Profound pulpal anesthesia can be difficult to achieve for patients with irreversible pulpitis due to factors such as altered resting potentials, reduced thresholds of excitability and the tetrodotoxin-resistant (TTXr) class of sodium channels. Clinicians might try various strategies to address this problem such as changing the anesthetic agent, for example using articaine instead of lidocaine injection, and by using a supplemental anesthetic injection delivery technique. The principal aim of this study was to provide a systematic review and meta-analysis to address the PICO question: in adults with symptomatic irreversible pulpitis who are undergoing endodontic treatment, what is the comparative efficacy of articaine compared with lidocaine in reducing pain and incidence of adverse events? The secondary aim was to identify, characterize and assess the quality of peer-reviewed clinical studies that investigated pulpal anesthesia achieved by the administration of supplemental anesthetic solution following prior anesthesia delivered via any route in adults with symptomatic irreversible pulpitis.