Pain Control Following Impacted Mandibular Third Molar Surgery: A Comparison of the Effectiveness of Two Different Protocols

doi:10.21203/rs.3.rs-4674620/v1

The Use of multimodal analgesia is a common practice in clinical settings, where a combination of drugs with different mechanisms of action is used to enhance the effectiveness of an analgesic and reduce its adverse effects. This study, which aimed to compare the efficacy of concurrent ibuprofen and paracetamol with alternate administration in the management of postoperative pain after the surgical removal of impacted mandibular third molars, has yielded significant findings with practical implications. A single-center, double-masked, parallel-group, randomized controlled clinical trial involved 56 patients undergoing scheduled surgical extraction of impacted mandibular third molars. Patients were randomly assigned to either Group A (Control), where they were instructed to take one tablet of ibuprofen 400 mg and two tablets of paracetamol 500 mg together every 8 hours for 48 hours, or Group B (Study), where they were instructed to take one tablet of ibuprofen 400 mg and two tablets of paracetamol 500 mg alternatively every 4 hours for 48 hours. The primary outcome measure was the intensity of postoperative pain, which was evaluated using a Visual Analogue Scale (VAS) ranging from 0 to 10. The secondary outcome measure was the timing of the onset of the analgesic effect, the duration of pain relief, the frequency of rescue drug administration, and the time interval between taking the recommended medication and the need for rescue medication. Investigators involved in analyzing the patients' responses were blinded to the pain control regime used by the participants. Pain intensity during the first 48 hours after the extractions showed that most participants experienced "some pain," including 50% in Group A and 35.7% in Group B. The percentage of patients reporting "no pain" was higher in group B than in group A, although the difference was not statistically significant (p = 0.495). More than half of the participants (53%) in group A reported needing an extra dose in the 48-hour follow-up period, while 85% in group B reported pain relief (p = 0.002). When correlating the mean pain score to the complexity level, in patients with moderate complexity of extraction, higher pain scores were recorded in group B. The study concludes that administering analgesics alternatively results in more effective pain relief for patients undergoing surgical extractions of the lower third molar, a finding that has practical implications for the management of postoperative pain in oral and maxillofacial surgery. The surgical extraction of the impacted mandibular third molar is the most common procedure in oral and maxillofacial surgery. However, it is often associated with postoperative complications. The most frequent complication following the surgical intervention is pain.

Third molar surgery

Postoperative care

Pain

Ibuprofen

Paracetamol

The use of non-prescription medications such as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and acetaminophen is common worldwide. NSAIDs like ibuprofen, diclofenac, and ketoprofen are effective in managing mild to moderately acute postoperative pain and inflammation. Ibuprofen is the most commonly recommended over-the-counter analgesic for controlling discomfort and pain following impacted third molar surgeries (1, 2). However, high dose and prolonged use of NSAIDs can lead to significant gastrointestinal side effects (3, 4). Acetaminophen, is often prescribed in combination with NSAIDs to enhance pain relief, especially in patients with gastrointestinal issues. While acetaminophen is generally considered safe, exceeding the maximum recommended dose can lead to liver toxicity and even failure (5). Using a combination of drugs with different mechanisms of action, known as multimodal analgesia, aims to improve pain relief while minimizing adverse effects. For example, a combination of ibuprofen and acetaminophen has been reported to provide better pain relief than using acetaminophen alone (3, 6).

Impacted mandibular third molars can cause discomfort, pain, infection, crowding, and damage to adjacent teeth, necessitating their removal to prevent further complications (7). Removal of symptomatic impacted lower third molars is the main definitive treatment option to address problems related to impaction (8, 9). Pain after impacted third molar tooth surgery is common and peaks within 6 to 12 hours after procedure (10). Effective pain control is crucial to prevent chronic pain and ensure the patient's well-being to facilitate recovery and maintain the quality of life. The ideal postoperative agent prescribed following third molar surgery should alleviate pain, reduce swelling and trismus, and should be free from side effects. Although such an ideal analgesic does not exist, the available analgesics may provide adequate pain relief to enable patients to recover uneventfully (11).

The aim of this study was to evaluate the effectiveness of two different protocols of combining acetaminophen and ibuprofen in relieving postoperative pain following extraction of impacted mandibular third molars.

Ethical approval

The study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Ethical approval was received from the University of Sharjah Research Ethics Committee (REC) under reference number REC-23-03-25-01-S. Before taking part in the study, all participants were provided with both verbal and written information about the study's objectives, procedures, potential risks, and benefits. Written informed consent was obtained from each participant. The confidentiality and anonymity of the participants were ensured throughout the study. This trial was registered at ClinicalTrials.gov with the following number: NCT06514222 on 08/07/2024.

.Study Design

This single-center, double-blind, parallel-group, randomized controlled clinical trial was conducted at the University Dental Hospital of the University of Sharjah, involving patients scheduled for impacted mandibular lower third molar surgical extractions.

Study groups

Participants were randomly assigned by a coin toss to one of two groups.

Group A (Control) received one tablet of ibuprofen 400 mg and two tablets of paracetamol 500 mg together every 8 hours for 48 hours.

Group B (Study) received one tablet of ibuprofen 400 mg and two tablets of paracetamol 500 mg alternately every 4 hours for 48 hours.

A validated questionnaire was administered to patients following the surgery to evaluate their post-surgical pain levels and the effectiveness of the medication.

The Surgical Removal Complexity Index

The difficulty of surgically removing impacted lower third molars is evaluated using the widely accepted and extensively researched Pederson difficulty index ¹². According to this index, scores of 3–4 indicate a minimally difficult extraction, often considered easy, while scores of 5–7 suggest a moderately difficult extraction. Scores of 7–10 indicate a difficult extraction. For the purpose of this report, the easy cases were assigned a value of 1, the moderate cases a value of 2, and the difficult cases a value of 3 to facilitate their description.

Inclusion and exclusion criteria

The eligibility criteria for the study included patients who were 18 years or older and were referred to the oral surgery unit at the University Dental Hospital, Sharjah, for surgical extraction of partially impacted lower third molars. Patients classified as ASA I or ASA II, and in need of surgical extraction of at least one impacted lower third molar, were eligible for inclusion if they were not allergic to paracetamol and ibuprofen. Patients who were allergic to either of the drugs, classified as ASA III or above, pregnant or breastfeeding, had consumed antibiotics in the week before the procedure, or had a radiolucency associated with the involved tooth were excluded from the study.

Sample size calculation

The sample size was determined to detect a between-group difference of ≥2 points in the average VAS-pain score over 48 hours, considering this to be a clinically relevant difference, with a confidence interval of 95% and statistical power of 90%, a common standard deviation of 2.5. Patients were consecutively admitted in the study following a scheme of balanced randomization every eight patients (4 patients per group) using a computer-generated randomization sequence to have up to 56 patients after exclusion (fig.1). Each participant was assigned (1:1 ratio) to a random code (A or B).

Data collection

Based on their group, participants were provided envelopes containing pain medication along with written instructions and were asked to complete a questionnaire over 48 hours following a dental extraction. The questionnaire included the following items:

.1. Rate your pain level from 0 to 10 using the VAS scale at 0, 2, 4, 6, 8, 12, 24, 36, and 48 hours after the extraction.

2. Describe the maximum pain experienced (no pain – some pain, noticeable pain, extreme pain) at 48 hours.

3. Average time between taking the trial drug and experiencing pain relief for the first time.

4. Average time between the first report of pain relief and the pain reappearing.

5. Did you need to take any extra doses?

6. If yes, how long did you need the extra dose after taking the recommended medicine?

7. Did you experience any side effects?

8.Would you recommend such medications and timing to others?

Outcome measures

The primary outcome measure was to evaluate the pain intensity, which was addressed by the first two questions. The secondary outcome measures included the time to onset of pain relief, duration of pain relief, time to take additional medication, and any side effects experienced from these medications were obtained from responses to the top listed questions.

The study maintained blinding by ensuring that the evaluators responsible for data collection and analyses were blinded to the analgesic medication regime used by the patients

Data analysis

All responses were processed and interpreted using SPSS software to analyze the means and standard deviations of each parameter. The authors used the Mann-Whitney test because the data was not normally distributed. The VAS readings obtained were categorized as mild, moderate, and severe pain for analysis purposes. Any differences in treatment were considered statistically significant at the P < 0.05 level.

A total of 72 patients actively participated in the assessment and screening to determine their eligibility for participation in the study. Of these, 56 patients met the inclusion criteria and were successfully followed up throughout the study. The baseline characteristics were homogeneous among both interventions (table 1). Gender was relatively distributed in both groups. The age range in years was comparable, with a mean of 32.71 ± 8.615 in group A and 31.57 ± 8.690 in group B. The surgical extraction complexity index was randomly distributed, with the majority having a moderate score (2.07 ± 0.663 in group A Vs. 2.04 ± 0.637 in group B).

The maximum pain level experienced during the 48 hours was measured, with most participants tolerating the pain control regimens well. 50% in group A and 35.7% in group B reported 'some pain '. The percentage of patients reporting 'no pain' was higher in group B than in group A, although the difference was not statistically significant in the current study sample (P=0.495). Both pain control regimens were well tolerated, with only two patients reporting side effects in group A compared to none in group B (p=0.491); the side effects reported were a stomach upset. According to the VAS pain score, group A reported higher pain scores in the 48 hours, with a mean value of 4.93 ± 2.92 compared to 3.75 ± 2.41 in group B. Group B reported less pain at 4 hours (39.3% with moderate-severe pain in group B vs. 50 % in group A; p=0.568), 8 hours (46.5% with moderate-severe pain in group B vs 67.8 in group A; p=0.317), 12 hours (46.4 with moderate-severe pain in group B vs. 50% in group A; p=0.443), 24 hours (32.2% with moderate-severe pain in group B vs. 46.4% in group A; p=0.380), and 36 hours (35.7% with moderate-severe pain in group B vs. 39.2% in group A; p=0.522); however, the difference was not statistically significant at any time of analysis (Figure 2).

Statistical analysis revealed a clear significant difference (P=0.002) in patients who took an extra dose among both groups. This is significant as it suggests that the standard intervention in group B was more effective in providing pain relief without additional medication. In group A, more than half of the patients, 15.3% (53%) reported their need to take an extra dose in the 48-hour follow-up period. In comparison, 85% of patients in group B reported adequate pain relief with the standard intervention without needing any extra dose. Group A and Group B experienced similar onset times for pain relief after the first dose, with mean values of 36.11±18.244 and 38.68 ± 26.789 minutes, respectively. After taking the first dose of medication, pain reappeared at 4 hours and 52 minutes in group A and at 4 hours and 15 minutes in group B. Although not statistically significant (p=0.669), compared to group A, more patients in group B would not like to recommend the medication to other people (only 2 and 4 patients, respectively).

The association between the complexity index and the need for additional dosage was examined, revealing that patients in group A with a moderate index score were more likely to require an extra dose than those with a difficult index score (62.5% vs 42.8%) (figure 3). This suggests that the complexity of the surgical extraction may influence the need for additional pain relief. Similarly, in group B, although the number of patients needing an extra dose was lower, patients with a moderate index score also required an additional dose more often than patients with a difficult index score (94.1% vs 66.6%).

Despite the lack of statistical significance in pain relief levels across the intervals, when the complexity was taken into consideration, the mean intensity of reported pain for patients with moderate complexity in group A was significantly higher (6.31±2.301 vs. 3.65 ± 2.370, p= 0.004) recorded after 8 hours (table 2). This finding underscores the importance of considering the complexity index in pain management. Similarly, at 24 hours, group A had a mean value of 4.19 ± 2.344 compared to group B, with a mean of 2.59 ± 2.717 and a p-value of 0.049 (figure 3).

A variety of regimens are reported for pain control in mandibular third molar surgery using pre-emptive as well as and postoperative analgesics. The concept of multimodal analgesia is commonly used following lower third molar surgical extractions, combinations like ibuprofen and paracetamol may be advantageous as over-the-counter options since they often provide effective pain relief without increasing the dose of individual medications. However, to the best of authors’ knowledge, this is study is a first assessing the effectiveness of alternate medications in the management of post-surgical pain after extraction of impacted mandibular third molars. In this study, patients in both interventions received a total of 3 g of paracetamol and 1.2 g of ibuprofen per day, which is below the maximum recommended dose and is deemed safe (13). Previous studies showsthat patients who received 400 mg ibuprofen +1000 mg acetaminophen had statistically higher pain relief than the patients who received the monotherapy form of each drug in the first 8 hours post operatively (14). In the current study, postoperative pain was managed by combining ibuprofen 400 mg and paracetamol 1000 mg at different time intervals. Ibuprofen 400 mg was selected as it reaches its analgesic ceiling at or around a dosage of 400 mg, regardless of the severity of the pain or the specific type of acute pain being treated (15). Gender and age were similar in both groups, and these factors had no significant impact on the results. The maximum experienced pain for patients receiving the combination of paracetamol and ibuprofen was reported to be more than the alternative group this is contradictory to the results of another study conducted that states that a combination of both medications provides more pain relief than when using each agent separately (16). A single pain control analysis indicated that the highest level of relief was experienced within the first 2 to 3 hours. By combining two agents, the duration of the impact can be prolonged for 6 to 8 hours (9).

Nevertheless, when the two medications are taken together, and their effects start simultaneously, they are likely to diminish similarly. The patient may take an extra dose of the medicine to continue experiencing pain relief. The results showed that “no pain” was reported more in patients who took the medication alternatively. Moreover almost half of the patients who took the medications simultaneously received an extra dose. Few patients in the alternate group required additional doses, compared to the group taking the medications simultaneously and this is mainly attributed to the pharmacokinetics of both drugs, after 4 hours when the drug is metabolized and excreted from the patient’s body, the alternate medication is taken to increase the plasma drug concentration. This finding was comparable to another study done which showed that a significant proportion of patients required rescue medication when using the combined medication approach (16).

Although the correlation between complexity and pain levels appears proportionate, the results of the current study demonstrate that postoperative pain is independent of extraction complexity, as additional analegesic dosages were taken by patients in the moderate level of impaction than severe cases. The uneven distribution of patients across the three difficulty scores could explain this finding. According to several reports, there was no significant association between Pederson scores and postoperative pain, consistent with our investigation's findings (17-19). Therefore, the exact dosages and protocol should probably be implemented regardless of the complexity index. As per the VAS readings, alternating medication regimens resulted in consistently lower pain scores throughout the assessment period. However, discrepancies emerged explicitly at the 0 and 48-hour postoperatively. Assessing pain levels before the patient's initial dose of medication might introduce differences due to the lingering effects of local anesthesia, potentially leading to inaccuracies in pain recordings. Additionally, despite VAS being widely utilized for pain intensity evaluation, its subjective nature persists as a limitation (20, 21).

In our study, pain relief was seen earlier in the combination group, which may be attributed to the fact that two different analgesics are taken simultaneously. Moreover, the return of pain in the group taking alternate medication was consistent with the second dose's timing. In contrast, in the combination group, pain returned an average of three hours before the following drug exposure. However, the average time for pain to return was similar for both groups. These results were consistent with another study that found no discernible difference in the duration of pain relief between the fixed-dose combination and Ibuprofen 400 mg by itself (22,23).

The results showed that patients who received Ibuprofen and Paracetamol concurrently reported a slightly higher frequency of adverse events. Nevertheless, both interventions were well tolerated, and the incidence of adverse effects was notably minimal and aligned with the expected side effects associated with the administered drugs.

This study has several limitations that must be acknowledged to interpret the results accurately. Firstly, the sample size was small and a higher increased sample size may provide a better statistical power. Secondly, the study focused on pain control following surgical removal of impacted mandibular third molars and inclusion of a wider range of dental and oral surgical procedures could provide a more broad-based evaluation of the effectiveness of different analgesic regimens.

In summary, the study revealed the combination of Paracetamol and Ibuprofen is well tolerated and effective option for post operative pain after surgical removal of mandibular third molars. Use of a Paracetamol and Ibuprofen alternatively in the first 48 hours is likely to provide a more effective pain control compared to concurrent use.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author contributions

KG and KA conceived the study. TD,MT,RS and RH, recruited the participants,collected the data and contributed to the manuscript writing up. KG analyzed the data, wrote, revised and submitted the manuscript. KA revised the manuscript. All authors have read and approved the final manuscript.

Competing interests

The authors declare no competing interests.

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Table 1. The characteristics of the participants

Characteristics	Group A Combined medications 8 hrly	Group B Alternate medications 4 hrly

Age (yrs) (mean ± SD)	32.71 ± 8.615	31.57 ± 8.690
Male [n (%)]	15 (53.6)	18 (64.3)
Female [n (%)]	13 (46.4)	10 (35.7)
Complexity index (mean ± SD)	2.07 ± 0.663	2.04 ± 0.637
Easy (1) [n (%)]	5 (17.9)	5 (17.9)
Moderate (2) [n (%)]	16 (57.1)	17 (60.7)
Difficult (3) [n (%)]	7 (25)	6 (21.4)

Table 2. Correlation of previous findings to complexity levels based on Pederson's scale.


Groups			Surgical complexity
Group A (Paracetamol 1000 Mg+ Ibuprofen 400 Mg ) Q8h			Easy		Moderate		Difficult
	Maximum Pain Experienced [N (%)] : (P= 0.086)	No Pain		1 (20%)	-		-
		Some Pain		4 (80%)	6 (37.5%)		4 (57.1%)
		Noticeable Pain		-	6 (37.5%)		3 (42.8 %)
		Extreme Pain		-	4 (25%)		-
	Extra Dose [N(%)] P=0.547			2 (40%)	10 (62.5%)		3 (42.8%)
	Recommend [N (%)] P=0.446			5 (100%)	14 (87.5%)		7 (100%)
	Receive Again [N (%)] P=0.511			4 (80%)	14 (87.5%)		7 (100%)
	Side Effects Reported [N(%)] P=0.624			-		1(6.25%)	1(14.2%)
Group B (Alternative Paracetamol 1000 Mg Then Ibuprofen 400 Mg) Q4H	Maximum Pain Experienced [N (%)] (P= 0.515)	No Pain		1 (20%)		1(5.8%)	-
		Some Pain		2 (40%)		7 (41.1%)	1(16.6%)
		Noticeable Pain		2 (40%)		4 (23.5%)	2(33.3%)
		Extreme Pain		-		5 (29.4%)	3 (50%)
	Extra Dose [N(%)] P=0.236			1 (20%)		1(5.8%)	2(33.3%)
	Recommend [N (%)] P=0.525			4 (80%)		14(82.3%)	6 (100%)
	Receive Again [N (%)] P=0.417			4 (80%)		16(94.1%)	6 (100%)
	Side Effects Reported [N(%)]			-		-	-

No competing interests reported.

Pain Control Following Impacted Mandibular Third Molar Surgery: A Comparison of the Effectiveness of Two Different Protocols

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Abstract

Figures

Introduction

Materials and Methods

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

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