Introduction

An impacted tooth refers to a tooth's partial or complete failure to erupt into its normal position. The surgical procedure known as odontectomy is employed to extract impacted teeth. Odontectomy is the most common type of oral and maxillofacial surgery [1-3]. Painful inflammation is experienced by over a third of postoperative patients, and the severity of pain can vary from mild to severe following an odontectomy. The level of pain increases proportionally with the number of teeth removed during the odontectomy procedure, eventually reaching moderate to severe levels. Pain ranges from mild to severe for 40% and 60% of patients [4]. The cyclooxygenase (COX) pathway is activated, which results in a rise in prostaglandin levels at the site of injury, resulting in these clinical signs and symptoms of local inflammation [5-7]. The most common postoperative complications are edema, pain, and trismus [1, 8]. Proinflammatory cytokines like tumor necrosis factor-alpha (TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6) are associated with the pathophysiology of pain and inflammation [1]. IL-6 is one of the earliest known cytokines; it controls and stimulates the synthesis of acute-phase proteins by hepatocytes in response to painful stimuli [9, 10]. IL-6 levels typically rise within 1-3 hours following surgical inflammation, peak between 4 and 24 hours later, remain elevated for 48-72 hours, and continue to increase for up to 10 days. It also serves as a marker that best represents the severity of tissue injury. The intensity level of IL-6 rises with surgical trauma [11-13]. Multimodal analgesia is recommended in guidelines for treating acute pain because it can increase analgesia and achieve benefits in low dosage, potentially reducing the side effects risk [3, 9, 14]. Multimodal analgesia uses several pharmacological analgesic drugs that target different receptors along pathways [15-19]. Multimodal analgesia may reduce postoperative pain intensity, decrease hospital stays, and reduce the likelihood of developing persistent postoperative pain [20-22]. The primary effects of paracetamol include the inhibition of prostaglandins and central and peripheral cyclooxygenase enzymes. Ibuprofen primarily affects the transduction stage by inhibiting the production of prostaglandins through cyclooxygenase and other inflammatory mediators. This impact makes pain-processing barriers more potent than they would be after a single use [4]. Research conducted by Atkinson et al. in New Zealand, involving 159 patients treated with a combination of paracetamol and ibuprofen at various doses, compared to a placebo, demonstrated that all doses of the analgesic combination had a more potent analgesic effect than a single analgesic [23]. This finding is consistent with Daniels' research, which revealed that the ibuprofen/paracetamol combination produced significantly superior analgesic effects compared to ibuprofen or paracetamol alone in patients experiencing severe postoperative pain following an impacted third molar odontectomy [24].

Recent studies have focused on the use of intravenous ibuprofen to alleviate pain after odontectomy. However, there is no consensus regarding its clinical application [2]. Tablet formulations are less efficient than intravenous ones due to their longer time to reach peak plasma concentrations [3]. According to a comprehensive study, the combination of ibuprofen 400 mg and paracetamol 1,000 mg has a Number Needed to Treat (NNT) of 1.5 to achieve a 50% or greater reduction in postoperative pain intensity [21]. This study aims to compare the reduction in pain intensity and IL-6 levels between multimodal analgesics (intravenous ibuprofen and paracetamol) and a single analgesic (intravenous paracetamol) in post-odontectomy patients.

Materials and Methods

This study constituted a comparative clinical study. Ethical approval for this study was obtained from the ethical committee health research, Unhas Dental Hospital (Approval No.: 0102/PL.09/KEPK FKG-RSGM UNHAS/2022, dated July 27^th, 2022). All procedures of this study adhered to the ethical principles outlined in the 2013 revision of the 1964 Declaration of Helsinki.

Sample

A total of thirty-eight patients who sought treatment at the Oral and Maxillofacial Department of Unhas Dental Hospital and Hasanuddin University Hospital from July to October 2022 and exhibited third molar impactions categorized as medium to difficult according to Pederson's classification were included in this study extracted third molar performed by one dentist. Eligible patients were between 18 and 45 years old, possessed class I or II physical conditions as per the American Society of Anesthesiologists (ASA) criteria, and expressed a willingness to participate in the study. Exclusion criteria encompassed individuals who had taken NSAIDs within 24 hours before surgery, had a Body Mass Index (BMI) exceeding 30, reported allergies to the drugs under investigation, had chronic pain conditions, presented with active third molar infections characterized by swelling, trismus, or purulent discharge, or had tumors surrounding the impacted third molars.

Prior to the surgical procedure, the participants were informed about the research methodology, and written informed consent was obtained from each of them. A preoperative blood sample of up to 1 ml was collected to measure IL-6 levels, and pain assessment was carried out using the Visual Analog Scale (VAS) pain scale rulers, ranging from 0 to 100 mm. To quantify IL-6 levels in serum, the Enzyme-Linked Immunosorbent Assay method was employed, utilizing the Quantikine HS Human IL-6 Immunoassay, and readings were taken using the ELISA Reader Organon 680 (Biorad) at a wavelength of 640 or 690 nm.

A one-hour surgical procedure was performed, involving the removal of three to four impacted third molars, under general anesthesia. Two treatment groups were randomly assigned to the study sample: Group A, which received IV ibuprofen 400 mg (Peinlos) in combination with IV paracetamol 1,000 mg (Paracetamol; Quantum Laboratories), and Group B, which received IV paracetamol 1,000 mg (Paracetamol; Quantum Laboratories) immediately after the completion of the operation. VAS scores were reassessed at 2, 8, 16, and 24 hours following the surgery. In addition, IL-6 levels were measured 24 hours post-surgery.

The VAS values were categorized into four groups: no pain (0-4 mm), mild pain (5-44 mm), moderate pain (45-74 mm), and severe pain (75-100 mm) [25]. The duration of hospitalization was set at three days. The first day was designated for surgical preparation, the second day for the surgical procedure, and the third day for postoperative care. Afterwards, patients continued as outpatients.

Data processing

Data processing was conducted utilizing SPSS version 27. To assess the normality of the data distribution, the Kolmogorov-Smirnov test was employed. If the data distribution was found to be normal, a parametric Independent Sample T-test was performed. In contrast, if the data distribution was non-normal, the Mann-Whitney and Wilcoxon non-parametric tests were employed. Significance was considered at a level of P < 0.05. The processed data was presented in the form of tables and diagrams.

Results and Discussion

The study involved 38 participants, with an average age of 22 years in group A and 25 years in group B. There are 19 male and 19 female participants distributed between 2 groups. The average BMI was 23 in group A and 22 in group B, as presented in Tables 1 and 2. Tables 1 and 2 inidcate no statistically significant differences between groups A and B concerning gender, age, BMI, or the number of teeth removed (P > 0.05). In other words, both groups can be considered homogeneous.

The mean VAS scores for group A increased after 2 hours post-surgery and decreased at 8, 16, and 24 hours post-surgery. Statistically significant differences (P < 0.05) were observed in pain scores (VAS) at the preoperative assessment and at 2, 8, 16, and 24 hours after surgery.

Group B exhibited similar trends (Table 3). However, there were no significant differences in pain scores (VAS) between the two groups at 2, 8, 16, and 24 hours after surgery (P > 0.05) (Table 4, 5, and Figure 1).

Table 1: Sex distribution in the two groups

Table 2: Distribution in the two groups

Table 3: Number of extracted teeth for each group

Table 4: Comparison of pain scores (VAS) for each time measurement in each group

Figure 1: Comparison of pain scores (VAS) for each time measurement in each group

Table 5: Comparison of pain scores (VAS) between groups at preoperative examination, 2 hours, 8 hours, and 24 hours after surgery

IL-6 levels

In group A, a significant difference in IL-6 levels was observed between the pre-surgery and 24 hours post-surgery (P = 0.009), indicating a notable decrease in IL-6 levels following the administration of the drug combination. However, in group B, no significant difference was noted in IL-6 levels between the pre-surgery and 24 hours post-surgery (P = 0.07), indicating that paracetamol alone did not lead to a significant decrease in IL-6 levels (Table 6). Moreover, significant differences in IL-6 levels were observed both preoperatively (P = 0.001) and 24 hours postoperatively (P = 0.003) between groups A and B (Table 7 and Figure 2).

This study observed an increase in VAS scores two hours following surgery (Group A = 22, Group B = 32) before a subsequent decrease at the eight-hour mark (Group A = 19, Group B = 22). We did not find a significant difference in pain scores (VAS) between the two groups at 2, 8, 16, and 24 hours after surgery. However, it is worth noting that the average VAS score was consistently lower in the combination group compared to the single paracetamol group at all time points. This suggests that the combination group, utilizing multimodal analgesia, continued to provide better pain relief after the third molar odontectomy, even though statistical significance was not achieved (P > 0.05). The lack of significance in the pain parameter (VAS Score) may be due to individual variations in pain perception and several contributing factors.

This finding aligns with a study conducted by Erdi et al., which demonstrated no statistically significant difference between acetaminophen and ibuprofen in terms of reducing abdominal pain, shoulder pain, nausea, vomiting, and the need for fentanyl in patients undergoing elective laparoscopic cholecystectomy surgery. However, a significant difference in pain was observed compared to the control group (normal saline). The timing bias of medication administration and pain score measurement may account for these results [21].

Table 6: Comparison of preoperative and postoperative IL-6 values in each group

Table 7: Comparison of IL-6 values in each group

Figure 2: Comparison of preoperative and postoperative IL-6 levels in each group

Postoperative pain is a subjective experience influenced by a multitude of variables, including age, gender, the type of surgery performed, concurrent medical conditions, as well as psychological factors such as fear, anxiety, and depression. The degree of tissue damage also plays a role in the intensity and duration of postoperative pain [4]. Variations in the extent of tissue damage and the intensity of postoperative pain can be attributed to the duration of the surgical procedure. Another research showed that the benefits obtained are proper pain control, being able to maintain the patient's hemodynamic indicators well and not causing bad effects after surgery. These are the advantages of using intravenous acetaminophen injection in controlling pain after caesarean section with a PCA pump (Bahman et al., 2023). Some researchers showed that the use of Diosmin 500 mg oral tablets can cause a decrease in pain intensity after hemorrhoidectomy (Mansour et al., 2023). In a different case, Kasper et al. reported that among postoperative patients who underwent total hip arthroplasty surgery, the combination of paracetamol 1,000 mg and ibuprofen 400 mg resulted in the lowest morphine consumption and resting pain scores, as well as a reduced risk of nausea at 24 hours following surgery, compared to other combination groups [26]. This finding aligns with Daniel et al., who observed that intravenous ibuprofen 300 mg and acetaminophen 1,000 mg produced a more effective analgesic effect than either drug alone following bunionectomy surgery. The combination group exhibited a quicker onset of analgesia and a longer duration to reach peak pain relief [27]. Akbas et al. found a similar outcome in postoperative lumbar disc patients, where IV ibuprofen significantly reduced VAS scores and cumulative opioid use compared to paracetamol [28]. In a study conducted by Andribert et al. among post-total knee arthroplasty patients, a significant difference in the Numeric Rating Scale (NRS) value for motion was observed when administering the combination of paracetamol and ibuprofen compared to single use [29].

Briggs and Closs emphasize that pain can be influenced by several intrinsic and extrinsic factors and different aspects of pain are assessed in various ways. Pain intensity is subject to the individual's perception, influenced by each person's pain threshold, and can serve as a reference for comparing pain intensities despite the unique nature of pain perception among individuals [30]. The choice of assessing IL-6 levels 24 hours after surgery was based on the observation that IL-6 levels typically peak 24 hours after an operation. Our analysis indicated that the combination group was more effective than the paracetamol-only group in reducing IL-6 levels. This is consistent with findings from Andrew et al., who reported that patients with persistent spinal injuries in the ibuprofen group exhibited IL-6 levels of 3.2 pg/ml compared to 4.0 pg/ml in the control group. James C. et al.'s research, involving high-dose ibuprofen (20-30 mg/kg intravenously, maximum 3200 mg) over 28 days in cystic fibrosis patients, revealed a decrease in IL-6 levels in sputum samples with a mean reduction of 0.13 pg/mL (P = 0.04) [31, 32]. One of the early cytokines, IL-6, regulates and stimulates the production of acute-phase proteins by hepatocytes in response to painful stimuli such as trauma. IL-6 serves as a robust indicator of tissue damage, with the duration of IL-6 presence in the plasma correlating with the severity of postoperative morbidity. A correlation exists between IL-6 levels and the extent of tissue injury and inflammation. For instance, abdominal hysterectomies typically exhibit higher IL-6 levels compared to laparoscopic hysterectomies. Kraychete et al. reported higher IL-6 levels in patients with chronic back pain related to herniated nucleus pulposus [9, 33, 34]. Various inflammatory mediators, such as IL-1b, tumor necrosis factor-alpha (TNF-α), and PGE2, have been demonstrated to stimulate the release of IL-6 in in vitro investigations. IL-6 subsequently triggers the secretion of chemokines such as IL-8 and CCL2. In the context of inflammatory pain, IL-6 can induce short-term prostaglandin (PG)-dependent hyperalgesia while also contributing to local analgesia through the secretion of opioids. The expression of cytokines and chemokines in response to inflammation and tissue injury is a dynamic and multifaceted process. The established mechanism of inflammatory hyperalgesia involves the induction of central sensitization by peripheral inflammation. Recent research suggests that IL-6 serves as a carrier of inflammatory information from the peripheral nervous system to the brain [13, 35].

Cyclooxygenase inhibitors play a role in reducing the production of prostacyclin and prostaglandin, which are associated with edema and hyperalgesia during surgery. By pharmacologically diminishing inflammation, postoperative consequences such as pain, edema, and trismus can be mitigated and rendered less severe [36]. Paracetamol primarily operates at the perceptual stage by inhibiting prostaglandins and central and peripheral cyclooxygenase enzymes. On the other hand, ibuprofen primarily acts at the transduction stage by inhibiting the synthesis of prostaglandins by cyclooxygenase and other inflammatory mediators [4]. In a study by Afif et al., postoperative patients who received a combination of IV Ibuprofen and Paracetamol following sectio secaria observed a decrease in IL-6 levels during the 6^th and 12^th-hour assessments. However, this decrease in IL-6 levels was not consistently followed by a reduction in pain as measured on the NRS scale. This observation can be explained by the subjective nature of pain perception, which is significantly influenced by numerous factors. Consequently, each individual interprets and perceives the NRS value uniquely [9].

Therefore, in this study, we suggest that IL-6 assessment may be a more appropriate method for evaluating the effectiveness of drugs in reducing pain following odontectomy surgery. Several findings support the notion that IL-6 has a modulating effect on nociception and pain in humans. IL-6 enters the systemic circulation, and its concentration is correlated with the surgical severity. The limitation of this study was the variation in the extent of postoperative trauma among samples due to differences in the total number of impacted teeth. In addition, IL-6 levels were not assessed at 1 hour postoperatively, making it difficult to determine the baseline levels of increased IL-6. Therefore, future studies should replicate the same sample and assess IL-6 levels at various time points postoperatively to further elucidate the relationship between IL-6 and postoperative pain. Besides, we did not make comparison among combination IV paracetamol + IV Ibuprofen and single IV Ibuprofen because need more sample and will need more funding and time for the research.   

Conclusion

The combination of intravenous Ibuprofen and Paracetamol has demonstrated its effectiveness in reducing the proinflammatory factor IL-6 in patients undergoing third molar odontectomy, which is likely to translate into lower pain scores. We recommend considering Paracetamol and Ibuprofen as viable analgesic options for third molar odontectomy surgery. Future research should further assess the efficacy of Paracetamol and Ibuprofen when administered through various routes and in the context of different surgical procedures.

Acknowledgements

We would like to express our gratitude to the Hasanuddin University Research and Community Service Institute (LPPM) for providing funding for this study under grant number No. 1477/UN4.22/PT.01.03/2022. We also extend our heartfelt appreciation to all the staff of the Department of Oral and Maxillofacial Surgery at Hasanuddin University, Hasanuddin University Hospital, and Unhas Dental Hospital for their valuable advice and unwavering support throughout the course of this study. 

ORCID

Mohammad Gazali

https://orcid.org/0009-0006-9839-8361

Hadira

https://orcid.org/0009-0003-5043-0789

Ahmad Nur Islam

https://orcid.org/0009-0009-9002-6952

Nilawati

https://orcid.org/0000-0003-2184-4985

HOW TO CITE THIS ARTICLE

Mohammad Gazali, Hadira, Ahmad Nur Islam, Nilawati, Effectiveness of Combination Intravenous Ibuprofen and Paracetamol on the Quality of Analgesia after a Third Molar Odontectomy – A Comparative Study. J. Med. Chem. Sci., 2024, 7(5) 670-680.

DOI: https://doi.org/10.26655/JMCHEMSCI.2024.5.3

URL: https://www.jmchemsci.com/article_190502.html