|Year : 2019 | Volume
| Issue : 4 | Page : 503-510
The effect of pregabalin and ibuprofen combination for pain after third molar surgery
A Degirmenci1, E Yalcin2
1 Clinic of Oral Surgery, Çanakkale Oral and Dental Health Center, Çanakkale, Erzurum, Turkey
2 Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Ataturk University, Erzurum, Turkey
|Date of Acceptance||28-Dec-2018|
|Date of Web Publication||11-Apr-2019|
Dr. A Degirmenci
Clinic of Oral Surgery, Çanakkale Oral And Dental Health Center, Çanakkale - 17020
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim: The objective of this study was to compare the efficacy of different doses of pregabalin and intravenous ibuprofen with regard to pain management and analgesic consumption after third molar surgery. Materials and Methods: Ninety patients who had been scheduled for third molar surgery were assigned to four different treatment groups. The inclusion criteria consisted of the presence of fully or partially bony retentive asymptomatic mandibular third molars. These groups are included the following: (Group 1) premedicated with oral placebo and intravenous (IV) placebo, (Group 2) premedicated with oral placebo and 400-mg IV Ibuprofen, (Group 3) premedicated with 75-mg oral pregabalin and 400-mg IV ibuprofen, and (Group 4) premedicated with 150-mg oral pregabalin and 400 mg IV ibuprofen. Postoperative pain was assessed with visual analog scale (VAS) every hour for the first 12 hs following the surgery. Pain was then assessed at different time intervals during 7 days following the surgery. Kruskal–Wallis tests were used to compare the four groups in terms of VAS pain scores, analgesic consumption, and first rescue analgesic request time after the surgery. Results: At the end of the study, the results of 80 patients (20 patients per group) were analyzed. The group 4 had lower pain intensity compared with other groups at various time intervals. This difference is statistically significant in between the first 3–10 h (first day) and single-time intervals in second, third, fifth, and sixth postoperative days. Postoperative analgesic consumption was not statistically different between the groups. The first rescue analgesic request time after surgery was different between the pregabalin combination groups and group 2. No significant difference in the side effects was observed. Conclusion: These findings suggest that preoperative coadministration of 150-mg pregabalin and IV ibuprofen may be useful in improving pain control after third molar surgery.
Keywords: Intravenous ibuprofen, postoperative pain, pregabalin, third molar surgery
|How to cite this article:|
Degirmenci A, Yalcin E. The effect of pregabalin and ibuprofen combination for pain after third molar surgery. Niger J Clin Pract 2019;22:503-10
| Introduction|| |
Pain was reported by 93% of the patients who underwent various oral and maxillofacial surgical procedures. Of those reports, 47% categorized the pain as being moderate and 34% as being severe. Postoperative pain is one of the most common complication of third molar extraction and it poses a great concern to patients given it can affect their quality of life. Both peripheral and central sensitization can contribute to the postoperative pain. Therefore, reliance only on a peripheral effective nonopioid-based analgesic method may not be sufficient in controlling moderate to severe postoperative pain; additionally, the excessive use of central effective analgesics can result in undesirable side effects.
Multimodal analgesia and preventive analgesia are the two novel methods aimed to prevent or reduce sensitization for better pain management., The concept of multimodal analgesia suggests that it is superior to combine analgesics that target different sites and act through different mechanisms. Preventive analgesia is based on the administration of one or more analgesics and/or local anesthetics any time before the pain develops.
Pregabalin was approved as an adjuvant therapy for neuropathic pain, partial seizures, and generalized anxiety disorder. Its use has been reported to reduce postoperative pain, analgesic consumption, and analgesic-related complications following major orthopedic, ENT, and orthognathic surgical procedures.,,,
Oral ibuprofen is the most commonly used NSAID after third molar surgery. The use of intravenous (IV) form of ibuprofen was approved for the treatment of mild to moderate pain; it was also approved to be used in combination with opioid analgesics for the treatment of moderate to severe pain.
To our knowledge, there was no previous study in the literature that reported on the combined use of IV Ibuprofen and pregabalin before impacted third molar surgery. Therefore, the objective of this study was to examine the effect of preoperative coadministration of IV Ibuprofen and a single dose of pregabalin (75 or 150 mg) on postoperative pain levels at different time intervals, the amount of analgesic consumption and extend the first rescue analgesic request time following third molar surgery.
| Materials and Methods|| |
Patients and study design
This study followed the Declaration of Helsinki on medical protocols and ethics; the institutional Ethical Review Board and Ethics Committee of The Faculty of Dentistry approved the study (HEC No. 3/2016). Written informed consent forms were obtained from each of the patients. A single-center, double-blind, randomized controlled clinical study was carried out on 90 patients who were scheduled to undergo third molar extraction at oral surgery clinic at Dentistry Faculty. The inclusion criteria consisted of the presence of fully soft tissue-impacted and fully or partially bony retentive mandibular third molars in II-B position according to Pell-Gregory classification that required surgical removal. The study exclusion criteria included patient refusal, the patients outside 18–24 years of age, ASA scores of III or IV, renal or hepatic failure, allergy to the study medication or related drugs, immune compromised status, psychological disorders, bleeding disorders, gastrointestinal system complaints, epilepsy or other neurological disorders, pregnancy or breastfeeding, analgesic medication use <10 days before the surgery, and lactose intolerance. Patients who have a history of pain or inflammation in the third molar area before surgery and those in which the duration of the surgical procedure exceeded 30 min were also excluded.
Patients were randomized to one of the four treatment arms using computer-generated numbers (generated in www.randomizer.org). The distribution of participants in groups is shown in [Figure 1]. Ninety opaque coded envelopes bearing serial numbers for the four treatment arms were prepared. A nurse, who was not a part of the study, performed the group allocation and medical intervention. Oral pregabalin (75 or 150 mg) (Lyrica; Pfizer, Inc., New York, NY) and oral placebo (using similar looking cornstarch capsules) were administered to the corresponding treatment groups 1 h before surgery. IV ibuprofen (400 mg) (Intrafen; Gen Pharmaceuticals, İstanbul, Turkey) and IV placebo (sterile saline solution) were administered via IV infusion 30 min before surgery [Table 1].
All patients, the surgeon, and the observer who followed-up with the patients were blinded to the medications being administered. All subjects were instructed to rate the severity of their pain using a horizontal, plain 100-mm length visual analog scale (VAS) with anchors of “no pain” on one side and “worst pain imaginable” on the other before surgery.
The single surgeon performed the surgeries in a standardized manner. Mandibular, buccal, and lingual anesthesia were performed using 2% articaine with 1:100,000 epinephrine (Ultracain; Sanofi-Aventis Deutschland GmbH, Germany). Releasing incision (from the distal segment of the second molar to the buccal sulcus) and an envelope incision (at the second molar) were made, and a full-thickness triangular flap was elevated. Bone removal and tooth sectioning were performed with a bur when necessary. The wound was closed with 3.0 silk sutures.
All participants received antibiotics (amoxicillin–clavulanate 875/125- or 300-mg clindamycin, for those with penicillin allergies) every 8 h for 6 days; they also received 500-mg paracetamol every 8 h for 6 days and used a 0.12% chlorhexidine mouthwash every 8 h for 6 days. The sutures were removed after 7 days.
Postoperative pain was assessed every hour for the first 12 h following the surgery. Pain was then assessed at every 8, 12, 16, and 20 h during the second and third days and at every 12 h during the fourth, fifth, and sixth postoperative days. Patients were instructed to record the first rescue analgesic request time and their total analgesic consumption during the postoperative period. Information regarding study variables, such as age, sex, duration of the operation, surgical difficulty, and complications were also gathered.
The surgeon used the Modified-Parant scale, with the following rating scores, to measure the surgical difficulty: extraction with forceps only (1); extraction by osteotomy (2); extraction by osteotomy and coronal section (3); and complex extraction (4). The primary outcomes measured and analyzed in this study were the VAS pain scores, postoperative nonnarcotic analgesic consumption, and the first rescue analgesic request time after the surgery.
The sample size was calculated using the statistical program G*Power 3.0 (Heinrich-Heine-Universität, Düsseldorf, Germany) with an alpha value of 0.05, a statistical power of 80%, and an effect size of 40% according to the pilot study. The final sample size was calculated to be19 per group.
IBM SPSS Statistics Standard Grad Pack version 22.0 for Windows (IBM Corporation, Armonk, NY) was used for the statistical analyses. The normality of the quantitative data distribution was evaluated using the Shapiro–Wilk test. Kruskal–Wallis tests were used to compare the four groups in terms of the duration of the surgical procedure, surgical difficulty, VAS scores at different time intervals, analgesic consumption, and first rescue analgesic request time after surgery. We did not have equal numbers of male and female patients in the study. Therefore, gender was not used as an independent variable. However, the ratio of male/female patients in each group was used as an independent variable. The demographic data and complications related to the medications were analyzed using χ2 tests.
| Results|| |
Of the 230 patients examined, 90 were enrolled in this study in between the dates of March 2016 and February 2017. Ten patients were excluded from the study and data analysis. A flow chart of the participants is shown in [Figure 1]. The study groups were indifferent in terms of the ratio of male/female patients, age, modified-Parant scale scores, and duration of the surgery [Table 2].
There was a difference in the severity of pain that was observed between group 4 and the other groups, with respect to the different time intervals. VAS pain scores in group 4 was significantly lower in the third, fourth, fifth, sixth, seventh, and eighth hours following surgery when compared with group 1 (placebo) and in the third, fourth, and ninth hours when compared to group 2. Postoperative pain intensities in group 4 were also significantly lower in the third, eighth, ninth, and tenth hours when compared with group 3. Pain scores in group 4 were significantly lower when compared with group 1 on the second day (16.00 h), third day (16.00 h), fifth day, and sixth day. They were also significantly lower when compared with group 3 on the fifth day and sixth day [Table 3] and [Figure 2]. The amount of analgesic consumption was not statistically different between study groups [Table 3] and [Figure 3].
|Table 3: Comparison of outcome variables of pain , total analgesic consumption and time to first rescue analgesia|
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|Figure 2: Pain scores (visual analog scale) during first six postoperative days|
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Based on the results of this study, preoperative coadministration of a single dose of 150 mg pregabalin and 400 mg IV ibuprofen significantly reduced the pain levels during the 3- to 10-h intervals following the surgery. Pain intensity was also found to be lower in the second and third days (at 16.00 h), and in the fifth and sixth days, when compared with the other treatment groups. The supplemental analgesic consumption did not differ between the groups [Table 3]. The mean time of the first rescue analgesia was greater in group 4 when compared with groups 1 and 2; the time of group 3 was also greater when compared with group 2 [Table 3] and [Figure 4]. No significant difference in the frequency and intensity of adverse effects were observed between the groups [Table 4].
|Table 4: Occurrence of complications related to the analgesics administered|
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| Discussion|| |
Even minor oral surgery in the orofacial region, such as impacted third molar extraction, may be sufficient to evoke central and peripheral sensitization for at least 1 week after surgery. Also, hyperesthesia in the adjacent area to the surgical site can proceed up to 30 days., Therefore, combining central and peripheral acting analgesic agents can provide significant relief of moderate to severe pain after third molar surgery. For healthy patients, the standard components of multimodal analgesia (used in major procedures) routinely include nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, an alpha-2-delta ligand (gabapentinoids), and a rescue opioid being a last resort. Gabapentinoid's mechanism of action is not exactly clear, but studies on these drugs have indicated that selective binding to the α2δ subunits of calcium channels is necessary for their associated analgesic, anticonvulsant, and anxiolytic-like properties. Pregabalin has a more suitable pharmacokinetic profile than gabapentin, including dose-independent absorption. Pregabalin's plasma concentration reaches maximum at 1 h after oral intake, and the elimination time of it is between five to seven h. It dosing for acute pain management ranges between 75 and 300 mg/day (with a maximum dose 600 mg/day) in adults.
Multimodal analgesia drugs, which reduce peripheral prostaglandin concentrations and peripheral sensitization, are a particularly useful component. However, pregabalin does not have any known activity at sodium channels, dopamine receptors, serotonin receptors, opiate receptors, and it does not modify the activity of cyclooxygenase. Pregabalin's analgesic effect may be increased regardless of its mechanism of action when combined with NSAIDs. The combined use of pregabalin and NSAIDs (celecoxib, ibuprofen, and dexketoprofen trometamol) and/or acetaminophen has been shown to be effective in the management of postoperative pain following orthopedic, orthognathic, and laparoscopic surgery.,,,
The preoperative administration of 400 mg of ibuprofen 30 min before surgery has been recommended to reduce pain after third molar surgery. The intravenous formulation was considered better than tablet formulation, as it achieved maximum plasma concentration more rapidly. It has been reported that IV ibuprofen administration can reduce postoperative pain and morphine consumption in nondental operations., Additionally, Decoteau et al. also reported significantly lower overall pain ratings and significant alterations of narcotic analgesic use in the IV ibuprofen group compared with the acetaminophen group after third molar surgery On the contrary, our study found no difference between pain ratings, non-narcotic analgesic consumption, and the first rescue analgesic request time between groups 1 and 2.
Previous studies showed that pregabalin administration could attenuate postoperative pain and reduce postoperative opioid consumption compared to placebo, but these effects were not found to be equal in different surgical models., There are currently limited studies on the effects of pregabalin on pain after oral and maxillofacial surgery.,,,, In our study, we compared the effect of primarily 75-mg pregabalin–ibuprofen and 150-mg pregabalin–ibuprofen combinations after third molar surgery. Although a single preoperative dose of pregabalin 300 mg resulted in better pain relief after third molar surgery, it is associated with more side effects than ibuprofen 400 mg and pregabalin 50 mg. Ahıskalıoǧlu et al. showed that sedation and other side effects were less frequently seen with a 150 mg dose, and that this dose was effective in improving VAS pain scores when compared to the placebo group. Therefore, in our study, we premedicated one combination group with 150-mg pregabalin and the other combination group with 75 mg pregabalin 1 h before surgery.
In previous studies, pain intensity in the first day after third molar surgery was reported to be significantly lower,, or no different in the pregabalin treatment groups when compared with placebo. We found that the ibuprofen 400 mg–pregabalin 150 mg group resulted in lowered pain intensity during the 3- to 8-h time intervals when compared with group 1, in the third, fourth, and ninth hours when compared with group 3, and in the third, eighth, ninth, and tenth hours when compared with group 2. Our findings gathered from the first postoperative day are consistent with those of other studies, which reported lowered pain scores during the first 1–12 h, first 30 min, first, second, fourth, eighth hours, and first 1 to 7 h; however, they were not consistent with the findings of Olmedo-Gaya et al., who reported no difference between the groups in the first 24 h following surgery. In these studies, which reported the reduction in postoperative pain, a single dose of ≥150 mg had been administrated to patients.,, On the contrary, Olmedo-Gaya et al. who reported no difference in pain intensity between placebo and treatment groups, used the same treatment but divided it into two doses (75 mg administered 1 h before surgery and 75 mg administered 1 h after surgery). Similar results were obtained by Cheung et al. and Hill et al. who used 75 and 50 mg of pregabalin, respectively, in third molar surgery. Based on these findings, it is assumed that a 75-mg dose of pregabalin is subtherapeutic in oral and maxillofacial surgery, whereas a dose of 150 mg is not. Moreover, given that the half-life of pregabalin is 5–7 h, administering a total 150-mg pregabalin via two 75-mg doses 2 h apart may reduce its efficacy.
Postoperative pain intensity at all evaluation periods was found to be lower in group 4, when compared with the other groups in the first postoperative week. This difference was statistically significant at 16.00 h in the second and the third days, and in the fifth and sixth days, postoperatively. Our findings were consistent with those of Cillo et al. who reported lower mean VAS pain scores in the 150-mg pregabalin to 400-mg celecoxib combination group when compared with the placebo group. On the contrary, Cheung et al. reported no difference in pain levels at the 24- to 72-h interval after surgery between groups that received preoperative vs postoperative administration of pregabalin. However, this study did not include a true placebo group or other medication group for comparison, and they used only half of the 150-mg pregabalin dose.
Ahıskalıoǧlu et al. and Cillo et al. observed a significant reduction in intravenous narcotic analgesic consumption at 24 h in the pregabalin group versus the placebo groups. Cillo et al. also reported a significant decrease in daily narcotic pill consumption in the pregabalin group versus the placebo group during the first seven outpatient days. In this study, it was found that even if group 2 had a higher mean of nonnarcotic analgesic consumption, the difference between groups was not statistically significant. The differences between this study and the others referenced here may have resulted from not using a narcotic agent as a postoperative analgesic. Olmedo-Gaya et al. supplied both groups with ibuprofen 600 mg as a rescue analgesic in their study, and they reported similar results to those in our study.
Ong et al. reported that preoperative wound infiltration with local anesthetics and NSAID administration improved both analgesic consumption and first rescue analgesic request time, but it did not affect pain scores in different surgical procedures. Hill et al. observed a longer duration of anesthesia after local anesthetic injection in the pregabalin 300 mg group compared to the ibuprofen 400 mg group. Similar to their findings, the first rescue analgesic request time was found to be greater in the pregabalin combination groups [groups 3 and 4] when compared with the group 2.
Hill et al. did not find any difference in the frequency of side effects between the placebo, pregabalin 50 mg, and ibuprofen 400 mg groups. However, they reported a higher side effect frequency with pregabalin 300 mg compared with other groups. Of the patients who received pregabalin 300 mg, 48% experienced associated adverse events which included dizziness, drowsiness, and vomiting. Olmedo-Gaya et al. reported that adverse effects were more frequent and intense in the pregabalin group (56.6%) than those in the placebo group (10%). In our study, dizziness (9%), drowsiness (45%), headache (9%), euphoria (18%), sedation (9%), and appetite increase (9%) were reported by patients. There was no significant difference on the occurrence of complications related to the analgesic administered between groups [Table 4].
To the best of our knowledge, this is the first study to evaluate the preoperative use of pregabalin and IV ibuprofen in third molar surgery. Coadministration of pregabalin 150 mg and IV ibuprofen 400 mg prior to third molar surgery resulted in improved pain scores during the postoperative period. More specifically, it provided better analgesia in the early postoperative period without an increased incidence of side effects. Further, we believe that the use multimodal analgesia regimens which used different drug combinations (including adjuvant analgesics) can be effective in pain management after third molar extraction.
The limitations of the study are as follows: first, we were not able to use a split-mouth design because we had four treatment arms in this study. Second, relatively light doses of study medications (pregabalin 75 mg, pregabalin 150 mg, and ibuprofen 400 mg) were used preoperatively and not maintained postoperatively. It may be possible to use multiple doses or higher doses to provide more effective treatment.
The study was registered retrospectively to the Australian New Zealand Clinical Trial Registry (Number ACTRN12618000969268),
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]