Abstract Objective: The aim of this prospective, randomised controlled study was to evaluate the efficacy of pulpal anaesthesia in the management of pain in mandibular first molars with symptomatic irreversible pulpitis (SIP) in relation to alternative adjunct therapies with a conventional inferior alveolar nerve block (IANB) versus the conventional IANB technique. Methods: In accordance with the CONSORT statement, a prospective, randomised controlled parallel-design clinical trial was created. Group 1: Conventional IANB (Control group); Group 2: IANB plus local infiltration; Group 3: IANB plus long buccal nerve block; Group 4: IANB plus premedication with paracetamol; and Group 5: IANB plus cryotherapy was the five groups comprised 50 participants who met the inclusion and exclusion criteria. People were asked to use the Heft-Parker Visual Analogue Scale (HP-VAS) to score their level of discomfort at three separate intervals during the treatment process: before treatment, during access opening, and during pulp extirpation. Results: During access opening, Tukey’s post hoc multiple comparison tests showed statistically highly significant differences (P < 0.001) between Group 1 and Group 4 and a statistically significant difference (P < 0.05) between Group 1 and Group 3. During pulp extirpation statistically significant difference (P < 0.05) between Group 1 and Group 4 were reported. While the other group shows a statistically insignificant difference. Conclusion: IANB alone does not provide painless endodontic treatment in SIP patients. Hence, adjunct therapy of premedication with paracetamol or a supplementarily anaesthetising long buccal nerve block can significantly increase anaesthetic efficacy of IANB.