Effect of pretreatment medication on postendodontic pain: A double-blind, placebo-controlled study

Abstract

Background:

Posttreatment endodontic pain has been reported in 25%–40% of all endodontic patients. Effective management of endodontic pain represents a continuing challenge.

Aim:

To evaluate and compare the efficacy of preoperative single dose of nonsteroidal anti-inflammatory drug, piroxicam (20 mg), with two types of corticosteroid drugs – dexamethasone (4 mg) or deflazacort (30 mg) – for the prevention and control of postendodontic pain.

Materials and Methods:

A total of 132 volunteers selected for nonsurgical root canal therapy were randomly divided into the following four groups (n = 30 each) according to preoperative medication given: Group 1, piroxicam (20 mg); Group 2, dexamethasone (4 mg); Group 3, deflazacort (30 mg); and Group 4, placebo. The preoperative medications were administrated 1 h before the start of standard endodontic treatment. Patients were instructed to complete a pain diary using Visual Analog Scale preoperatively and at 6-, 12-, 24-, 48-, and 72-h intervals after root canal instrumentation.

Statistical Analysis:

The correlation between preoperative endodontic pain to postoperative pain and pair-wise comparison of four groups was evaluated by Kruskal–Wallis analysis of variance test followed by Mann–Whitney U-test.

Results:

Compared to the placebo group, piroxicam, dexamethasone, and deflazacort resulted in a statistically significant reduction in postendodontic pain at 6, 12, and 24 h (P < 0.05).

Conclusion:

Preoperative single oral dose of piroxicam or dexamethasone or deflazacort is equally effective in controlling postendodontic pain.

INTRODUCTION

Effective management of endodontic pain represents a continuing challenge. In spite of advances in root canal treatment procedures and better knowledge of pulpal and periapical inflammation, up to 40% of endodontic patients report postoperative pain of different degrees.[1] Postendodontic pain results from irritation to periradicular tissues during instrumentation and/or obturation of root canals. Pain is usually more intense in the first 48 h and progressively reduces with time and usually disappears after 4–7 days.[2] Therefore, it is critical for the clinician to minimize or prevent pain by following appropriate treatment regimens supplemented with analgesics.

Postoperative endodontic pain is often linked to inflammatory mediators among which prostaglandins play a critical role in the pathogenesis of pulpal and periradicular diseases.[3] Prostaglandins increase vascular permeability, elevate chemotactic activity, and increase the sensitivity of pain receptors to other active inflammatory mediators.[4]

Several studies have emphasized that a preoperative single oral dose of anti-inflammatory drugs can modulate the release of inflammatory mediators and reduce the occurrence of side effects compared with repeated doses during the postoperative period. The maximum benefit of the anti-inflammatory drugs is obtained when therapeutic levels are reached before tissue manipulation.[5,6,7,8]

The major analgesic drug class for treating endodontic pain is nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. The NSAIDs are thought to produce their analgesic and anti-inflammatory effects by the inhibition of cyclooxygenase (COX).[3] Piroxicam is a nonsteroidal COX-1 inhibitor that has long-acting anti-inflammatory action with minimal side effects such as gastric intolerance.[9] Piroxicam has a half-life of 50 h, and its oral dose reaches peak concentration within 2 h.

Dexamethasone is a steroidal anti-inflammatory drug (SAID) that inhibits phospholipase-A₂ and consequently reduces prostaglandin and leukotriene synthesis, decreasing the polymorphonuclear leukocyte chemotaxis.[1] Deflazacort is a glucocorticoid, a synthetic oxazoline derivative of prednisolone. Its anti-inflammatory and immunosuppressive effects are used in treating various diseases and are comparable to other anti-inflammatory steroids.[10] Hence, the objective of the study was to compare the efficacy of NSAID – piroxicam (20 mg), with two corticosteroids – dexamethasone (4 mg) and deflazacort (30 mg) – and a placebo (lactose anhydrate), administered as a single preoperative oral dose for the prevention and control of postendodontic pain.

MATERIALS AND METHODS

The study protocol was approved by the Joint Research and Ethics Committee of Health University. One hundred and thirty-two patients (62 men and 70 women) within the age group of 18–50 years were selected to take part in this double-blind, parallel-randomized, placebo-controlled clinical trial.

A clinical examination was conducted for the volunteers that included thermal and electric pulp testing, percussion and palpation evaluation, periodontal probing, mobility assessment, and a periapical radiograph. All the past and present symptoms were noted. A diagnosis of irreversible pulpitis was determined on the basis of the history and clinical and radiographic features.

The inclusion criteria for selecting the volunteers were as follows: patients who required nonsurgical endodontic therapy in single or multirooted posterior teeth (premolars and molars) with vital or nonvital pulp and symptomatic teeth with mild-to-moderate pulpalgia. Exclusion criteria were as follows: patients who had taken analgesics and anti-inflammatory drugs within the last 12 h; presence of acute endodontic or periodontal abscess; patients having systemic diseases that require prophylactic antibiotics; pregnant and lactating women; and individuals with any known sensitivity or other adverse reactions to test medications.

The method used to measure preoperative pain intensity was the Visual Analog Scale (VAS) anchored by two extremes, “no pain” and “pain as bad as it could be.” Patients were asked to make a mark as a line that represented their level of perceived pain. Thus, pain intensity was assigned into four categorical scores as follows: none, 0; mild, 1–33; moderate, 34–66; and severe, 67–100.

The volunteers were randomly divided into four groups based on the type of preoperative medication given: Group 1 (n = 33) received a NSAID, piroxicam 20 mg (Dolonex DT, Pfizer Ltd., Hyderabad, Telangana, India. Lot No. 320-04221V); Group 2 (n = 33) received dexamethasone 4 mg (Decdek-4, Wockhardt Ltd., Mumbai, Maharashtra, India. Batch No. TMP3001); Group 3 (n = 33) received deflazacort 30 mg (Defcort 30, Aristo pharmaceuticals, Mumbai, Maharashtra, India. Batch No. GDE206A); and Group 4 (n = 33) received a gelatin capsule filled with lactose anhydrate (placebo). Medications were administered 1 h before the conventional root canal therapy. To maintain the double-blind design, a second investigator provided the tablets to volunteers so that the patient was not aware of the medication he/she was taking.

Endodontic treatment was completed by two postgraduate students for all the selected teeth. One hour after oral administration of the premedication, each patient was anesthetized with 2% lidocaine with 1:80,000 epinephrine (2% Lignox, Warren, Indoco remedies Ltd., Mumbai, Maharashtra, India) followed by rubber dam isolation. Access cavity preparations were done using Endo access burs (Dentsply Maillefer, Ballaigues, Switzerland). Working length of each canal was determined by using apex locator (Formatron D10, Parkell Inc. Edgewood, NY, USA) and was confirmed by taking radiographs. Cleaning and shaping of the root canals were completed in crown-down manner with ProTaper rotary Ni-Ti files (Dentsply Maillefer, Switzerland). The canals were irrigated with 2 ml of 3% sodium hypochlorite (Prime Dental Products Pvt., Ltd., Thane, Maharashtra, India. Lot No. 111130-01) after each instrumentation, with a syringe and 27G side-vented needles (RC TWENTS, Prime Dental Products Pvt., Ltd., Mulund West, Mumbai, Maharashtra, India. Lot No. 20140311). Following cleaning and shaping, dry cotton pellet without any medicament was placed in the pulp chamber, and the access cavity was temporarily restored with intermediate restorative material (IRM, Dentsply, Caulk, USA), and the occlusion was checked.

Patients were instructed to complete a pain diary on VAS at 6-, 12-, 24-, 48-, and 72-h intervals after root canal instrumentation. The volunteers received rescue medication of ibuprofen with acetaminophen (Flexon, Aristo pharmaceuticals, Nani Daman, Daman, India. Batch No. D926M697) and were instructed to take this medication as needed; however, in this case, those patients were excluded from the study. Patients were recalled for obturation, 72 h after instrumentation of the root canals.

The recorded data were transformed to IBM SPSS software version 20.0 (IBM, Armonk, NY, USA) for statistical analysis. The correlation between preoperative and postoperative pain at different time periods was evaluated by Kruskal–Wallis analysis of variance test, followed by Mann–Whitney U-test. Within the groups, comparison of postendodontic pain at different time periods was done using Wilcoxon signed-rank test. The level of statistical significance was set at α = 5%.

RESULTS

Out of the 132 patients included, only 122 patients could complete the study protocol. Three patients in the dexamethasone group and two patients in the piroxicam group were withdrawn from the study owing to a protocol violation. Five patients in the placebo group were excluded as they had to take rescue medication due to the intensity of postoperative pain. Thus, to standardize the number in each test group, statistical analysis of VAS scores was done for 120 patients, keeping 30 patients each for four groups.

The sample was distributed in a similar way in regard to age, type of involved teeth, and the intensity of preoperative pain, and no significant difference was found between the groups. In all the groups, volunteers with preoperative pain intensity levels were equally distributed, individuals having higher percentage of moderate pain (74%) than mild intensity pain (26%).

Intensity and occurrence of pain was decreased in all the four experimental groups between all time intervals after cleaning and shaping of root canals. Although statistically not significant, the pain reduction was greatest in Group 2 (dexamethasone), followed by Group 1 (piroxicam) and Group 3 (deflazacort) and least reduction was found in Group 4, where the volunteers received placebo.

The percentage of patients reporting no pain after 6-h period was 77% for dexamethasone group and 23% for the placebo group [Table 1]. After 72 h, 100% of patients in the dexamethasone group and 87% of placebo group reported no pain.

Table 1.

Percentage of patients reporting no pain postoperatively at 6, 12, 24, 48, and 72 h

Groups	At 6 h	At 12 h	At 24 h	At 48 h	At 72 h
Group 1 (%)	70	83.3 3	86.66	93.33	93.33
Group 2 (%)	76.66	83.33	90	90	100
Group 3 (%)	60	70	76.66	86.66	93.33
Group 4 (%)	23.33	30	43.33	73.33	86.66

Statistically no significant difference was observed when Group 1 was compared to Group 2 or Group 3 between preoperative and postoperative pain levels at different time intervals [Table 2]. However, with Group 4, all the other three groups (Groups 1, 2, and 3) showed statistically significant difference up to 24-h time interval and after that, no difference was observed between the four groups.

Table 2.

Pair-wise comparison of P-Value of four groups (1, 2, 3, 4) with respect to Visual Analog Scale scores at different time intervals by Mann-Whitney U-test

	Preoperative	At 6h	At 12h	At 24h	At 48h	At 72h
Group 1 versus Group 2	0.5250	0.7618	0.9882	0.8303	0.8360	0.6574
Group 1 versus Group 3	0.9882	0.5592	0.5692	0.9764	0.9882	0.9882
Group 1 versus Group 4	0.3671	0.0007*	0.0005*	0.0028*	0.1761	0.6467
Group 2 versus Group 3	0.5346	0.4333	0.5642	0.8073	0.8534	0.6574
Group 2 versus Group 4	0.7731	0.0003*	0.0004*	0.0017*	0.2198	0.3751
Group 3 versus Group 4	0.3831	0.0013*	0.0009*	0.0050*	0.1984	0.6627

P Value less than or equal to 0.05 is considered to be statistically significant

DISCUSSION

Postoperative pain is more likely to arise within a few hours following root canal treatment. Patients who have postoperative pain need analgesics that have fewer side effects for relieving the pain. Reduction in postoperative pain after prophylactic single-dose administration of NSAIDs and SAIDs has been proved in endodontic models.[11,12,13] Administration of NSAIDs before root canal treatment can block the COX pathway, and thus the pain sensation can be blocked even before it begins. In contrary with these findings, Attar et al. declared that preoperative administration of NSAID treatment did not significantly reduce postoperative pain.[14] However, in the present study, the administration of piroxicam or dexamethasone or deflazacort reduced postoperative pain after 6, 12, and 24 h effectively compared to the placebo group. In addition, all the drugs including placebo showed similar pain ratings at other time intervals (48 and 72 h). Mokhtari et al. stated that ibuprofen and indomethacin significantly reduced the postoperative pain in comparison with placebo during treatment and 8 h after treatment; however, there was no significant difference between them at 12 and 24 h after treatment.[15]

Glucocorticoids are believed to excite the production of anti-inflammatory cytokine tumor growth factor-β in target cells through pre- and post-transcriptional mechanisms. The bioequivalence of deflazacort and prednisolone has been investigated in various situations. In normal controls, 15-mg deflazacort inhibits T-cell reactivity to the same extent as 12.5 mg prednisolone, but for a longer period of time. Patients treated with long-term corticosteroids might be expected to have some complications during the endodontic treatment such as a rapid periapical bone destruction caused by the combined effect of a subclinical infection, suppressed immune response, reduced bone mineral content, and negative balance of the bone remodeling process in the jaws. However, single oral doses are safe over short-term usage, without side effects or contraindications.[1,16,17]

Piroxicam is a long-acting NSAID with a potent anti-inflammatory activity similar to indomethacin and has good analgesic activity. They lower prostaglandin release at inflammatory site and decrease the production of IgM rheumatoid factor. Chemotaxis of leukocytes and ratio of T-helper to T-suppressor lymphocytes are also reduced. Thus, it can inhibit inflammation in diverse ways.[18] Piroxicam's half-life of 50 h could favorably overcome the intense pain up to 48 h following the endodontic treatment. Piroxicam was compared with corticosteroids in this study as this drug is suitable for short-term analgesic and long-term anti-inflammatory actions.

Placebo groups are commonly used in drug efficacy studies.[1,5,14,17,18] For ethical reasons, all patients were informed about the possibility of receiving a sham (placebo) treatment. Gelatin capsules filled with lactose anhydrate were used as placebo in this study to reduce bias and to improve reliability of the study. In this study also, placebo group exhibited more intake of rescue medication compared to other groups. Smith et al. also reported that the combination of ibuprofen 600 mg and acetaminophen 1000 mg is more effective than placebo.[19] The double-blind, randomized study design minimized bias and allowed sufficient comparison between the groups. VAS was used to evaluate pain intensity; this scale has been used in most of the previous studies that analyzed pain after endodontic treatment. The VAS is more sensitive to small changes than simple descriptive ordinal scales.[20]

Among the test medications, dexamethasone resulted in greater reduction in pain followed by piroxicam and deflazacort at all time intervals, but statistically significant difference was not found among them. Differences between the groups might have been seen at earlier time points (before 6-h measurement), but these measurements could have been confounded by local anesthetic residual effects. Due to its diverse activity in the control of inflammatory process, dexamethasone group resulted in greater reduction of postoperative pain, similar to published literature.[1,5,7] Among the tested two corticosteroid drugs, deflazacort resulted in less reduction of postoperative pain that may be attributed to its lower potency than dexamethasone. Published equivalency tables suggested that dexamethasone is approximately eight folds more potent than deflazacort.[21] Thus, deflazacort resulted in less pain reduction than dexamethasone during test periods.

This study demonstrated that prophylactic administration of 20 mg of piroxicam before initiating root canal treatment was more effective in reducing postoperative pain compared to deflazacort. Compared with SAIDs, it presents certain advantages with minimal side effects. Furthermore, it is characterized by lower penetration into tissues, which explains reduced incidence of adverse reactions owing to this drug, compared to many other NSAIDs.

CONCLUSION

Within the limitations of the present study, postendodontic pain was substantially reduced by preoperative single oral dose administration of piroxicam or dexamethasone or deflazacort compared with placebo.

Administration of preoperative single oral dose instead of multiple postoperative doses improved patient compliance and reduced side effects from medications. Further clinical studies should be carried out to analyze the potential of these drugs and other regimens examining different clinical conditions such as single- versus multiple-visit endodontic treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.