Kynurenic Acid and Serotonin as Perioperative Neuroinflammatory Biomarkers in Sequential Third Molar Surgery (KYNA-3M)

Influence of Serotonin and Kynurenic Acid on Postoperative Pain, Neuroinflammation and Anxiety Following Surgical Removal of Impacted Mandibular Third Molars

A prospective cohort of 40 consecutive patients with bilateral impacted mandibular third molars underwent two sequential surgical extractions separated by a two-week interval. Serum kynurenic acid (KYNA) and serotonin were measured preoperatively and 24 hours after each procedure. The study examined longitudinal dynamics of kynurenine pathway biomarkers, their variation across Pederson surgical difficulty grades, and their relationship with postoperative pain and state anxiety.

Study Overview

• Status: Completed
• Conditions: Postoperative Pain; Anxiety; Neuroinflammation; Impacted Third Molar
• Intervention / Treatment: Drug: Placebo; Drug: Ibuprofen; Drug: Ibuprofen + Gabapentin

Detailed Description

Participants were randomised to placebo, ibuprofen 400 mg, or ibuprofen 400 mg plus gabapentin 300 mg administered preemptively 1 hour before incision and continued at 8-hourly intervals for 24 hours. Blood samples were collected at four timepoints (T0 Op1, T24 Op1, T0 Op2, T24 Op2) and analysed by ELISA for serum KYNA and serotonin. Postoperative pain was assessed by VAS at 2, 6, 12, 24, 48, and 72 hours. State-trait anxiety was assessed using the STAI Form Y before each operation. Pederson difficulty index was applied independently by two calibrated examiners. The biomarker analysis is reported observationally with pharmacological allocation treated as a covariate. Clinical data and samples were collected at the Department of Oral Surgery, Faculty of Dental Medicine, Medical University of Plovdiv, Bulgaria, during 2017-2018; laboratory biomarker analyses were conducted under Project No. DPDT-12/2019, Medical University of Plovdiv, and completed in 2020.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv
    • Plovdiv, Plovdiv, Bulgaria, 4002
      • Faculty of Dental Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Bilateral impacted mandibular third molars requiring surgical extraction
• Age 18-38 years
• Written informed consent
• Ability to comply with study procedures

Exclusion Criteria:

• Systemic inflammatory disease
• Autoimmune disease
• Neurological disease
• Psychiatric disorders
• Chronic pain conditions
• Use of immunomodulatory medications
• Use of psychotropic medications
• Use of analgesic medications
• Pregnancy
• Drug hypersensitivity
• Active pericoronitis at enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Identical-appearing capsules administered 1 hour before incision, repeated every 8 hours for 24 hours. N=10.	Drug: Placebo; Identical-appearing oral capsules administered preemptively 1 hour before incision and every 8 hours for 24 hours.
Active Comparator: Ibuprofen; Ibuprofen 400 mg oral capsules administered 1 hour before incision, repeated every 8 hours for 24 hours. N=15	Drug: Ibuprofen; Ibuprofen 400 mg oral capsules administered preemptively 1 hour before incision and every 8 hours for 24 hours.
Experimental: Ibuprofen + Gabapentin; Ibuprofen 400 mg plus Gabapentin 300 mg oral capsules administered 1 hour before incision, repeated every 8 hours for 24 hours. N=15	Drug: Ibuprofen + Gabapentin; Ibuprofen 400 mg plus Gabapentin 300 mg oral capsules administered preemptively 1 hour before incision and every 8 hours for 24 hours.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum kynurenic acid (KYNA) concentration	Change in serum KYNA from preoperative baseline (T0) to 24 hours postoperative (T24) at each of two sequential operations, assessed by ELISA	Preoperative baseline and 24 hours postoperative at each operation
Serum serotonin concentration	Change in serum serotonin from preoperative baseline (T0) to 24 hours postoperative (T24) at each of two sequential operations, assessed by ELISA	Preoperative baseline and 24 hours postoperative at each operation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative pain intensity	Pain assessed using a 100 mm Visual Analogue Scale (VAS; 0 = no pain, 100 = worst imaginable pain)	2, 6, 12, 24, 48, and 72 hours postoperative at each operation
State anxiety	Preoperative state anxiety assessed using the State-Trait Anxiety Inventory (STAI Form Y), State subscale	Preoperative baseline at each operation
KYNA variation across Pederson surgical difficulty grades	Serum KYNA at 24 hours postoperative compared across Pederson difficulty grades (5-9), assessed by Kruskal-Wallis test	24 hours postoperative at Operation 1

Collaborators and Investigators

• Sponsor: Plovdiv Medical University
• Collaborators: Radka Ivanova Masaldzhieva, Dept. of Health Care Management, Faculty of Public Health, MU-Plovdiv; Mariya Vlado Ivanovska, Dept. of Microbiology and Immunology, Faculty of Medicine, MU-Plovdiv; Ralitsa Dimitrova Raycheva, Dept. of Social Medicine and Public Health, Faculty of Public Health, MU-Plovdiv
• Investigators: Principal Investigator: Deyan Neychev, MD, PhD, Medical University of Plovdiv

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2019
• Primary Completion (Actual): May 17, 2020
• Study Completion (Actual): September 30, 2020

Study Registration Dates

• First Submitted: June 8, 2026
• First Submitted That Met QC Criteria: June 8, 2026
• First Posted (Actual): June 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 16, 2026
• Last Update Submitted That Met QC Criteria: June 13, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: postoperative pain; serotonin; IDO; third molar surgery; kynurenic acid; kynurenine pathway; perioperative biomarker; Pederson index
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Nervous System Diseases; Mental Disorders; Postoperative Complications; Pathologic Processes; Inflammation; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neuroinflammatory Diseases; Pain, Postoperative; Anxiety Disorders; Amino Acids, Peptides, and Proteins; Organic Chemicals; Hydrocarbons; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Acids, Acyclic; Carboxylic Acids; Amines; Amino Acids; gamma-Aminobutyric Acid; Aminobutyrates; Butyrates; Acids, Carbocyclic; Cyclohexanecarboxylic Acids; Phenylpropionates; Gabapentin; Ibuprofen
• Other Study ID Numbers: DPDT-12/2019; Protocol No. P-604/28.02.2020 (Other Identifier: Ethics Committee MU-Plovdiv)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data are not planned for public sharing. Anonymized data are available from the corresponding author on reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No