Cryotherapy, PGE2, NGF Levels and Pain After Endodontic Retreatment

Asymptomatic Apical Periodontitis, Cryotherapy, Endodontic Retreatment

Intracanal Cryotherapy, Postoperative Pain, Prostaglandin E2, Nerve Growth Factor, Endodontic Retreatment, Gingival Crevicular Fluid, Saliva Biomarkers

This prospective, randomized, controlled, single-blind, parallel-group clinical trial evaluates whether intracanal cryotherapy reduces postoperative pain and inflammatory biomarker levels following single-visit endodontic retreatment of teeth with asymptomatic apical periodontitis. A total of 100 patients (18-65 years, systemically healthy, ASA I-II) requiring non-surgical retreatment of a single-rooted mandibular premolar tooth will be randomly assigned via computer-generated randomization to one of two equal groups (n=50 each): a cryotherapy group, receiving intracanal final irrigation with sterile saline cooled to 2.5°C for 5 minutes, and a control group, receiving the same irrigation protocol with saline at room temperature (20-22°C). Salivary nerve growth factor (NGF) and gingival crevicular fluid (GCF) prostaglandin E2 (PGE2) levels will be measured by ELISA at baseline (T0), 24 hours (T1), and 72 hours (T2). Postoperative pain will be assessed using a visual analog scale (VAS, 0-100 mm) at 6, 12, 24, 48, and 72 hours and on day 7, with the 24-hour VAS score as the primary comparison point. Rescue analgesic (paracetamol) consumption will also be recorded and compared between groups. The study aims to determine whether intracanal cryotherapy lowers postoperative pain and biomarker levels compared to standard-temperature irrigation, and to evaluate the correlation between PGE2/NGF levels and pain intensity.

Postoperative pain following endodontic retreatment is associated with periapical inflammation mediated by prostaglandin E2 (PGE2) and nerve growth factor (NGF). Intracanal cryotherapy has been proposed to reduce postoperative pain through local hypothermia-induced vasoconstriction, neuropraxia, and reduced metabolic and inflammatory mediator activity. While prior studies have examined cryotherapy's effect on postoperative pain, no randomized controlled trial has jointly measured PGE2 and NGF using minimally invasive sampling methods (GCF and saliva) in the context of single-visit retreatment. Eligible patients will be systemically healthy adults (18-65 years, ASA I-II) with a single-rooted mandibular premolar tooth requiring non-surgical retreatment due to a previously inadequate root canal treatment, presenting with asymptomatic apical periodontitis and periapical radiolucency (PAI ≥ 3). Key exclusion criteria include pregnancy or lactation, uncontrolled diabetes mellitus (HbA1c \> 7%), autoimmune disease, immunosuppressive therapy, systemic corticosteroid use within the past 3 months, BMI \> 35 kg/m², acute infection (abscess/cellulitis), advanced periodontal breakdown, heavy smoking (\>10 cigarettes/day), recent analgesic/NSAID or antibiotic use, and chronic pain syndromes. Patients will be randomly allocated (computer-generated randomization, sealed envelopes) to one of two parallel groups: Group A (Cryotherapy): Following standard non-surgical retreatment instrumentation, final intracanal irrigation with sterile saline cooled to 2.5°C, 20 mL, over 5 minutes. Group B (Control): Identical protocol using sterile saline at room temperature (20-22°C), 20 mL, over 5 minutes. All treatments will be performed in a single visit by one calibrated operator following a standardized protocol; the two groups differ only in irrigation temperature. Given the nature of the intervention, the operator cannot be blinded; however, laboratory personnel analyzing saliva/GCF samples and statisticians will remain blinded to group allocation (single-blind design). Outcome measures: Primary: Postoperative pain intensity measured by VAS (0-100 mm) at 6, 12, 24, 48, and 72 hours and on day 7, with the 24-hour time point as the primary comparison. Secondary: Salivary NGF levels (ELISA) and GCF PGE2 levels (ELISA) at baseline (T0), 24 hours (T1), and 72 hours (T2); rescue analgesic (paracetamol 500 mg, oral, as needed) consumption over 7 days; and correlation between biomarker levels and VAS pain scores. Each patient will be followed for a total of 7 days. Saliva and GCF samples will be collected between 08:00-10:00 to minimize circadian variation. Sample size was calculated using G\*Power 3.1.9.7 (repeated-measures ANOVA, 80% power, α=0.05, f=0.25), yielding a minimum of 34 participants per group; accounting for an estimated 20% dropout rate, 50 patients per group (100 total) will be enrolled. Statistical significance will be set at p\<0.05. The study is sponsored and funded internally by Alanya Alaaddin Keykubat University, with no external funding or industry sponsorship.

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Turkey (Türkiye)