Abstract
Aims
To assess preemptive analgesic efficacy of oral ketorolac with submucous placebo versus oral ketorolac with submucous tramadol during impacted mandibular third molar surgery.
Methodology
A double-blind, split-mouth clinical study was carried on 40 patients having bilateral impacted mandibular third molars. They were divided as group A comprising of 40 patients in whom oral ketorolac with submucous tramadol was administered and group B comprising of 40 patients in whom oral ketorolac with submucous placebo was administered. The study parameters included were pain intensity scores, duration to take 1st rescue analgesia, need of analgesic intake during the first 24 h postoperatively and patient’s experience.
Results
The patient’s experience was found to be better in the group A as compared to group B while evaluating mean pain intensity scores (VRS, VAS); need of postoperative analgesics and drug-related complications.
Conclusion
Preemptive oral ketorolac with tramadol in comparison to oral ketorolac results in better pain relief, longer pain free intervals with minimum rescue analgesics requirement & lesser postoperative analgesics consumption.
Keywords: Impacted third molars, Ketorolac, Preemptive analgesics
Introduction
Surgical extraction of impacted mandibular third molar is the most common minor surgical procedure which involves mild to moderate trauma to bone, periosteum and muscles causing postoperative algesia, edema and trismus. This postoperative pain-induced anxiety makes the patient more apprehensive by altering the harmony between circulatory and endocrine system [1, 2]. The literature advocated numerous drugs in various combinations via different routes to achieve acceptable analgesia with minimum side effects. [3–6] Among the various modalities used, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are most preferred due to their ease in availability and high patient’s compliance rate. However, it presents with a range of side effects, the commonest being are gastrointestinal [7, 8]. Hence arises, the requirement of a new strategy which efficiently reduces postoperative pain with reduction in frequency of intake of NSAIDs in addition to reducing the adverse effects [9, 10].
Crile noted that by inhibiting the pain transmission before giving surgical incision using preemptive analgesia, we can reduce the postoperative mortality as it prevents our central nervous system to become hyper-excitable to afferent inputs [11, 12]. Therefore, it enhances effective pain management with the minimum need of analgesic requirements postoperatively [13, 14]. Ketorolac (NSAIDs) is a potent analgesic with rapid onset of action, good oral bioavailability, short duration of action in addition to causing minimal gastrointestinal side effects [7, 15].
Tramadol is an opioid analgesic (synthetic codeine) whose efficacy for mild to moderate pain was found comparable to morphine. It shows 100% bioavailability on intramuscular administration. But, its primary metabolite, O-demethylated is two to four times more potent than the parent drug and is responsible for its analgesic effect [7, 16, 17]. This study is conducted to assess preemptive analgesic efficacy of oral ketorolac with submucous placebo versus oral ketorolac with submucous tramadol during impacted mandibular third molar surgery.
Methodology
In 40 patients belonging to the age group of 18–30 years, a double-blind, split-mouth placebo-controlled clinical study was conducted after getting approval of the institutional ethical committee. All patients who required surgical removal of identical bilateral mandibular third molars, during January 2015 to October 2016 were included. All patients with ASA grade I category, having an asymptomatic bilateral identical impacted mandibular third molars along with grade II or III difficulty of extraction were included. Following thorough case history, hematological and radiographic examination was performed for all patients who satisfied the inclusion criteria. Written informed consent was taken.
Those patients were excluded who failed to give written informed consent for the study, having uncontrolled diabetes, peptic ulcers, Gastro-esophageal reflux disorder (GERD), autoimmune disease, lactation or pregnant, under oral contraceptive use, acute infections, history of seizure disorder, respiratory disorders, impaired renal or hepatic function, had taken analgesic 24 h prior to the surgical procedure and known allergy to the drugs used in this study.
The patients were randomly divided into two groups. Each patient was tested for allergy to mixture of tramadol + 2% lignocaine through subcutaneous injection of test dose of 0.02–0.05 ml under standard observation technique, a wheal reaction of > 3 mm would be considered hypersensitive and excluded from the study. All patients are advised to undergo impaction surgery on two separate visits with a refractory period of 1 month. They were given preemptive analgesics 30 min before surgery, {tramadol or a placebo (normal saline) are administered in the same area using an insulin syringe} as per their groups as follows: GROUP A: oral ketorolac 10 mg with submucous local tramadol 50 mg (1 ml solution).GROUP B: oral ketorolac 10 mg with submucous local placebo (1 ml saline solution). In every patient one side belonged to Group A and the other side belonged to Group B. (Figs. 3, 4).
All surgical cases was done out by the single same operator and postoperative parameters were assessed by another investigator.
After giving local anesthesia (2% Lignocaine with 1:80,000 adrenaline) study drugs were administered in the same area using an insulin syringe.
Fig. 3.
Graph 3 showing complications in both the groups
Fig. 4.
Graph 4 showing comparison of overall assessment between the two groups
After achieving adequate local anesthesia, incision was given and following mucoperiosteal flap reflection, distobuccal bone guttering with rotary cutting instruments under copious saline irrigation was done. Once tooth was removed, smoothing of bone margins, wound toilet of extraction socket with betadine and normal saline was done. After achieving homeostasis, primary closure was done using 3–0 black braided silk suture.
Intraoperatively, time from giving incision to final suturing was recorded. Following which immediate postoperative medications and instructions was given to the patient. The patients were given four oral ketorolac (10 mg) tablets and were advised to have one tablet as rescue analgesic and should be taken at 6 h interval only if needed.
An evaluation format was given to each patient and explained in their vernacular language about the markings on the self-analysis pain performa, to document the time of taking the first ketorolac after the surgery and also to mention the total number of analgesic ketorolac 10 mg consumed in the next 24 h. They were also asked to note any postoperative complications like nausea; vomiting; headache; dizziness; pain on injection of tramadol/saline; erthyema; itching or other.
After assessment period of 24 h postoperative, the patients had to return the unused ketorolac. The number of consumed tablets was counted and noted. On the evening of operative day, all the patients were evaluated for any adverse events or symptoms, either from medications or surgical procedures. Double blinding was done with the patient and the investigator.
All patients recalled after 24 h to assess self assessment Performa and for noting any local complications due to the surgical procedure. The self analysis sheets will be assessed and confirmed verbally. Pain scale will be evaluated according to visual analog scale and verbal response scale at 1st hour, 2nd hour, 3rd hour, 4th hour, 6th hour and at 12th hour postoperatively. After a week, suture removal was done.
Results
For the statistical analysis of the data, the SPSS version 16.0 was employed. Frequency distribution and Chi-square tests at 95% confidence interval were calculated for analyzing the results. Z test, unpaired t test to find difference between two means, χ2 Chi-square test for comparison of qualitative data between the groups were used.
Demographic features and other variables were found to be similar among both the groups (Tables 1, 2). The postoperative pain intensity scores according to Verbral Response Scale (VRS) Table 3, Fig. 1. The patients experienced significantly lower pain intensity scores from 1st to 12th postoperative hours with oral ketorolac plus local tramadol in group A as compared to group B of oral ketorolac plus local saline as placebo. (Table 3, Fig. 1)
Table 1.
Age and genderwise distribution of patients
| Age | Male | Female | Total | Z value | P value and significance | |||
|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | |||
| ≤ 20 | 10 | 41.7 | 6 | 37.5 | 16 | 40.0 | Z = 0.46 | P > 0.05, not significant |
| 21–25 | 10 | 41.7 | 9 | 56.2 | 19 | 47.5 | ||
| 26–30 | 4 | 16.6 | 1 | 6.3 | 5 | 12.5 | ||
| Total | 24 | 100.0 | 16 | 100.0 | 40 | 100.0 | ||
| Mean ± SD | 22.30 ± 3.2 | 21.86 ± 3.1 | 22.10 ± 3.15 | |||||
There is no statistical significance difference of age among males and females
Table 2.
Duration of surgery
| Duration of surgery in minutes | Group A | Group B | Total | Z value | P value and significance | |||
|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | |||
| 15–20 | 8 | 41.7 | 7 | 37.5 | 15 | 40.0 | Z = 0.43 | P > 0.05, not significant |
| 21–25 | 3 | 41.7 | 5 | 56.2 | 5 | 47.5 | ||
| 26–30 | 10 | 16.6 | 10 | 6.3 | 20 | 12.5 | ||
| 31–35 | 5 | 100.0 | 2 | 100.0 | 7 | 100.0 | ||
| 36–40 | 6 | 100.0 | 8 | 100.0 | 14 | 100.0 | ||
| > 40 | 8 | 16.6 | 8 | 6.3 | 16 | 12.5 | ||
| Total | 40 | 100.0 | 40 | 100.0 | 80 | 100.0 | ||
| Mean ± SD | 32.15 ± 10.73 | 33.25 ± 10.25 | 32.70 ± 10.48 | |||||
There is no statistical significance difference of duration of surgery in group A and group B
Table 3.
Comparison of mean pain intensity between the groups using VRS
| Time period | Group A | Group B | t test values | P value & significant |
|---|---|---|---|---|
| Mean ± SD | Mean ± SD | |||
| 1st hour | 0.8 ± 0.46 | 1.0 ± 0.22 | t = 2.45 | P = 0.017, S |
| 2nd hour | 1.0 ± 0.22 | 1.17 ± 0.44 | t = 2.23 | P = 0.030 S |
| 3rd hour | 1.47 ± 0.55 | 1.92 ± 0.57 | t = 3.57 | P = 0.001 HS |
| 4th hour | 2.17 ± 0.54 | 2.62 ± 0.54 | t = 3.69 | P = 0.000 HS |
| 6th hour | 2.57 ± 0.50 | 2.25 ± 0.49 | t = 2.92 | P = 0.005 S |
| 12th hour | 2.27 ± 0.45 | 2.57 ± 0.50 | t = 2.82 | P = 0.006 S |
| 24th hour | 2.2 ± 0.40 | 2.3 ± 0.46 | t = 1.02 | P = 0.308 NS |
S significant, NS not significant, HS highly significant
Fig. 1.
Graph 1 showing comparison of mean pain intensity between the two groups
According to Visual Analog Scale (VAS), both the groups had nearly equal effect for up to 2 h postoperatively. But, at 3rd hour, highly significant pain relief was noted which gradually persists to give a significant pain relief at hours 3rd, 4th, 6th postoperatively. (Table 4). It means that patients reported a significantly lower pain intensity scores at hours 3rd, 4th, 6th postoperatively in group A as compared to group B.
Table 4.
Comparison of mean pain intensity between the groups using VAS
| Time period | Group A | Group B | t test values | P value & significant |
|---|---|---|---|---|
| Mean ± SD | Mean ± SD | |||
| 1st hour | 2.12 ± 0.33 | 2.12 ± 0.33 | t = 0.04 | P > 0.05, P = 0.961 NS |
| 2nd hour | 2.71 ± 0.52 | 2.90 ± 0.80 | t = 1.36 | P > 0.05, P = 0.157 NS |
| 3rd hour | 3.48 ± 1.07 | 4.59 ± 1.32 | t = −3.818 | P < 0.001, P = 0.000 HS |
| 4th hour | 5.45 ± 1.62 | 6.50 ± 1.25 | t = − 2.76 | P < 0.05, P = 0.012 S |
| 6th hour | 6.35 ± 1.57 | 5.35 ± 1.40 | t = 2.278 | P < 0.05, P = 0.024 S |
| 12th hour | 5.45 ± 1.21 | 6.15 ± 1.20 | t = 0.687 | P < 0.05, P = 0.494 NS |
| 24th hour | 5.22 ± 0.71 | 5.59 ± 1.02 | t = − 1.54 | P > 0.05, P = 0.085 NS |
S significant, NS not significant, HS highly significant
The pain-free interval was found to be significantly longer in the group A (6.96 ± 1.47 h) (highly significant P < 0.001) as compared to group B (4.59 ± 0.99 h) as assessed by mean time to take first rescue analgesic. (Fig. 2)
Fig. 2.
Graph 2 showing comparison of mean time of first dose of rescue analgesia between the groups
When total number of analgesic consumed in first 24 h postoperatively were compared, a highly significant difference (P < 0.001) was noticed with mean 1.29 ± 0.45 and 2.53 ± 0.66 for group A and group B, respectively. This suggests that use of combination of analgesics (ketorolac + tramadol) as preemptive analgesics proved better than use of single analgesic (ketorolac) and needs less consumption of analgesics postoperatively. (Table 5).
Table 5.
Comparison of number of total analgesics consumed in 24 h postoperatively between the groups
| No. of doses | Group A | Group B | ||
|---|---|---|---|---|
| No of cases | % | No of cases | % | |
| 1 | 28 | 70.0 | 0 | 0.0 |
| 2 | 11 | 27.5 | 22 | 55.0 |
| 3 | 1 | 2.5 | 14 | 35.0 |
| 4 | 0 | 0.0 | 4 | 10.0 |
| Total | 40 | 100.0 | 40 | 100.0 |
There is statistically highly significance difference of total analgesics consumed in 24 h PO between the groups
χ2 = 21.36 P < 0.001 very highly significant
Complications like headache; nausea; vomiting; local changes like itching, pain at injection site if experienced by the patient were recorded. Headache were noticed in 5 patients of group A (12.5%) and in only one patient of group B (2.5%). Whereas, 8 patients (20%) after injecting tramadol complains of nausea and 3 patients (7.5%) reported vomiting. They were prescribed antiemetic in group A. Only 5 patients (12.5%) of group A had compliant of local reactions like pain at injection site and 3 patients (7.5%) reported itching on tramadol injection as compared to none of local reactions noted in group B. (Fig. 3).
Global assessment shows patients of group A, on 32 occasions of oral ketorolac with local tramadol treatment and patients of group B, on 9 occasions of oral ketorolac with local saline rated the overall surgical procedure as good. (Fig. 4) There was statistically highly significance difference of global assessment experienced between the groups (P < 0.001).
Discussion
Preemptive analgesia is an anti-nociceptive therapy to block transmission of altered central processing of afferent inputs from preoperative or intraoperative injuries (central desensitization) which causes pain enhancement in postoperative period. To attain its maximum effectiveness, establishing an optimum level of analgesia before, during and after injury period is necessary to reduce central sensitization during inflammation [9, 10, 18].
Based on the intensity and severity of pain, a specific analgesic drug can be chosen. The opioid and non-opioid (NSAIDs) analgesic drugs mostly selected for moderate to severe type of dental pain. Whereas, on reviewing literature, it had been shown that the combined usage of drugs having different modes of action like morphine, meperidine with NSAIDs gives more efficacy with even the reduced dose of opioids and increases anti-nociceptive effects [6, 19]. This was also proved in our study by the additive agonism of oral ketorolac with local tramadol, reporting increased pain free duration of 6.96 h postoperatively in group A as compared to 4.59 h in group B where only oral ketorolac was used. Thus, our study supports the synergistic analgesic effective of ketorolac with tramadol as suggested by various authors in the past. [3–5, 14, 15, 20–22].
In our study, the mean pain intensity scores as per Verbal Response Scale (VRS) reported a significant pain relief from 1st to 12th hours postoperatively and according to Visual Analog Scale (VAS), showed a significant pain relief from 3rd to 6th hours postoperatively. It was according to Mario A et al. who noted statistically significant difference in pain intensity score (VAS) measured at 6 h post-surgery between studied groups [23].
The mean time to take first rescue analgesic for group A was found statistically significant with 6.96 h with oral ketorolac along with local tramadol and 4.59 h with oral ketorolac along with local saline as placebo in group B which was found significant clinically as pain after third molar surgery was most severe between 6 and 8 h. This was in contrast to the study by Mario A et al. who reported the mean time to take first rescue analgesic was of approximately 5.13 min for both the groups which was not found statistically significant (P > 0.05) [23].
We found that 3 patient in group A needed no pain medication within 10 h after surgery as compared with all 40 patients from group B. This finding was according to the study by Mario A et al. who reported that only 1 patient in group A needed no analgesic within 12 h postoperatively as compared with 10 patients in group B [23]. This suggests that use of combination of analgesics (ketorolac + tramadol) as preemptive analgesics proved better than use of single analgesic (ketorolac) and needs less consumption of analgesics after surgery.
But in terms of postoperative complications associated with the study drugs, nausea, headache and vomiting are the major adverse effects of tramadol same as suggested by previous studies [19]. In our study, after receiving submucous tramadol, 5 patients (12.5%) complained headache, 8 patients (20%) complained nausea and 3 patients (7.5%) reported vomiting out of which only 3 demanded the rescue antiemetic in group A. Intraoperative complaints like respiratory depression and perspiration on injection of tramadol was not reported in any patient in our clinical trial which was consistent according to previous studies [24]. Local reactions like itching and pain on injection, erythema were also reported with tramadol administration in our study. This was consistent as reported in a meta-analysis on a paracetamol and tramadol combination. [25].
By adapting such analgesic combination and preemptive study design, postoperative quality of the life of patients improves which can be assessed by doing Global assessment. Our study shows that patients of group A, on 32 occasions and patients of group B, on 9 occasions, graded the overall patients satisfaction as good which was found to be consistent with the previous studies [26, 27]. Few studies advocated that submucosal tramadol injection during surgical procedure has remarkable effect to reduce postoperative pain and extension of anesthetic duration of articaine [28, 29].
Conclusion
Our clinical trial suggests that preemptive use of oral ketorolac along with local tramadol are better tolerated than ketorolac and can be used as an alternative for the treatment of acute pain following surgical removal of third molars. The patients experienced significantly lower pain intensity scores in the immediate postoperative phase with oral ketorolac plus local tramadol. The results of this study also reveal that the drugs are associated with minimal side affects or local reactions in addition to the need for less number of analgesics consumed in first 24 h postoperatively providing a good patient compliance. Hence, it can be concluded that preemptive oral ketorolac with tramadol in comparison with oral ketorolac results in better pain relief, longer pain free intervals with minimum rescue analgesics requirement & lesser postoperative analgesics consumption.
Funding
Self funded.
Compliance with Ethical Standards
Conflict of interest
None.
Ethical Approval
Institutional ethical clearance taken.
Informed Consent
Patient consents taken.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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