at the 4thhour of post cesarean section(p <0.05). The multimodal use of combined paracetamol and dexamethasone had resulted fewer use of opioid and anti-emetic frequencies compared to that of paracetamol. Conclusion : The combined paracetamol and dexamethasone was more effective to reduce pain and PONV in samples with post cesarean section.


Background
Cesarean section is the removal of a baby with an incision in the abdominal wall 1 . The postoperative effects include pain caused by tissue or organ lesions, stretching, and nerve compression that can cause neuropathic pain 2 . Acute inflammation due to tissue damage has an important role in the development of postoperative pain, nausea, and vomiting 3 . Pain management after surgery has its own difficulties despite the acute pain that can be predicted to occur after surgery 4 . Opioids and nonopioids can be used for pain management. The use of opioids has side effects such as nausea, vomiting, pruritus, somnolence, and respiratory depression 5 . The American Society of Anesthesiologists (ASA) combines non-opioids in the form of paracetamol, with or without adjuvant analgesics in the form of dexamethasone as first-line pain management 6 .. Moderate to severe acute pain can occur after surgery with an incidence of 30-80% 4 . The percentage of acute pain after cesarean section is around 85%, whereas in vaginal delivery only 57% 7 . Acute pain, if not treated properly, can increase catabolism, heart rate, and blood pressure, thus causing immunosuppression. Inadequate treatment of acute pain can also prolong healing time which has an impact on the increase in the cost of hospital care 8 . The breastfeeding and interaction processes between the mother and her baby can be disrupted if acute pain after cesarean section is not handled properly 2 . Poor management of acute pain can cause nerve damage, which is a risk factor for chronic pain. Postoperative nausea and vomiting can occur in 30% of patients with the highest incidence of the first 6 hours 9 . If postoperative nausea and vomiting still continue to occur, they can lead to dehydration, electrolyte imbalance, tension in the sutures, and aspiration pneumonia 10 . Prevention of postoperative pain needs to be done well, so that acute pain does not change into chronic pain. The provision of multimodal analgesics before the surgical procedure is necessary to deal with the pain and reduce the use of opioids 11 . The administration of multimodal analgesics can be a combination of paracetamol and dexamethasone. Paracetamol is an analgesic or anti-pyretic which can inhibit the activity of the cyclooxygenase enzyme, which leads to inhibition of the prostaglandin production, equivalent to the NSAID (Non-Steroid Anti-Inflammatory Drug). The study conducted by Kartapraja (2016) 12 reported that paracetamol is less effective at reducing pain and requires the initiation of analgesics more quickly than parecoxib.Another trial shows that multimodal analgesic administration between dexamethasone in combination with morphine and paracetamol can reduce pain and opioid use significantly compared to the combination of morphine and paracetamol, but it does not eliminate the inflammatory process 13 . Another analgesic commonly administered is dexamethasone, which is a glucocorticoid class of drugs that has antiinflammatory and anti-emetic effects that can be used as a prevention of postoperative nausea and vomiting. Glucocorticoids can reduce edema and postoperative pain 8 .The study of Mohtadiet al. (2014) 3 suggested that the use of single-dose dexamethasone can significantly reduce postlaparoscopic cholecystectomy pain significantly compared to placebo.The study of Cardoso (2013) 14 proved that dexamethasone is also useful to prevent PONV after cesarean surgery.
A comparison between dexamethasone and paracetamol has not been done. This study aims to prove whether the combination of paracetamol and dexamethasone is better than a single dose of paracetamol in reducing pain and PONV (Post-Operative Nausea and Vomiting) after cesarean section.

Material and Method
The study belongs to the experimental research with the post-test only control group design. The population in this study included patients who were going to deliver a baby by cesarean section in 2019 at Sultan Agung Islamic Hospital Semarang. The patients who underwent cesarean section were given an explanation of the study to be conducted before being given the informed consents. The patients who agreed with the informed consents were then identified for the inclusion and exclusion criteria.
The sample size in this study was 20 people. There were two groups in this study, namely the paracetamol-dexamethasone combination group (PD) given 8-mg intravenous dexamethasone 30 minutes before induction and 1-gram intravenous paracetamol immediately after induction, and the single paracetamol group (P) given paracetamol 1 gram immediately after induction. Measurements of pain and PONV were performed at the 4 th , 6 th , 12 th , and 24 th hours using the Wong Baker Faces Scale, Numeric Rating Scale, and a frequency table for nausea and vomiting. The data obtained were processed using the SPSS for Windows program. Shapiro Wilk's and Levene's tests were used for the normality and homogeneity tests. The data were not normally distributed and not homogeneous. Then, the Mann Whitney test was performed with the result of p<0.05, implying that there were significant differences between the two treatment groups.

Results
The comparative test of pain and PONV scores between the two treatment groups was carried out with the Mann Whitney test.       Table 4 describes the frequency of administration of anti-emetics at the 4 th hour to 12 patients, consisting of 9 patients in the single paracetamol group (75.0%) and 3 patients in the paracetamoldexamethasone combination group (25.0%). Antiemetics were not administered at the 12 th and 24 th hours.

Discussion
This result is relevant to that of Kamath and Lasrado's study in India in 2014, which shows that the use of intravenous paracetamol is more effective than intravenous butorphanol in managing pain in obstetric and gynecological operations 15 .The study conducted by Choy and Isquandar (2014) shows that giving multimodal analgesic paracetamol can reduce pain significantly compared to placebo 16 . Paracetamol is a p-aminophenol derivative, which has an analgesic effect by inhibiting the cyclooxygenase enzyme (COX) weakly in the peripheral, and therefore inhibits prostaglandin synthesis that can reduce pain 12 . This result is also relevant to the study conducted by Mohtadiet al.
(2014) about the use of a single dexamethasone that can reduce pain significantly after laparoscopic cholecystectomy than the use of placebo 3 .The study of Badawy and Sakka in 2015 suggests that dexamethasone given as multimodal can reduce pain and PONV after abdominal hysterectomy significantly compared to placebo 8 .
The study of Cardoso et al.(2013) shows that the use of dexamethasone is also useful for preventing PONV after cesarean section 14 .Dexamethasone is a glucocorticoid class of drugs, which inhibits the enzyme phospholipase A2 so that it inhibits the release of arachidonic acid to produce the cyclooxygenase enzyme (COX), which results in the formation of prostaglandins as a mediator of pain not occurring. Dexamethasone is also an anti-inflammatory that reduces inflammation due to afferent nerve stimuli to the vomiting center 17 . Multimodal analgesics are a combination of several drugs given before the surgical procedure that are needed to deal with the pain and reduce the use of opioids 11 . Badawy and Sakka (2015) state that acute pain must be treated adequately so as not to prolong healing time that will not lead to the increase in the hospital-treatment cost 8 .
Postoperative pain is an effect caused by tissue or organ lesions, stretching, and nerve compression 2 .
Acute inflammation due to tissue damage has an important role in the development of postoperative pain, nausea, and vomiting 3 .
The limitations in this study include differences in pain and PONV thresholds in each individual because it is subjective, the analysis of side effects after the drug administration that has not done yet, and additional analgesics and anti-emetic that cannot be controlled.

Conclusion
The administration of combined paracetamol and dexamethasone could manage pain and PONV after cesarean section better than that of a single paracetamol. The frequency of opioid use after cesarean section is higher in the single paracetamol than in the paracetamoldexamethasone combination.The frequency of anti-emetic use after a cesarean section is higher in the single paracetamol than in the paracetamoldexamethasone combination.

Conflict of Interest:
The authors declare that they have no competing interests. The authors alone are responsible for the writing and content of this paper.

Acknowledgment:
The authors wish to thank Faculty of Medicine Universitas Islam Sultan Agung, for funding the project and all patients who participated in the study.

Mohamad Riza
Writing and submitting manuscript: Dian Ayu,

Ethical clearance
The ethical clearance of this study wasissued by