Cryotherapy, PGE2, NGF Levels and Pain After Endodontic Retreatment

NCT07733700 | Not Yet Recruiting

• 1 other identifier: ALKU-EC-2026-44
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Asymptomatic Apical Periodontitis; Endodontic Retreatment; Cryotherapy

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Postoperative pain intensity (VAS score)

  Postoperative pain intensity assessed using a Visual Analog Scale (VAS, 0-100 mm, where 0 = no pain and 100 = worst imaginable pain), self-reported by patients. The 24-hour time point is designated as the primary comparison between the cryotherapy and control groups.

  Baseline, then at 6, 12, 24, 48, and 72 hours and on Day 7 postoperatively (primary comparison at 24 hours)

Secondary Outcomes (2)

• Salivary nerve growth factor (NGF) levels

  Baseline (T0), 24 hours (T1), and 72 hours (T2) postoperatively

• Gingival crevicular fluid (GCF) prostaglandin E2 (PGE2) levels

  Baseline (T0), 24 hours (T1), and 72 hours (T2) postoperatively

Other Outcomes (2)

• Rescue analgesic (paracetamol) consumption

  Over 7 days postoperatively

• Total rescue analgesic dose consumed

  Over 7 days postoperatively

Study Arms (2)

Cryotherapy group

EXPERIMENTAL

Following standard non-surgical endodontic retreatment instrumentation, participants received final intracanal irrigation with sterile saline (0.9% NaCl) cooled to 2.5°C, 20 mL, over 5 minutes, in a single visit.

Procedure: Intracanal cryotherapy

Control group

ACTIVE COMPARATOR

Following the same standard non-surgical endodontic retreatment instrumentation, participants received final intracanal irrigation with sterile saline (0.9% NaCl) at room temperature (20-22°C), 20 mL, over 5 minutes, in a single visit.

Procedure: Room-temperature saline irrigation

Interventions

Intracanal cryotherapy PROCEDURE

Final intracanal irrigation with sterile 0.9% saline solution cooled to 2.5°C (using an ice-water bath), 20 mL administered over 5 minutes, performed after canal instrumentation during single-visit non-surgical endodontic retreatment.

Also known as: Cold Saline Irrigation

Cryotherapy group

Room-temperature saline irrigation PROCEDURE

Final intracanal irrigation with sterile 0.9% saline solution at room temperature (20-22°C), 20 mL administered over 5 minutes, performed after canal instrumentation during single-visit non-surgical endodontic retreatment - identical protocol to the cryotherapy group except for irrigant temperature.

Control group

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-65 years, systemically healthy individuals (ASA I-II)
• Single-rooted mandibular premolar teeth with a previous root canal treatment, requiring non-surgical retreatment due to asymptomatic apical periodontitis
• Presence of periapical radiolucency (Periapical Index \[PAI\] ≥ 3)
• No antibiotic use within the past 1 month
• Willing to participate and has signed the informed consent form

You may not qualify if:

• Pregnancy or lactation
• Uncontrolled diabetes mellitus (HbA1c \> 7%), diagnosed autoimmune disease, or receiving immunosuppressive therapy
• Systemic corticosteroid use within the past 3 months
• Body mass index (BMI) greater than 35 kg/m²
• Presence of acute infection (e.g., acute apical abscess or cellulitis)
• Conditions precluding retreatment, including advanced periodontal breakdown (clinical attachment loss \> 5 mm), root resorption, perforation, or advanced canal calcification
• Absence of an opposing (antagonist) tooth resulting in lack of functional occlusal contact
• Diagnosed chronic pain syndrome or currently receiving active psychiatric treatment
• Smoking more than 10 cigarettes per day
• Use of analgesics or NSAIDs within the past 24 hours
• Antibiotic use within the past 1 month

Sponsors & Collaborators

• Alanya Alaaddin Keykubat University: lead

Study Sites (1)

Alanya Alaaddin Keykubat University, Faculty of Dentistry

Antalya, ALANYA, 07400, Turkey (Türkiye)

Location

Related Publications (3)

• Kaya Mumcu A, Tuzcu E, Kurnaz S, Kiraz G. Evaluation of the effect of intracanal cryotherapy on postoperative pain after retreatment: a randomized controlled clinical trial. Clin Oral Investig. 2025 Jun 25;29(7):355. doi: 10.1007/s00784-025-06435-w.

  PMID: 40560202 BACKGROUND

• Keskin C, Aksoy A, Kalyoncuoglu E, Keles A, Ilik AA, Komec O, Yuzgulec E, Akgun H, Alak SG, Tokur O. Effect of intracanal cryotherapy on the inflammatory cytokine, proteolytic enzyme levels and post-operative pain in teeth with asymptomatic apical periodontitis: A randomized clinical trial. Int Endod J. 2023 Aug;56(8):932-942. doi: 10.1111/iej.13937. Epub 2023 May 30.

  PMID: 37222468 BACKGROUND

• Vera J, Ochoa J, Romero M, Vazquez-Carcano M, Ramos-Gregorio CO, Aguilar RR, Cruz A, Sleiman P, Arias A. Intracanal Cryotherapy Reduces Postoperative Pain in Teeth with Symptomatic Apical Periodontitis: A Randomized Multicenter Clinical Trial. J Endod. 2018 Jan;44(1):4-8. doi: 10.1016/j.joen.2017.08.038. Epub 2017 Nov 1.

  PMID: 29079057 BACKGROUND

MeSH Terms

Conditions

Pain, Postoperative; Hereditary Sensory and Autonomic Neuropathies

Condition Hierarchy (Ancestors)

Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Pain; Neurologic Manifestations; Signs and Symptoms; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Study Officials

• Hatice BÜYÜKÖZER ÖZKAN, Associate Professor

  Alanya Alaaddin Keykubat University, Faculty of Dentistry, Department of Endodontics

  STUDY DIRECTOR

• Bilge Karcı, Associate Professor

  Alanya Alaaddin Keykubat University, Faculty of Dentistry, Department of Periodontology

  PRINCIPAL INVESTIGATOR

• Ertan Küçüksayan, Associate Professor

  Alanya Alaaddin Keykubat University, Faculty of Medicine, Department of Biochemistry

  PRINCIPAL INVESTIGATOR

• Gizem Pelin Yoldaş, Research Assistant

  Alanya Alaaddin Keykubat University, Faculty of Dentistry, Department of Endodontics

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hatice Büyüközer Özkan, Associate Professor

CONTACT

+90 530 971 02 52; hatice.ozkan@alanya.edu.tr

Gizem Pelin Yoldaş, Research Assistant

CONTACT

+90 5462446097; pelin.yoldas@alanya.edu.tr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: Laboratory personnel analyzing saliva and GCF samples (PGE2, NGF via ELISA), as well as the statisticians performing data analysis, will be blinded to group allocation. The treating clinician cannot be blinded due to the nature of the intervention (irrigation temperature).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: July 9, 2026
• First Posted: July 29, 2026
• Study Start: August 1, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): September 1, 2027
• Last Updated: July 29, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

TU (1)