The analgesic efficacy and safety of non-steroidal anti-inflammatory agents (NSAIDs) in patients undergoing oral and maxillofacial surgery—a systematic review

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used by perioperative patients to reduce pain and inflammation experienced after surgery (1). This common postoperative inflammation is often triggered by the biosynthesis of prostaglandins-lipid compounds synthesized by the cyclooxygenase (COX) enzyme and generated at infectious or tissue damaged sites (2). NSAIDs function to decrease inflammation through acting as competitive inhibitors that bind to one monomer of the COX dimer’s active site, thereby inhibiting the synthesis of prostaglandins, and blocking any inflammatory response (2). The analgesic and anti-inflammatory effects of NSAIDs thus effectively induce temporary pain relief in patients, and stand as lower risk alternatives in comparison to opioid-based anesthetics (1).

As with any drug, NSAIDs do come with their own risks. The use of NSAIDs can impact various physiological systems within the body, presenting an increased risk of serious adverse events (AEs) such as gastrointestinal bleeding or cardiovascular disease (3). However, opioids pose more significant risks to patients, not only regarding their physical side effects (respiratory depression, nausea, drowsiness, dizziness, etc.), but additionally due to the tolerance that patients build over time, thereby leading to misuse, and eventual addiction (4). Currently, the United States stands amid an ongoing epidemic, where a rise in opioid-related drug overdose deaths has reached an alarming rate. The origins of this epidemic date back to the early 1990s, where pharmaceutical companies began initially prescribing opioid prescriptions for acute and chronic pain, under the impression that these analgesics posed minimal risks to patients (5). However, patients rapidly began to develop a tolerance towards opioids, and the dangerously addictive nature of the drug soon led to severe ramifications including misuse, overdose, and in more extreme cases, death. Consequently, in 2017, U.S. Department of Health and Human Services subsequently declared the opioid crisis to be a public health emergency (6). With the many risks that the ongoing opioid epidemic has given rise to, anesthesiologists have thus recently begun to transition towards prescribing NSAIDs more frequently as an effective alternative.

Various studies have assessed randomized controlled trials (RCTs) and ongoing clinical trials on the efficacies of opioid-free NSAID therapy, as a suitable alternative treatment (7). For example, a systematic review conducted by Bailey et al. [2013] has assessed the efficacies of opioid-free treatment with ibuprofen and/or paracetamol after wisdom teeth surgery. Results from the Bailey et al. review showed that ibuprofen could bring significant post-operative pain relief, indicating that NSAIDs can provide similar clinical benefits that opioids bring, while eliminating the added risks of addiction and misuse (7). Thus, this review will evaluate the efficacies of various NSAIDs compared to those of opioids, and examine the beneficial outcomes of transitioning to primarily NSAID-based therapies in the field of oral and maxillofacial surgery (OMFS). We present this article in accordance with the PRISMA reporting checklist (available at https://joma.amegroups.org/article/view/10.21037/joma-22-25/rc).

Methods

A systematic review was conducted for literature pertaining to the use of both NSAIDs and opioids in OMFS, to compare the efficacies of both drugs.

Literature search

A search of relevant literature spanned databases including PubMed, The Cochrane Library, and https://www.clinicaltrials.gov/ and included all relevant publications from origin dating up to 01/05/2023. The following search strategy was utilized: ((((“anti inflammatory agents non steroidal”[Pharmacological Action] OR “anti inflammatory agents, non steroidal”[MeSH Terms] OR (“anti inflammatory”[All Fields] AND “agents”[All Fields] AND “non steroidal”[All Fields]) OR “non-steroidal anti-inflammatory agents”[All Fields] OR “nsaid”[All Fields] OR “nsaids”[All Fields] OR “nsaid s”[All Fields] OR ((“nonsteroid”[All Fields] OR “nonsteroidal”[All Fields] OR “nonsteroidals”[All Fields] OR “nonsteroids”[All Fields]) AND (“anti inflammatory agents”[Pharmacological Action] OR “anti inflammatory agents”[MeSH Terms] OR (“anti inflammatory”[All Fields] AND “agents”[All Fields]) OR “anti inflammatory agents”[All Fields] OR (“anti”[All Fields] AND “inflammatory”[All Fields] AND “drug”[All Fields]) OR “anti inflammatory drug”[All Fields]))) AND (“analgesics opioid”[Pharmacological Action] OR “analgesics, opioid”[MeSH Terms] OR (“analgesics”[All Fields] AND “opioid”[All Fields]) OR “opioid analgesics”[All Fields] OR “opioid”[All Fields] OR “opioids”[All Fields] OR “opioid s”[All Fields]) AND “OMFS”[All Fields]) OR ((“mouth”[MeSH Terms] OR “mouth”[All Fields] OR “oral”[All Fields]) AND “maxillofacial”[All Fields])) AND (“pain”[MeSH Terms] OR “pain”[All Fields])) AND (“clinicaltrial”[Filter] OR “randomizedcontrolledtrial”[Filter]). No formal protocol registration was performed.

Selection criteria

A predetermined eligibility criteria for this literature search included (I) head-to-head RCTs concerning the efficacy of a NSAID to an opioid; (II) clinical trials assessing patient populations after undergoing OMFS. Exclusion criteria included (I) non-RCT studies (e.g., retrospective studies, single-arm trials, etc.); (II) studies that used external drugs other than NSAIDs and opioids in the experimental arm (anesthetics, steroids, paracetamol, etc.); (III) crossover studies that did not primarily compare the efficacies of a specific NSAID and opioid in the experimental arms; (IV) ongoing clinical trials that had no results released at the time of the literature search (V) systematic literature reviews, meta-analyses, etc.

Quality assessment

The risk of bias in this study was assessed through the Cochrane Collaboration’s Risk of Bias tool. Each study’s risk of bias was assessed based upon the protocol’s blinding, study design, and data/results. Different types of biases evaluated include selection bias, performance bias, detection bias, attrition bias, reporting bias, and other biases (Figure 1).

Figure 1 Risk of bias assessment. +, low risk of bias; ?, unknown risk of bias.

Outcomes

The primary outcome of this study was assessments of numerical pain scores measured using the visual analogue scale (VAS). The secondary outcomes included (I) total rescue analgesic consumption for measuring efficacy, and (II) total number of AEs witnessed for measuring safety. All results that were compatible with each outcome in each study were sought and included in data extraction.

Statistical analysis

All analyses were executed using the IBM SPSS statistics 28.0 software. VAS scores and rescue analgesic consumption were analyzed separately in continuous meta-analyses, by measuring the unstandardized mean difference (unequal group variances), with a 95% confidence interval (CI) to assess overall efficacy of each drug. AEs were analyzed through a binary meta-analysis by measuring relative risk (RR), with a 95% CI to assess risk of adverse outcomes associated with each drug. Heterogeneity between each study was measured through τ², H², and I² calculations. A random-effects model was used. For the VAS scores and rescue analgesic consumption analyses, studies where the outcome was reported as a mean ± standard deviation (SD) were incorporated. For the AEs analysis, all studies that analyzed the AEs in question as outcomes, were incorporated into the analysis. Studies that did not measure certain outcomes of interest were not included in the respective analyses. Studies with data that were unable to be converted appropriately were also not included in the respective analyses.

Results

Literature search

A total of 1,616 records were identified amongst the aforementioned databases using the specified keywords. Among them, 151 duplicates were initially removed. The remaining 1,465 titles/abstracts were screened, and 1,438 articles were removed using the predetermined inclusion/exclusion criteria. Subsequently, 27 full-text articles were screened for final eligibility. Six identified studies that met the inclusion/exclusion criteria were included in the final review (Figure 2).

Figure 2 Flow diagram of included records.

Study characteristics

The selected studies from this literature search include 6 head-to-head RCTs utilizing one specifically selected NSAID and one specifically selected opioid for a head-to-head comparison (Table 1). The specific NSAID/opioid comparisons assessed include three tramadol vs. ketorolac studies, one tramadol vs. celecoxib study, one tramadol vs. lornoxicam study, and one fentanyl vs. ketorolac study. Sample sizes ranged from 40 to 90 patients, and each RCT used a study population of patients having undergone some type of oral-maxillofacial surgery (i.e., third molar extraction, reduction, and internal fixation, etc.). The efficacies of each NSAID and opioid in question were assessed by various means across all studies including (but not limited to) VAS pain scores, time to first rescue analgesic, total rescue analgesic consumption, total number of AEs, and overall global assessments.

VAS analysis

The mean VAS scores from 4 studies (n=200) (9,10,12,13) were pooled into the data analysis: Gopalraju et al. [2013], Ong et al. [2004], Jain et al. [2017], and Rather et al. [2022]. Degala et al. [2018] (8) was excluded in the analysis, because the VAS scores were reported in ranges, and no mean/SD was reported, that could be used for the purposes of a meta-analysis. Akinbade et al. [2019] (11) was also excluded in this analysis, because the study reported VAS scores in terms of median and range, which could not be used in meta-analysis. For the 4 studies included in the analysis, the mean and SD data for VAS scores at 12-hour post-operatively in both opioid and NSAID groups were analyzed. The analysis demonstrated no significant difference (P=0.45) between the opioid and NSAID group with heterogeneity [mean difference (MD) =5.26; 95% CI: (−8.50, 19.01); I²=95%] (Figure 3).

Figure 3 VAS pain scores meta-analysis. VAS, visual analogue scale; NSAID, non-steroidal anti-inflammatory drug.

Rescue analgesic analysis

The mean values for rescue analgesic consumption from 2 studies (n=120) (10,13) were pooled into another analysis: Ong et al. [2004] and Rather et al. [2022]. The remaining 4 studies were not included in this analysis because total rescue analgesic consumption was not measured for either group. For the 2 studies included in the analysis, the mean and SD data for total rescue analgesic tablets consumed within a 5-day recovery period, in both opioid and NSAID groups were analyzed. The analysis demonstrated no significant difference (P=0.62) between the opioid and NSAID group with heterogeneity [MD =−1.93; 95% CI: (−9.57, 5.70); I²=98%] (Figure 4).

Figure 4 Rescue analgesic consumption meta-analyses. NSAID, non-steroidal anti-inflammatory drug.

AEs analysis

Four AEs including dizziness, drowsiness/somnolence, nausea, and vomiting were included in the analysis for 4 of the selected studies (8,11-13). Akinbade et al. [2019] and Rather et al. [2022] were included in analysis for all 4 AEs, while Degala et al. [2018] and Jain et al. [2017] were only included in the analysis for nausea. The remaining studies were not included in this analysis because the AEs in question were not measured for either group. For the purposes of this analysis, the opioid group was considered the “treatment” group.

Dizziness

The meta-analysis for dizziness included Akinbade et al. [2019] and Rather et al. [2022] (n=150) (11,13), which indicated a significant difference in occurrence (P=0.03) between the opioid and NSAID groups, with no heterogeneity [RR =1.26; 95% CI: (0.15, 2.37); I²=0%]. This analysis indicated that the NSAID group showed more favorable results pertaining to less AEs for dizziness (Figure 5).

Figure 5 Adverse effects meta-analysis-dizziness. RR, relative risk; NSAID, non-steroidal anti-inflammatory drug.

Drowsiness/somnolence

The meta-analysis for drowsiness/somnolence included Akinbade et al. [2019] and Rather et al. [2022] (n=150) (11,13), which indicated a significant difference in occurrence (P=0.04) between the opioid and NSAID groups, with no heterogeneity [RR =2.11; 95% CI: (0.05, 4.18); I²=0%]. This analysis indicated that the NSAID group showed more favorable results pertaining to less AEs for drowsiness/somnolence (Figure 6).

Figure 6 Adverse effects meta-analysis-drowsiness and somnolence. RR, relative risk; NSAID, non-steroidal anti-inflammatory drug.

Nausea

The meta-analysis for nausea included Akinbade et al. [2019], Degala et al. [2018], Jain et al. [2017], and Rather et al. [2022] (n=236) (8,11-13), which indicated a significant difference in occurrence (P=0.01) between the opioid and NSAID groups, with no heterogeneity [RR =1.87; 95% CI: (0.39, 3.34); I²=0%]. This analysis indicated that the NSAID group showed more favorable results pertaining to less AEs for nausea (Figure 7).

Figure 7 Adverse effects meta-analysis-nausea. RR, relative risk; NSAID, non-steroidal anti-inflammatory drug.

Vomiting

The meta-analysis for vomiting included Akinbade et al. [2019] and Rather et al. [2022] (n=150) (11,13), which indicated a significant difference in occurrence (P<0.001) between the opioid and NSAID groups, and no heterogeneity [RR =1.64; 95% CI: (0.58, 2.71); I²=0%]. This analysis indicated that the NSAID group showed more favorable results pertaining to less AEs for vomiting (Figure 8).

Figure 8 Adverse effects meta-analysis-vomiting. RR, relative risk; NSAID, non-steroidal anti-inflammatory drug.

Discussion

Pain scores

In each of the 6 RCT studies (8-13), postoperative pain was evaluated in accordance with the VAS. Using the VAS, patients physically mark their perceived acute pain intensity along a 10 cm scale, where each end of the scale represents extreme limits of either no pain at all, or the most intense pain possible (14). The VAS serves as an essential measurement of experienced pain intensity, which can easily be attributed to the efficacy of NSAIDs and opioids in reducing postoperative pain. The 6 selected RCTs showed varying results for VAS scores when comparing each study’s opioid group to the NSAID group (Table 2). In Degala et al. [2018], patients who were given preoperative 100 mg intravenous (IV) tramadol reported lower VAS scores in comparison to patients who were given 30 mg IV ketorolac, when measured 2, 4, 6, 12, and 24 h post-operatively (8). In Gopalraju et al. [2013], patients who were given 50 mg ketorolac preoperatively reported lower VAS scores, in comparison to patients given 30 mg tramadol preoperatively (9). In Ong et al. [2004], 50 mg ketorolac preoperatively reported lower VAS scores over the course of 12h, in comparison to those given 30 mg tramadol preoperatively (10). Akinbade et al. [2019] additionally indicated lower median VAS scores for patients given treatment with celecoxib in comparison to those who received tramadol, when measured at 0, 4, 8, 16, 24, and 48 h post-operatively (11). In Jain et al. [2017], patients who received 8 mg lornoxicam preoperatively reported lower mean VAS scores than those who received 50 mg tramadol, when measured at 2, 4, 6, 12, and 24 h postoperatively (12). Lastly, in Rather et al. [2022], patients given a 25 mcg/h fentanyl patch reported lower mean VAS scores over the course of 6 days post-operatively, when compared to patients who consumed a 10 mg ketorolac tablet (13). Overall, 4 out of the 6 studies indicated that patients who received NSAIDs for pain treatment reported lower VAS scores in comparison to those who received opioids. As seen through the meta-analysis, no statistically significant difference was found between the pooled NSAID and opioid groups with regards to self-reported VAS scores. Thus, future research will be essential in establishing if NSAIDs can truly provide better pain control in terms of reduced VAS scores in comparison to opioids.

Rescue analgesic needs

Within 3 of the studies (9,10,13), standard protocol allowed for rescue analgesics to be administered post-operatively, for enhanced management of pain (Table 3). Each study selected paracetamol—a non-opioid analgesic—to serve as the rescue drug. Measurements taken for each group included time elapsed prior to first rescue analgesic intake, and total rescue analgesic consumption. In Gopalraju et al. [2013], patients were given the option of taking 500 mg paracetamol as needed post-operatively (9). Looking at the median time to re-medication within the two groups, the ketorolac group appeared to show better control of post-operative pain when it came to rescue analgesic consumption, with a median time of 10 h, in comparison to the tramadol group with a median time of 7 h. In Ong et al. [2004], patients were advised to take 1,000 mg paracetamol as a rescue analgesic for postoperative pain (10). A total of 16.7% of the patients who received opioids did not consume any rescue analgesic within the 12 h observation period, while 36.7% of the patients who received NSAIDs did not consume any rescue analgesic (10). Overall, the ketorolac group reported both longer times before the first rescue analgesic consumption (9.5±3.0 h) and less tablets consumed total (4.4±3.1), in comparison to the tramadol group (7.6±2.7 h) and (6.4±3.8) respectively (10). According to the average times, ketorolac provided an additional 2h of pain relief in comparison to tramadol, and given the lower number of tablets consumed in the ketorolac group, this indicates that the NSAID may have better control of postoperative pain overall. Lastly, in Rather et al. [2022], a total average of 2.16±1.53 tablets of paracetamol medication were consumed amongst patients in the fentanyl group throughout a 6-day observational period (13). This number was significantly lower in comparison to the 8.50±3.98 average tablets consumed in the ketorolac group (13). Overall, results from all studies indicated a mixed need for rescue analgesic for patients given treatment with opioids, in comparison to those who were given NSAIDs. The use of ketorolac appeared to provide better pain control (both in terms of time elapsed prior to the first intake and total amount consumed), when compared head-to-head with IV tramadol in the first two studies. However, when ketorolac was compared with a fentanyl patch in the third study, the fentanyl patch seemed to provide better pain control postoperatively. As seen through the meta-analysis, no statistically significant difference was found between the pooled NSAID and opioid groups with regards to rescue analgesic consumption. Thus, future research must be conducted, comparing other NSAIDs to other opioids, in order to affirm whether or not NSAIDs can truly provide better pain control in regards to less rescue analgesic needs.

AEs

Four out of the 6 studies monitored vitals and various AEs to assess the safety and tolerability of the drugs in question (Table 4) (8,11-13). In Degala et al. [2018], vitals and AEs were monitored between the tramadol and ketorolac group (8). Vitals were found to remain normal, while two reportings of nausea/vomiting were found in the tramadol group, and one event of sweating and nausea was reported from the ketorolac group (8). In Akinbade et al. [2019], AEs including drowsiness, nausea, vomiting, and dizziness were measured between the celecoxib and tramadol groups (11). Within the tramadol group, 25 (55.56%) out of the total 42 patients experienced AEs of some sort, whereas none of the 45 patients in the celecoxib group reported no AEs of any kind (11). In Jain et al. [2017], vital signs and side effects such as nausea/vomiting and gastric acidity were evaluated between the group who received 8 mg lornoxicam and those who received 50 mg tramadol (12). Data indicated that 2 out of the 20 patients in the tramadol group experienced nausea/vomiting, while 1 out of the 20 patients in the lornoxicam group experienced gastric acidity (12). Both statistics, however, were not significant, and could potentially be attributed to normal side effects of anesthesia and pre-surgical fasting (12). Additionally, all patients had vitals within normal limits (12). Lastly, in Rather et al. [2022], several AEs including nausea/vomiting, somnolence, dizziness, headache, application site reaction, constipation, and epigastric pain were monitored between the fentanyl and ketorolac group (13). Overall, (with the two exceptions of headache and epigastric pain), a greater number of patients in the fentanyl group seemed to experience more AEs in comparison to those in the ketorolac group (13). This study also measured antiemetic consumption amongst the opioid and NSAID group. While no antiemetics were consumed within the ketorolac group, the fentanyl group averaged a total of 0.56±1.30 tablets of antiemetic medication over the course of the 6-day observational period (13). The consumption of antiemetic medication within the fentanyl group aligns with the indication that the use of fentanyl for pain relief may present a greater likelihood of observed AEs associated with nausea and vomiting. In the end, although some studies showed insignificant differences in side effects between the opioid and NSAID group, it should be noted that patients receiving opioids appear to be experiencing more AEs, particularly when looking at the tramadol vs. celecoxib trial and the fentanyl vs. ketorolac trial. As seen through the meta-analysis, the NSAID groups within the pooled studies all exhibited significantly more favorable outcomes for AEs in comparison to the opioid groups. Thus, there is an evident benefit to using NSAID treatment over opioid treatment, with regards to mitigating the occurrence of such AEs.

Limitations

This study is primarily limited in the sense that only head-to-head trials that compared the efficacies of one specific NSAID and one specific opioid were included. The goal of this review was to evaluate the efficacies of NSAIDs independently, in comparison to other types of opioid treatments; thus, studies that compared the efficacies of combinatorial therapies (i.e., NSAIDs and opioids combined) or treatments involving other types of anesthetics were excluded. Moreover, primary and secondary outcomes for VAS scores, rescue analgesic consumption, and AEs were oftentimes not reported in a consistent means across all 6 studies assessed. For example, not every study reported their VAS outcomes as a mean ± SD; some reported them as a median, and others reported them in ranges. While reporting VAS scores as a median or range may have been a more comprehensive statistic given the nature of the results for certain studies, this made it difficult to incorporate all 6 studies together within a quantitative meta-analysis. Consequently, only 4 studies were included in the analysis for the primary outcome of VAS pain scores. This same limitation was seen in the analysis for rescue analgesic consumption and AEs, where certain studies in the review did not measure these given outcomes in a way that could be incorporated into the analysis. Particularly for the outcome of AEs, only a limited number (4) of AEs were analyzed. Thus, future head-to-head trials have the potential to assess more AEs to a greater degree when comparing the efficacy and safety of both drugs. Finally, the sample sizes for each RCT were also relatively small, with the largest sample size only consisting of 90 patients. Thus, further studies generalizing research to a larger population would be increasingly beneficial in confirming the results found from these studies.

Conclusions

In conclusion, this review demonstrates that NSAIDs have the potential to serve as a safe and suitable therapy in treating postoperative pain with OMFS, when considering assessments of pain control and AEs. While no significant difference in VAS scores and rescue analgesic consumption was indicated in the meta-analysis, 4 out of the 6 studies still exhibited lower VAS scores in the NSAID group, when compared to the opioid group. Additionally, the NSAID groups exhibited significantly better outcomes in terms of AEs. This finding is important when assessing the safety and tolerability of opioids, when considering the consequences of the ongoing global epidemic. If opioids pose patients at a greater risk for AEs in addition to addiction, it may be worthwhile to consider transitioning from primarily opioid-based therapies to opioid-free or opioid-sparing anesthesia. In the end, the studies assessed in this review focused primarily on the independent efficacies of NSAIDs and opioids in OMFS. However, future research looking into an assessment of combinatorial therapies with NSAIDs and opioids used in conjunction with one another, can also be useful in understanding the potential benefits of opioid-sparing therapies.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Oral and Maxillofacial Anesthesia, for the series “Opioid-Free Anesthesia and Opioid-Sparing Anesthesia in OMF Surgery”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://joma.amegroups.org/article/view/10.21037/joma-22-25/rc

Peer Review File: https://joma.amegroups.org/article/view/10.21037/joma-22-25/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://joma.amegroups.org/article/view/10.21037/joma-22-25/coif). The series “Opioid-Free Anesthesia and Opioid-Sparing Anesthesia in OMF Surgery” was commissioned by the editorial office without any funding or sponsorship. JW serves as an unpaid editorial board member of Journal of Oral and Maxillofacial Anesthesia from August 2021 to July 2023 and served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Gupta A, Bah M. NSAIDs in the Treatment of Postoperative Pain. Curr Pain Headache Rep 2016;20:62. [Crossref] [PubMed]
2. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol 2011;31:986-1000. [Crossref] [PubMed]
3. Davis A, Robson J. The dangers of NSAIDs: look both ways. Br J Gen Pract 2016;66:172-3. [Crossref] [PubMed]
4. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician 2008;11:S105-20.
5. Volkow ND, Blanco C. The changing opioid crisis: development, challenges and opportunities. Mol Psychiatry 2021;26:218-33. [Crossref] [PubMed]
6. Salmond S, Allread V. A Population Health Approach to America's Opioid Epidemic. Orthop Nurs 2019;38:95-108. [Crossref] [PubMed]
7. Bailey E, Worthington HV, van Wijk A, et al. Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth. Cochrane Database Syst Rev 2013;CD004624. [Crossref] [PubMed]
8. Degala S, Nehal A. Comparison of intravenous tramadol versus ketorolac in the management of postoperative pain after oral and maxillofacial surgery. Oral Maxillofac Surg 2018;22:275-80. [Crossref] [PubMed]
9. Gopalraju P, Lalitha RM, Prasad K, et al. Comparative study of intravenous Tramadol versus Ketorolac for preventing postoperative pain after third molar surgery--a prospective randomized study. J Craniomaxillofac Surg 2014;42:629-33. [Crossref] [PubMed]
10. Ong KS, Tan JM. Preoperative intravenous tramadol versus ketorolac for preventing postoperative pain after third molar surgery. Int J Oral Maxillofac Surg 2004;33:274-8. [Crossref] [PubMed]
11. Akinbade AO, Ndukwe KC, Owotade FJ. Comparative analgesic efficacy and tolerability of celecoxib and tramadol on postoperative pain after mandibular third molar extraction: A double blind randomized controlled trial. Niger J Clin Pract 2019;22:796-800. [Crossref] [PubMed]
12. Jain AD, Vsm R, Ksn SB, et al. A Comparative Assessment of Postoperative Analgesic Efficacy of Lornoxicam versus Tramadol after Open Reduction and Internal Fixation of Mandibular Fractures. Craniomaxillofac Trauma Reconstr 2017;10:171-4. [Crossref] [PubMed]
13. Rather AM, Rai S, Rattan V, et al. Comparaison of Efficacy and Safety of Fentanyl Transdermal Patch with Oral Ketorolac for Pain Management in Dry Socket: A Randomized Clinical Trial. J Maxillofac Oral Surg 2022; [Crossref]
14. Haefeli M, Elfering A. Pain assessment. Eur Spine J 2006;15:S17-24. [Crossref] [PubMed]