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The purpose of this prospective study was to determine the effect of a combination of nitrous oxide/oxygen and 1 set of supplemental intraligamentary/periodontal ligament (PDL) injections followed by a second set of PDL injections on anesthetic success in patients with symptomatic irreversible pulpitis (SIP). Ninety-four patients with a mandibular posterior tooth diagnosed with SIP received nitrous oxide/oxygen and an inferior alveolar nerve block (IANB) with 2% lidocaine with 1:100,000 epinephrine. Patients rated the pain of PDL injections and endodontic access on a visual analog scale. If moderate to severe pain was felt during treatment, the operator administered 1 set of supplemental PDL injections with 4% articaine with 1:100,000 epinephrine. If moderate to severe pain was felt again during treatment, the operator administered a second set of supplemental PDL injections. Anesthetic success was defined as having no to mild pain during endodontic treatment. The success of the IANB with nitrous oxide was 44% (95% confidence interval [CI], 34%–54%). The overall anesthetic success rate (IANB with PDL injections) was increased from 69% (95% CI, 60%–78%) with 1 set of PDL injections to 80% (95% CI, 72%–88%) with a second set of PDL injections. Although the second set of PDL injections increased anesthetic success, it was not sufficient to ensure complete pulpal anesthesia. [ABSTRACT FROM AUTHOR]