Analgesic Efficacy of Ketoprofen Transdermal Patch versus Ibuprofen Oral Tablet on Postendodontic Pain in Patients with Irreversible Pulpitis: A Randomized Clinical Trial

Materials and Methods In this randomized clinical trial, 64 patients who had mandibular first and second molars with irreversible pulpitis were randomly divided into two groups (n = 32) by stratified permuted block randomization. The experimental group used 60 mg KTP every 6 hours, and the control group received 400 mg ibuprofen tablets every 6 hours for 1 day. The severity of pain experienced by patients was quantified before and at 2, 4, 8, 12, 24, and 48 hours after endodontic treatment, using the numerical rating scale (NRS). Data were analyzed by using the t-test, Mann–Whitney test, and generalized estimating equation (GEE) (alpha = 0.05). Results The pain score was not significantly different between the two groups at the baseline or any other postoperative time point (P > 0.05). The reduction in the pain score was significant in both groups from 2 to 10 hours and 10 to 48 hours, postoperatively (P < 0.001). The interaction effect of time and group was not significant on the postoperative pain score in the abovementioned time intervals, and the pattern of pain reduction was the same over time in both groups (P > 0.05). Conclusion Both KTP and ibuprofen effectively decreased postendodontic pain. Considering the comparable pattern of pain reduction, KTP can be used as an alternative to ibuprofen tablets for effective pain control after endodontic treatment of mandibular first and second molars with irreversible pulpitis.


Introduction
Pain is an unpleasant sensory experience, which is often associated with possible or actual tissue injury [1]. Prevention and control of pain is an important aspect in endodontic treatments. Te prevalence of postendodontic pain is relatively high [2], and it ranges from 3% to 58% [3]. A successful dental treatment requires the appropriate use of professional techniques and control of postoperative pain [4].
Postoperative administration of analgesics is often imperative to decrease postendodontic pain especially in teeth with irreversible pulpitis [5]. Patients with higher levels of preoperative pain often experience higher levels of postendodontic pain, compared with asymptomatic patients [6]. Also, a strong correlation exists between the pulp status and the level of postoperative pain [7]. Gotler et al. [8] indicated that postendodontic pain was signifcantly higher in teeth with vital pulp that underwent root canal therapy compared with teeth with necrotic pulp.
A high level of postoperative pain is a common concern for both patients and dental clinicians, and it can underline patients' trust in treatment. Tus, analgesics, particularly nonsteroidal anti-infammatory drugs (NSAIDs), are commonly prescribed before and after endodontic treatment [9,10]. NSAIDs exert their anti-infammatory and analgesic efects by inhibiting the cyclooxygenase enzyme and synthesis of prostaglandins [11].
Ibuprofen is among the most commonly prescribed NSAIDs for arthritis, menstrual pain, postoperative pain, edema, and fever. Approximately 80% of ibuprofen is absorbed through the gastrointestinal system when taken orally, and the analgesia onset occurs 30 minutes after use. It is metabolized in the liver and has a half-life of 1.8 to 2 hours. Also, it is mainly excreted in urine and slightly through the bile [12].
Ketoprofen is another NSAID that has a similar structure to ibuprofen since it has a P-phenylpropionic group [12]. Like Ibuprofen, it is metabolized in the liver and has a halflife of 2 to 2.5 hours. Since prostaglandins stimulate the pain receptors, inhibition of their synthesis by ketoprofen leads to analgesia [13].
Analgesics can be used through oral, injection, inhalation, and transdermal routes. Oral medication intake is associated with possible hepatic primary metabolism, resulting in subsequent elimination of a large part of medication prior to its systemic absorption [14]. Moreover, oral medication intake results in high plasma levels of drug and the associated risks of gastrointestinal complications, renal failure, hepatotoxicity, sodium retention, hypertension, and developing resistance to antihypertensive drugs [15,16].
Transdermal patch is a relatively novel form of medication delivery. Te patch adheres to the skin and releases a certain dose of drug that passes through the skin and underlying tissues to reach the blood vessels [17]. Te advantages of transdermal patches include nonhepatic primary metabolism, lower plasma concentration, and subsequently lower systemic cytotoxicity and side efects [18,19]. Moreover, transdermal patches are better accepted by patients [20].
Considering the limited number of studies on the efcacy of analgesic transdermal patches for postendodontic pain control, this study aimed to compare the efcacy of ketoprofen transdermal patch (KTP) and ibuprofen tablets for pain control after endodontic treatment of mandibular frst and second molars with irreversible pulpitis.

Materials and Methods
Tis study was conducted at the Shahid Beheshti University of Medical Sciences between February 2019 and April 2021. Te study was approved by the Ethics Committee of this university (IR.SBMU.DRC.REC.1398.226) and registered in the Iranian Registry of Clinical Trials (IRCT20190716044230N1).

Trial
Design. An intention-to-treat randomized clinical trial was designed in which the experimental group received KTP, while the control group received ibuprofen tablets to control postendodontic pain. Te results were reported according to the guidelines of the Consolidate standards of Reporting Trials [21].

Participants, Eligibility Criteria, and Settings.
Te inclusion criteria were age between 18 and 65 years, ASA class I physical health status [22], having a mandibular frst or second molar with irreversible pulpitis and moderate (pain score of 4 to 7) or severe (pain score of 8 to 10) pain according to the numerical rating scale (NRS), positive response to electric pulp test, moderate to severe abnormal response with/without a prolonged response to cold test (confrming the diagnosis of irreversible pulpitis for the respective tooth), and no history of gastrointestinal bleeding or problem, no allergy to aspirin-like drugs such as ibuprofen, and no analgesic intake within the past 48 hours prior to admission.
Te exclusion criteria were emergency cases, presence of radiolucency on the radiograph, presence of edema and fstula, use of more than 2 anesthetic cartridges for inferior alveolar nerve block or supplemental injections during the endodontic procedure, noticing pulpal necrosis in general or in one canal after initiation of treatment, not being able to complete endodontic treatment of the respective tooth within a 2-hour single session, iatrogenic errors during treatment (such as perforation, accidental overinstrumentation, or extension of root flling material into the periapical region or beyond the working length), postoperative edema and the need for postoperative antibiotic therapy, and noncompliant patients not precisely reporting the postoperative pain scores.
Te sample consisted of 64 eligible patients with mandibular frst or second molars with irreversible pulpitis and moderate to severe pain presenting to the Endodontics Department of School of Dentistry, Shahid Beheshti University of Medical Sciences.

Interventions.
Eligible patients were enrolled after signing informed consent forms. Tey were briefed about the study protocol and objectives and the advantages and possible side efects of medications.
Demographic information of patients was recorded, and their preoperative level of pain and anxiety was quantifed using an NRS. Accordingly, they were requested to select a number from 0 to 10 that best described their pain level (0 indicated no pain at all, while 10 indicated most severe pain imaginable). A graded NRS with information below each number was used in this study for easy understanding and high accuracy [23]. Mandibular molars were evaluated by the electric pulp test (Te Elements Diagnostic Unit; Sybron Endo, Glendora, CA, USA) and cold test (Roeko Endo-Frost; Roeko Langenau, Germany). Patients with positive response to the electric pulp test and moderate (scores 4-7) or severe (scores 8-10) pain scores were diagnosed with irreversible pulpitis and enrolled. Sensitivity to percussion was also recorded.
All procedures were entirely performed under rubber dam isolation. Patients received 1 cartridge of 2% lidocaine with 80,000 epinephrine (Persocaine, Darupakhsh, Tehran, Iran) for inferior alveolar nerve block. If the patients had pain during access cavity preparation or root canal therapy, they received a PDL supplemental injection of lidocaine. An apex locator (Root ZX, Morito Corporation, Kyoto, Japan) was used for determination of the working length. Te working length was determined 1 mm shorter than the radiographic apex and confrmed by a periapical radiograph. In addition, 1 mL of 2.5% sodium hypochlorite was used for root canal irrigation after using each fle to the working length. First, the coronal part of the canals was fared with # 2 and # 3 Gates-Glidden drills, and then SP1 rotary system (Shanghai Fanta Dental Materials Co., Ltd., China) was used by the crown-down technique to accomplish root canal preparation. Te mesial canals were prepared to # 30 with 4% taper, and the distal canals were prepared to # 35 with 4% taper. Te root canals were then dried with paper points (Aradent, Iran) and flled with gutta-percha and AH26 sealer (Dentsply DeTrey, Konstanz, Germany) by the lateral compaction technique. All patients underwent endodontic treatment by two calibrated postgraduate students of endodontics under the supervision of an experienced endodontist. Te teeth were then temporarily restored with temporary restorative material (Cavit; 3M, USA). Immediately after the treatment, the patients were instructed to record their level of pain at 2, 4, 8, 12, 24, and 48 hours after treatment using the NRS. Te patients then randomly received an envelope containing pain medication and instructions for use. To ensure that the patients had fully understood the instructions for use of medications after opening the envelopes, the instructions for use were once again explained to patients and the patients used their frst dose right after completion of their treatment [24]. Te patients were requested to use 1 KTP (in KTP group) or 1 ibuprofen tablet (in ibuprofen tablet group) every 6 hours for the frst 24 hours, post-treatment. Te patients were instructed to apply the KTP on a hairless area such as the forearm. Te patients also received an envelope containing 10 acetaminophen tablets (500 mg) [25] as a rescue drug and asked to contact the researcher and use the rescue drug if the KTP or ibuprofen tablets did not alleviate their pain. Such patients were excluded from the study. Also, to ensure that the patients fll out the NRS form regularly, the researcher contacted each patient every 6 hours and reminded them to record their pain level (as mentioned earlier, at 2, 4, 8, 12, 24, and 48 hours after treatment). Te forms were then collected from patients, and the pain severity was classifed as no pain (score 0), mild pain (scores 1-3), moderate pain (scores 4-6), or severe pain (scores 7-10).
Side efects and complications reported by patients were also recorded.

Outcomes (Primary and Secondary).
Te main objective of this study was to compare the efcacy of KTP and ibuprofen tablets for pain control after endodontic treatment of mandibular frst and second molars with irreversible pulpitis. Te efects of sensitivity to percussion preoperatively, type of tooth, and gender of patients on postoperative pain were also assessed as the secondary outcome measures.

Sample Size Calculation.
Te sample size was calculated to be 28 in each group (a total of 56) according to a previous study by Murthykumar and Varghese [26] assuming alpha � 0.05, beta � 0.2, and study power of 80%. To increase the accuracy and control for the possible dropouts, 64 patients were enrolled.

Interim Analyses and Stopping Guidelines.
No interim analyses were performed, and no stopping guidelines were established.

Randomization.
Te patients were randomly divided into two groups by stratifed permuted block randomization with block size � 4 using sequentially numbered, sealed, opaque envelopes [27]. Since 64 patients were enrolled, four groups (n � 16) were considered for randomization: (I) males with a mandibular frst molar with irreversible pulpitis, (II) males with a mandibular second molar with irreversible pulpitis, (III) females with a mandibular frst molar with irreversible pulpitis, and (IV) females with a mandibular second molar with irreversible pulpitis. In each of the four groups, each patient randomly received KTP or ibuprofen tablets. Tus, frst, four sequences of 16 of the two drugs were randomly created by flliping a coin. Next, 64 envelopes with aluminum covers (to mask the contents) were created and coded. Te medications were placed in the envelopes and sealed. A copy of the list of blocks was created by an assistant (who had no involvement in the next phases of the study).

Blinding.
A dental assistant randomly assigned the medication envelopes to patients. Te dental clinician, researcher, and statistician who analyzed the data were all blinded to the group allocation of patients. Only the dental assistant who randomly assigned the coded envelopes to patients was aware of the contents of the envelopes. To ensure allocation concealment, sequentially numbered sealed opaque envelopes were used [27].

Statistical
Analysis. Normal distribution of pain data was evaluated by the Kolmogorov-Smirnov test. Te results showed that distribution of pain data was normal at 2, 4, 8, and 12 hours. Tus, comparisons at these time points were performed by the t-test. Pain data had non-normal distribution at 24 and 48 hours. Tus, comparisons at these time points were carried out by the Mann-Whitney test. Te independent t-test was used to compare the level of pain of patients in the two groups before treatment. Spearman's correlation coefcient was applied to analyze the correlation of pain and anxiety before treatment with pain after treatment.
Considering the diferences in distribution of data at diferent time points, the quantitative trend of pain over time was analyzed by generalized estimating equation (GEE). Since the trend of pain reduction over time was not linear, the Spline technique was used to analyze the trend of pain score change over time such that one line was considered from 2 to 10 hours and a second line was considered from 10 to 48 hours post-treatment. Te overall form of the linear regression formula was as follows: Mean pain score: (1) Finally, Fisher's exact test was used to compare the two groups regarding complete analgesia (NRS score 0) at different time points. All statistical analyses were carried out using SPSS version 20 at the 0.05 level of signifcance.

Results
Te sample consisted of 64 patients including 32 males and 32 females, in two groups with equal gender distribution (16 males and 16 females in each group). Te mean age of patients was 34.87 ± 11.16 years in the experimental group and 35.81 ± 11.19 years in the control group. Te two groups had no signifcant diference regarding the mean age (P > 0.05). Figure 1 shows the CONSORT fow diagram of patient selection and allocation.

Harms.
No patients were harmed during the study. Table 1 presents the demographic variables in the two groups. Table 2 indicates the mean pain score at diferent time points in the two groups. Considering the normal distribution of pain data at 2, 4, 8, and 12 hours, the two groups were compared regarding the pain score at these time points by the t-test, which revealed no signifcant diference at any time point (P > 0.05). At 24 and 48 hours, the groups were compared by the Mann-Whitney test, which revealed no signifcant diference (P > 0.05). Also, the Mann-Whitney test showed no signifcant diference in the pain score between the frst and second molars (P > 0.05).
Comparison of patients with pain score 0 between the two groups at each time point by Fisher's exact test revealed no signifcant diference (P > 0.05).
Regarding sensitivity to percussion before treatment, 21 patients were evaluated (since the results of the percussion test had been recorded for only 21 patients); out of which, 5 were sensitive and 16 were not sensitive to percussion. Te ttest showed that the diference in the pain score between sensitive patients and not sensitive to percussion was only signifcant at 2 hours postoperatively, and the pain score was higher in the group not sensitive to percussion (P � 0.027). At other time points, pain was higher in the group not sensitive to percussion but not signifcantly (P > 0.05).
Two out of 32 patients in the ibuprofen tablet group reported gastrointestinal problems in the form of mild pain. Also, one patient in the KTP group experienced slight redness and itchiness when used the frst KTP. Since he wanted to continue using the patch, he applied the next patch on another area with no problem.
Assessment of the pain score over time showed a nonlinear trend of reduction in pain over time in both groups ( Figure 2). Tus, by using the Spline technique, two lines were considered: one from 2 to 10 hours and the other one from 10 to 48 hours.
Although the mean preoperative pain score was higher in the KTP group, the diference between the two groups was not signifcant (P � 0.141). In both groups, the reduction in the pain score in both the frst (2-10 hours) and second (10-48 hours) intervals was signifcant (P < 0.001 for both).
Te interaction efect of time and medication was not signifcant at any interval in any group (P � 0.432 for KTP and P � 0.571 for tablet group), which means that the pattern of pain reduction over time was the same in both the groups.
GEE was applied to assess the efect of type of tooth on postoperative pain and showed that although patients with a second molar with irreversible pulpitis had higher postoperative pain than those with a frst molar with irreversible pulpitis (Figure 3), this diference was not signifcant (P � 0.298).
GEE was also used to analyze the efect of gender, and it indicated that although females in both groups had a higher pain score than males (Figure 4), this diference did not reach statistical signifcance (P � 0.472).

Discussion
Tis study compared the efcacy of KTP and ibuprofen tablets for pain control after endodontic treatment of mandibular frst and second molars with irreversible pulpitis. Te severity of preoperative pain and pulpal diagnosis are among the factors that can afect postoperative pain [10].
Tus, the two groups were standardized regarding these parameters. Also, regular administration of medications adopted in this study was due to the advantages of the regular technique such as lower pain experience by patients [28]. Selection of 400 mg ibuprofen tablets for the tablet group in this study was because 400 mg dosage of ibuprofen is required for its ceiling efect and that increasing the dosage does not signifcantly increase the analgesic efcacy [29]. Moreover, selection of 60 mg ketoprofen administered every 6 hours was according to a previous study [30].
In the present study, the NRS was used for quantifcation of pain due to its slightly superior efcacy to the visual analog scale [31]. Also, the NRS has higher reliability in both literate and illiterate patients [32]. It has been shown that the amount of apically extruded debris also afects the level of postoperative pain; thus, a rotary system with the crowndown technique was used in both groups in this study, which has been shown to minimize apical extrusion of debris [33].
Te results revealed no signifcant diference in the pain score between the two groups at any time point, and both groups demonstrated a similar trend of pain reduction over time.
Evidence shows that preoperative pain and periapical allodynia (sensitivity to percussion) can signifcantly affect postendodontic pain [34]. In addition, the preoperative anxiety of patients increases their postendodontic pain experience [35]. Similarly, the present study showed signifcant positive correlations between preoperative pain and preoperative anxiety with postoperative pain up to 24 hours. However, patients sensitive to percussion experienced lower postoperative pain, and this correlation was signifcant at 2 hours posttreatment. Te same results were reported by Parirokh et al. [38] who showed that preoperative pain had a greater efect than sensitivity to percussion on postendodontic pain. However, since the number of patients sensitive to    percussion was low in the present study, further investigations are required on this topic. Assessment of the efect of gender on the postoperative pain score by GEE in the present study showed that although females in both groups had a higher pain score than males, this diference did not reach statistical signifcance, which was in line with a previous study [37]. However, Gear et al. [38] used opioids for reduction of pain after oral surgical procedures and reported greater pain reduction in females than males. Variations in the results can be attributed to physiological diferences of males and females and diferent individuals, as well as diferent pharmacodynamics of medications [39]. Also, pain perception is subjective and diferent individuals have diferent levels of pain perception thresholds, which can explain variations in the results.

Pain Research and Management
GEE also assessed the efect of type of tooth on postoperative pain, and it showed that although patients with a second molar with irreversible pulpitis had higher postoperative pain than those with a frst molar with irreversible pulpitis, this diference was not signifcant. No previous study is available on this topic to compare our results with.
In the present study, 2 patients in the ibuprofen tablet group had mild gastrointestinal pain, which was reported in 12 out of 16 patients in a study by Mangal et al. [40]. Diference between the present results and those of Mangal et al. [40] in this respect may be due to greater gastrointestinal problems caused by diclofenac compared with ibuprofen and inclusion of patients with no history of gastrointestinal problems and allergy to ibuprofen in the present study. In the study by Mangal et al. [40], no skin reaction to diclofenac patch was reported, while in the present study, one patient developed slight redness and itchiness at the site of KTP.
In the current study, although the mean preoperative pain score was higher in the KTP group, the diference between the two groups was not signifcant. In both groups, the reduction in the pain score in both the frst (2-10 hours) and second (10-48 hours) intervals was signifcant. Te interaction efect of time and medication was not signifcant at any interval in any group, which means that the pattern of pain reduction over time was the same in both the groups.

Pain Research and Management
As mentioned earlier, several studies have evaluated the efects of NSAIDs in the form of transdermal patch on pain after tooth extraction [2,14,20,41], periodontal surgery [26,42], and maxillofacial surgical procedures [43,44]. However, only one study was found on the efcacy of diclofenac sodium transdermal patch for postendodontic pain control [40], which reported results similar to the present fndings and revealed that diclofenac patches had a comparable analgesic efcacy to ibuprofen tablets.
Moreover, controversy exists in the literature regarding the efcacy of transdermal patches. Tree studies on pain control by oral intake of diclofenac sodium and its transdermal patch following periodontal fap surgery showed that its transdermal patch could have a higher [45], comparable [42], or lower [26] efcacy than its oral form. Such diferences may be due to the use of diferent daily doses and fap elevation techniques. Also, studies on postextraction pain indicated that diclofenac patch can have equal [2,41] or slightly lower efcacy in the frst 24 hours and comparable efcacy at 48 hours [14] to diclofenac tablets. Although the severity and nature of periodontal and postextraction pains are diferent from postendodontic pain since a certain plasma concentration of analgesic is required for pain control (irrespective of type of pain), and transdermal patches have systemic efects as well, it may be concluded that such patches can be used to obtain plasma concentrations similar to oral tablets and successfully alleviate pain.
To the best of the authors' knowledge, this study is the frst to assess the efcacy of KTP for postendodontic pain control, which is a major strength of this study. Assessment of the efect of gender on postoperative pain was another strength of this study.
Tis study had some limitations as well. Absence of a placebo group was a limitation of this study. However, it was not ethically possible to have a placebo group. Also, subjective nature of pain is another limitation, which cannot be controlled for. Moreover, the age range of the study population was high, which can afect the pain threshold.
Future studies on a larger sample size are required to increase the generalizability of the results.

Conclusion
Both KTP and ibuprofen efectively decreased postendodontic pain. Nonetheless, considering the optimal analgesic efcacy of KTP comparable to that of ibuprofen tablets and lower side efects of KTP, it may be used as an alternative to oral ibuprofen tablets for pain control following endodontic treatment of mandibular frst and second molars with irreversible pulpitis.

Data Availability
Te patients' data used to support the fndings of this study are included within the supplementary pdf fle, named "data."

Conflicts of Interest
Te authors declare that they have no conficts of interest regarding the publication of this article.