Pain is an unpleasant sensation for the patient and can be influenced by many factors.¹ In this regard, nociceptive stimulation results in increased central sensitization and hyperexcitation because of the tissue damage that occurs during surgery. Therefore, pain is a predictable part of the postoperative stage. It is also the cause of delayed patient recovery and poor postoperative outcomes.² In addition, although knowledge about pain mechanisms is now widely developed, administering good and adequate anti-pain is still challenging.

Moreover, although opioids are currently still widely used for postoperative analgesic therapy, opioids are known to have many adverse side effects, such as nausea, vomiting, and itching, to the risk of respiratory depression.^3,4 Consequently, the current management of pain management focuses on reducing the side effects of opioids and providing more effective pain relief therapy, which is expected to increase patient satisfaction. One pain management is preemptive analgesics, which is the administration of analgesic drugs before surgery to prevent central sensitization.

Several studies have been conducted to determine the effectiveness of preemptive analgesic management of various drugs, such as non-steroidal analgesic drugs (NSAIDs), which are non-opioid analgesics.^5,6,7 NSAIDs limit the cyclooxygenase enzyme, which inhibits the synthesis of prostaglandins. Here, ketorolac is a nonselective NSAID for moderate to severe pain and has analgesic, anti-inflammatory, and antipyretic effects. In addition, the effect of ketorolac is longer lasting than other NSAIDs and has both enteral and parenteral preparations. It makes ketorolac a desirable choice for postoperative pain management.^8,9

Paracetamol is also a non-opioid drug, similar to NSAIDs, but its mechanism of action is not known with certainty. The mode of action of paracetamol is to inhibit prostaglandin synthesis by cyclooxygenases 1 and 2. In recent studies, paracetamol inhibits peripheral prostaglandin synthesis and acts on serotonergic derived pathways and spinal 5-HT receptors to prevent central nociception.¹⁰ The analgesic effect of paracetamol is also lower than that of NSAIDs, but paracetamol has fewer side effects than NSAIDs and can quickly reach the highest concentrations in the cerebrospinal fluid, which is essential for its analgesic effect.¹¹

Furthermore, ketorolac and paracetamol are often used for postoperative pain therapy. However, clinical trials comparing the effect of ketorolac and paracetamol preemptive management on the amount of opioid consumption required postoperatively are limited, and some results are contradictory.^12,13 For this reason, this study aims to compare ketorolac and paracetamol preemptive management in reducing the postoperative pain level scale and the consumption of opioid drugs (tramadol). This study was also conducted to determine the side effects and the level of patient satisfaction during postoperative recovery.

After obtaining approval from the Research Ethics Committee at the Muhammadiyah Babat Hospital and the consent of the patient or family to participate in the study, 60 patients (15 males and 45 females) were included in this study. Patients were aged 20 to 65 years, and on physical examination, they have declared American Society of Anesthesiologists (ASA) 1 or 2. Then, the study did not include patients with a history of allergic reactions to NSAIDs, malignancy, bronchial asthma, or other chronic diseases, such as heart, lung, nerve, kidney, liver, or blood disorders.

Patients were randomized into three groups: ketorolac, paracetamol, and control. Each group consisted of 20 patients. The ketorolac group received a 30 mg intravenous dose of ketorolac; the paracetamol group received a dose of paracetamol 1000 mg intravenously; the control group received 0.9% NaCl as a placebo. All drugs were administered via drip infusion of 0.9% NaCl 100ml with a duration of 30 minutes and completed 30 minutes before surgery.

ECG lead II monitoring, blood pressure, oximetry, and capnography were monitored during the operation duration. For induction of anesthesia, propofol at a dose of 1.5 mg/kg, atracurium at a dose of 0.1 mg/kg, and fentanyl at a dose of 1.5 mcg/kg, inhalation anesthetic by titrating 1-2% sevoflurane, in a 50:50 mixture of nitrous oxide and oxygen were all given. At the end of the operation, atropine injection at a dose of 0.01 mg/kg and neostigmine injection at a dose of 0.04 mg/kg were all administered to reverse residual muscle relaxation. All patients were also given an intravenous injection of metoclopramide at a dose of 10 mg as a prophylactic antiemetic. After extubation, the patients were transferred from the operating room to the recovery room. The patients would be given tramadol (titrated dose 1-2 mg/kg diluted with 100ml NaCl 0.9%) when the patients' VAS scores were more than equal to 3. In addition, VAS scores and adverse events, such as nausea, vomiting, respiratory failure, and magnitude of tramadol administration, were recorded at 20 minutes, 1 hour, 2 hours, 8 hours, 12 hours, and 24 hours postoperatively. Postoperative patient satisfaction was also assessed on a Likert scale, consisting of 1 = poor; 2 = enough; 3 = good; 4 = very good; 5 = excellent. The patient's pain level was then assessed using the VAS score. Grade 0 means no pain to 10, which means the worst pain.

Then, before being analyzed, the data were entered, edited, and tabulated utilizing SPSS version 25. The statistical analysis test in this study used an unpaired numerical comparative hypothesis test for more than two groups. One-Way ANOVA test would be used when the data distribution was normal. On the other hand, if the data distribution were not normal, the Kruskal-Walli’s test would be used. In addition, the normality test of this study employed the Kolmogorov-Smirnov test. Meanwhile, the statistical analysis test on postoperative tramadol consumption in the ketorolac and the paracetamol groups used an unpaired numerical comparative hypothesis test in two groups. It would be carried out with an unpaired T-test if the data distribution was normal, while it would be conducted with the Mann-Whitney test if the data distribution was not normal. 

After statistical tests were performed, in Table 1, data were obtained that for the variables of age, height, weight, surgery duration, and anesthesia duration, p>0.05 was found, so there was no statistically significant difference. Then, Table 2 shows the types of operations from the three study groups. Types of surgery included head and neck surgery, digestive, orthopedic, and general surgery. In addition, the number of samples for each group was 20 patients.

In Table 3, the control group had the highest mean VAS score at 20 min (M ± SD: 4.2 ± 1.07 minutes). This result was clinically higher than the paracetamol group (3.8 ± 1.18 minutes) and the ketorolac group (3.1 ± 0.59 minutes). However, it was found that the value of p = 0.90. Thus, it can be concluded that there was no statistically significant difference. Furthermore, in Table 3, it was revealed that the value of the VAS score decreased over time, without statistically significant differences between groups in the measurement period.

Then, in Table 4, it was found that there was a statistically significant difference between the study groups in tramadol consumption, with a p-value of < 0.001. In the control group, the mean postoperative tramadol consumption was the highest at any time. Meanwhile, the ketorolac group consumed more tramadol than the paracetamol group at all times, except at time 1 (20 minutes), but statistically, a significant difference was found (p < 0.05) only at 1 hour (p = 0.048), 2 hours (p = 0.047), and 8 hours (p = 0.040).

Table 5 reveals that the most common side effects experienced by patients were nausea and vomiting. Meanwhile, no side effects of gastrointestinal bleeding were found.

Furthermore, in Table 6, the postoperative patient satisfaction scores were uncovered to be similar for all groups. In the ketorolac group, 55% were found to be "excellent" and 50% in the paracetamol group, while only 35% of patients in the control group scored "excellent."

Table 1: Characteristics of patients undergoing surgery

Data are expressed as mean ± standard deviation.

Table 2: Characteristics of various operations

Data are expressed as the number of patients (%).

Table 3: Postoperative visual analog scale (VAS) scores

Data are expressed as mean ± standard deviation.

Table 4: Postoperative tramadol consumption

Data are expressed as mean ± standard deviation.

* is p < 0.001 compared to other groups; † is p < 0.05 compared to the paracetamol group.

Table 5: Postoperative side effects

Data are expressed in the number of patients (%). GIS = Digestive system.

Table 6: Postoperative satisfaction level of patients

Data are expressed as the number of patients (%).

This study showed that postoperative patients who had been given preemptive management of paracetamol or ketorolac significantly reduced postoperative opioid consumption in the first 24 hours compared to the control group. Many researchers have previously investigated preemptive analgesic management since Crile first proposed this concept.¹⁵ Preemptive analgesics can reduce pain in postoperative conditions, which is supported by previous experimental and clinical studies, but there has been no conclusive evidence for selecting the ideal drug that should be used.¹⁶ Currently, NSAIDs and paracetamol are still the most widely used analgesics for the treatment of pain, and the preemptive use of these drugs is effective in reducing pain, reducing opioid consumption, and lowering postoperative patient VAS scores ^14,17,18,19

A previous study uncovered that preemptive management of ketorolac reduced postoperative VAS scores compared to the placebo group. In addition, another study on the preemptive management of paracetamol in patients undergoing laparoscopic surgery showed a decrease in pain scale in the early phase of postoperative recovery compared to the placebo group.^14,20 In this study, statistically no significant difference in VAS scores was found in the paracetamol, ketorolac, or control groups. This difference could be due to differences in postoperative pain management methods. However, the main aim of this study was to reduce opioid consumption in postoperative patients. 

In this study, significant results were also obtained that the highest need for tramadol consumption was found in the control group and occurred at any time. The ketorolac group consumed more tramadol than the paracetamol group at each time interval, except for the 1st time. It aligns with the study of Guner et al., who stated that using paracetamol with tramadol could reduce the need for opioids after major abdominal surgery.²¹ Another study also found that giving paracetamol intravenously had the effect of reducing the consumption of opioids use by 24-46% of the opioid requirement that should have been.²²

In general, the mechanism of action of paracetamol is known to act centrally, but recent research has shown that paracetamol can act on both central and peripheral cyclooxygenase enzymes. This mode of action makes paracetamol preferred for treating postoperative pain over NSAIDs. Common side effects of NSAIDs are gastrointestinal bleeding and kidney failure.²³ Yet, data comparing the effectiveness of paracetamol and ketorolac in postoperative pain management are scant, and results vary.

In a study by Fatemeh et al., ketorolac was more effective than paracetamol for managing postoperative CABG pain.²⁴ In addition, ketorolac may reduce the need for additional postoperative analgesics compared to paracetamol. Ketorolac is also fully absorbed after reaching peak plasma concentrations within 2.5 hours, and there is no significant difference in analgesic efficacy with oral, intramuscular, and intravenous administration.^8,25 Other studies have also found that paracetamol must undergo metabolism in the liver first so that oral paracetamol absorption is slower and unpredictable. The estimated bioavailability of oral paracetamol is between 63% and 89% in adults, whereas intravenous administration provides a more predictable initial plasma paracetamol concentration.^26,27

Another objective of this study was to determine whether preemptive management of paracetamol and ketorolac could increase patient satisfaction postoperatively. It was found that all groups had a prominent level of satisfaction. These results might be based on the relationship of patient satisfaction with postoperative pain.²⁸ The same VAS score gave the same patient satisfaction in all groups.

Meanwhile, the weaknesses in this study included the limited time of sample measurement and the sample size. The researchers measured VAS scores only in the early postoperative period at 20 minutes and then at five other times in the early 24 hours postoperatively. As a result, several episodes of high-grade pain might be missed. In addition, the relatively small sample size might influence the statistical differences in the study results. Hence, the researchers' suggestion for future research is for larger sample size coverage and better assessment of postoperative pain scale scores. This study can also be continued with future studies with different drug variants and larger sample sizes to obtain an advantageous effect for patients, and various preemptive analgesic management options can be considered for patients. 

In this study, it can be concluded that preemptive management of ketorolac and paracetamol could reduce postoperative opioid consumption compared to the placebo group. Thus, both drugs may be a viable alternative for postoperative pain treatment to avoid the side effects of opioid drugs.

Conflict of Interest: No

Funding: No funding sources

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