This randomized clinical trial aimed to evaluate the effects of intracanal cryotherapy and two intracanal medicaments-calcium hydroxide and metformin-on postoperative spontaneous and percussion pain following root canal treatment in teeth with symptomatic apical periodontitis. In this double-blind, randomized, 2×2 factorial clinical trial, 80 patients with symptomatic apical periodontitis in mandibular premolars were enrolled and randomly assigned to four groups: calcium hydroxide, metformin, cryotherapy plus calcium hydroxide, and cryotherapy plus metformin. All teeth underwent standardized single-visit root canal treatment, and in the cryotherapy groups, final irrigation was performed using sterile saline at 4 °C. Spontaneous pain was assessed preoperatively and daily for 7 postoperative days, while percussion pain was evaluated preoperatively and postoperatively. Pain intensity was recorded using a 100-mm visual analog scale (VAS). Data were analyzed using mixed-effects models for repeated measures and analysis of covariance (ANCOVA) (α = 0.05).

Inclusion Criteria:

• systemically healthy
• Mandibular premolar teeth diagnosed with pulpal necrosis and indicated for root canal treatment.
• Periapical index score between 0 and 2.
• Aged between 18 and 70 years.
• Able to understand and complete visual analog scale (VAS) assessments.
• Provided written informed consent.

Exclusion Criteria:

• Any systemic disease or pregnancy.
• Use of analgesics within 24 hours prior to treatment.
• Severe bruxism.
• Presence of acute apical abscess or swelling.
• Periodontal pocket depths greater than 5 mm or tooth mobility exceeding grade 1.
• Teeth deemed unrestorable.
• Presence of vital pulpal tissue or immature apices
• Radiographic evidence of root resorption, root fracture, perforation, or canal calcification.

Individual patient data will not be shared to protect patient confidentiality and privacy, and are accessible only to researchers with approved ethical consent.

The treating clinician was blinded to the type of intracanal medicament and method until the final stage of the procedure. The previously randomized treatment protocol was disclosed to the clinician by an assistant.