This study was designed as a double-blind, randomized, placebo-controlled clinical trial. This trial was carried out according to the latest update of the Declaration of Helsinki guidelines (October 2013) and approved by the Vision Colleges Research Ethics Committee (approval number 20-5/2). The patients were pre-selected to participate based on a preoperative pain scale of preliminary clinical assessment following the guidelines suggested by the CONSORT group for planning and reporting clinical trials. A total of 275 adult patients were screened for participation in this study. They were emergency patients of the Vision Colleges Dental Clinics and were in good health based on their medical histories and oral questioning. Subjects who were less than 18 years old, had a history of serious medical problems, had used central nervous system depressants or any analgesic medication within the previous 6 hours, were pregnant or were unable to give informed consent were all excluded from the study. Finally, 50 patients were enrolled in each group, for a total of 250 patients.

The inclusion criteria were active pain in a mandibular molar first or/and the second molar, prolonged response to cold testing (Endo-frost; Roeko, Langenau, Germany), absence of any periapical radiolucency on periapical radiographs, and a vital coronal pulp on access opening. The Modified Dental Anxiety Scale assessed the level of anxiety among the patients. The pain of the patients was categorized into four categories using the Heft-Parker visual analogue scale (HP VAS):

0 mm: no pain 0-54 mm: faint, weak, or mild 55-114 mm: moderate pain \>114 mm: strong, intense, and maximum possible All patients were randomly divided using block randomisation to ensure the homogeneity of the five groups. The patients were randomly given tramadol 50 mg, tramadol 100 mg, ibuprofen 600 mg, ibuprofen 600 mg/acetaminophen 1000 mg or placebo by mouth 60 min before administering IANB. To blind the experiment, each of the 50 patients in each group was randomly allocated a code consists of 2 letters and one number. Only the random numbers identified the medications; thus, the patient and doctor were uninformed of which medication was given to them. The medication and placebo were blinded in the following way. In opaque yellow size "000" capsules, a certified pharmacist prepared identical-appearing capsules of the medications and placebo in identical separate containers for each medication. At 60 minutes after receiving the medication or placebo, the operator used a cotton tip applicator to put anaesthetic gel (20 percent benzocaine; Patterson Dental Supply, Inc, St Paul, MN, USA) at the IANB injection site for 60 s.

The participants were then given regular IANB injections and 0.9 mL long buccal injections containing 2% lidocaine and 1:100,000 epinephrine (Xylocaine; Astra Zeneca LP, Dentsply, York, PA, USA). The first author used self-aspirating syringes (Septodont, Sant-Maur-des-Fosses Cedex, France) and 27-G long needles to inject the anaesthetic solution (Septoject, Septodont). Each patient was asked for lip numbness every 5 min for 15 min after the IANB. The block was considered missed if substantial lip numbness was not reported by 15 min, and the participant was excluded from the trial. Due to a lack of lip numbness, no patients were excluded.

After that, a rubber dam was used to isolate the teeth and endodontic access was conducted. During the endodontic process, patients were asked to rate any pain they experienced. If the patient was in pain, the treatment was stopped, and the patient used the HP VAS to rate his/her discomfort. The success of the IANB was defined as the ability to access and clean and shape the tooth without pain (VAS score of 0) or mild pain (VAS rating ≤54 mm). The rubber dam was removed if the patient had moderate or severe pain (VAS rating ≥ 55 mm), and a buccal infiltration of a cartridge containing 4% articaine with 1:100,000 epinephrine (Septocaine; Septodont) was administrated buccally to the tooth that required emergency treatment. After 5 min, the rubber dam was replaced, and endodontic access was continued. The success of the buccal infiltration was defined as the ability to access and instrument the tooth without pain (VAS score of 0) or with mild pain (VAS rating ≤54 mm). Intraosseous anaesthesia was administrated to the patients who still had moderate to severe pain. The intraosseous injection was administrated with the Stabident intraosseous anaesthetic system (Fairfax Dental Inc, Miami, Fl, USA) using a cartridge of 2% lidocaine with 1:100,000 epinephrine as described previously. If that was not successful, an intrapulpal injection was given, and endodontic debridement was completed. The extent of access preparation and/or instrumentation was recorded as within dentine, within pulp space, and instrumentation of canals.

The VAS satisfaction form was used to record the post-treatment satisfaction of the patient. The patient was asked to draw a vertical line on the VAS (0-100 mm) to indicate their satisfaction with the entire treatment. The VAS was classified into four categories; 0: not satisfied, \>0 mm and ≤33 mm: somewhat satisfied, \>33 mm but \<66 mm: moderately satisfied and ≥66 mm: completely satisfied.

Data of the study were collected and statistically analysed (SPSS 22.0 software; IBM Corp., Armonk, NY, USA) using chi-square χ2 test to compare between different groups for anaesthetic success, gender, and tooth type. Normality of data was tested by Shapiro-Wilk test. The Modified Dental Anxiety Scale, age, and initial pain ratings were analysed by using Kruskal-Wallis test. The level of statistical significance was set at P \< 0.05. GPower v3.1.3 software (University of Düsseldorf; Düsseldorf, Germany) was used to calculate the sample size. According to a power analysis, a sample size of 50 patients per group meets the constraints of 0.05 and power = 0.95.