This randomized controlled trial evaluates whether a final flush with 3% hypertonic saline, compared with 0.9% normal saline, reduces post-operative pain and periapical Substance P (SP) levels after single-visit root canal treatment in mandibular premolars with symptomatic irreversible pulpitis. Forty adult patients will be randomized 1:1. Pain will be measured with the Visual Analogue Scale (VAS) at 6, 12, 24, and 48 hours post-operatively. Periapical fluid SP levels will be measured by ELISA at two intra-operative time points (after working length determination, and after the final flush). The number of ibuprofen 400 mg tablets consumed within 24-48 hours will also be recorded.

Post-operative endodontic pain is linked to periapical release of Substance P (SP), a neuropeptide that sustains neurogenic inflammation via NK-1 receptor binding. 3% hypertonic saline has documented osmotic decongestant and NF-κB-mediated anti-inflammatory/cytokine-suppressive effects in non-dental models, providing biological rationale for its use as a final irrigant. This is a two-arm, parallel-group, participant- and assessor-blinded RCT conducted at the outpatient endodontic clinic, Faculty of Dentistry, Cairo University. After standardized access, working length determination, and a baseline periapical fluid sample (S1), canals will be shaped with continuous rotary NiTi instrumentation and irrigated with 2.5% NaOCl. After smear layer removal (2.5% NaOCl then 17% EDTA), participants receive a final flush of either 5 mL 0.9% normal saline (control) or 5 mL 3% hypertonic saline (intervention), delivered via a 30-gauge side-vented needle 2 mm short of working length. A second periapical fluid sample (S2) is then collected. Canals are obturated by lateral compaction in the same visit. Participants record VAS pain scores pre-operatively and at 6, 12, 24, and 48 hours, and log ibuprofen 400 mg tablet consumption at 24 and 48 hours. SP will be quantified from S1/S2 samples by ELISA, blinded to group allocation.

Inclusion Criteria:

• Age 18-60 years, any sex
• Systemically healthy
• Mandibular premolar with clinically/radiographically diagnosed symptomatic irreversible pulpitis (prolonged, exaggerated response to cold testing; no periapical radiolucency)
• Able to use the VAS scale and complete follow-up

Exclusion Criteria:

• Medically compromised patients
• Pregnant or lactating women
• Allergy/hypersensitivity to local anesthetics or NSAIDs
• Analgesics, anti-inflammatories, or antibiotics within 12 hours pre-treatment
• Vertical root fracture, root resorption, or previous RCT
• Radiographic periapical pathology
• Non-restorable teeth
• TMD, bruxism, or traumatic occlusion interfering with pain assessment

Masking Description: Both irrigants are clear, colorless, odorless aqueous solutions administered identically, so participants cannot distinguish allocation. The laboratory technician performing ELISA and the biostatistician performing final analysis are blinded to group via coded datasets; unmasking occurs only after analysis is complete. The treating investigator cannot be blinded due to the nature of the intervention.