Clinical Pharmacogenetic of Ibuprofen After Lower Third Molar Surgeries

Clinical Pharmacogenetic of Ibuprofen Enantiomers After Lower Third Molar Surgeries

The present clinical trial randomized will be to assess the link between the different haplotypes of CYP2C8 and CYP2C9 genes and the clinical efficacy of ibuprofen after lower third molar extractions. Onset, duration of postoperative analgesia, duration of anesthetic action on soft tissues, intraoperative bleeding, hemodynamic parameters, postoperative mouth opening and wound healing at the 7th postoperative day were evaluated. For this purpose, 200 healthy volunteers underwent removal of one lower third molar, under local anesthesia with articaine 4% (1:200,000 adrenaline) will be genotyped and phenotyped for these genes and their postoperative records with all data collected will be compared with the haplotypes found in the Brazilian population.

Study Overview

• Status: Unknown
• Conditions: Pain; Impacted Third Molar Tooth; Other Surgical Procedures
• Intervention / Treatment: Drug: Ibuprofen 600 mg

Detailed Description

The aim of this study will be to assess the link between the different haplotypes of CYP2C8 and CYP2C9 genes and the clinical efficacy of ibuprofen after lower third molar extractions regarding pain, swelling and trismus, adverse reactions, the amount of pain medication used, the patient satisfaction with the drug and the influence of the ability on preoperative modulation of conditioned pain. We will evaluate also the relationship between the different haplotypes of OPRM1 gene (SNP A118G), the salivary concentrations of pro-inflammatory cytokines (IL-2, IL-4, IL-6, IL-10 and TNF-±), and preoperative conditioned pain modulation. Therefore, 200 patients will be genotyped and phenotyped for these genes and their postoperative records with all data collected will be compared with the haplotypes found in the Brazilian population.

For analysis of the proposed genes, saliva will be collected, which will serve as a source of genomic DNA. For molecular analysis it will be performed polymerase chain reaction (PCR). All tests will be conducted and validated by Applied Biosystems®. Also it will be held in the research, genetic sequencing of the genes CYP2C8, CYP2C9 and OPRM1, to verify possible correlations of these genes with postoperative pain and pain modulation.

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • SP
    • Bauru, SP, Brazil, 17017-901
      • University of Sao Paulo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Need of lower third molar surgeries

Exclusion Criteria:

• Presence of systemic diseases;
• Presence of local inflammation and/or infection;
• Any history of allergic reaction to local anesthetics, gastrointestinal bleeding or ulceration;
• Cardiovascular, kidney or hepatic diseases;
• Patients who are making use of antidepressants, diuretics or anticoagulants;
• Asthma and allergy to aspirin, ibuprofen or any other nonsteroidal antiinflammatory drug;
• Regular use of any nonsteroidal antiinflammatory drug,
• Pregnancy or breast feeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental Group Ibuprofen 600mg; Two Hundred healthy volunteers underwent removal of one lower third molar, will be treated to control pain, swelling and trismus with ibuprofen 600mg. Therefore, these 200 patients will be genotyped and phenotyped for these genes and their postoperative records with all data collected will be compared with the haplotypes found in the Brazilian population.

Drug: Ibuprofen 600 mg; After lower third molars surgeries, pharmacogenetic and clinical efficacy of Ibuprofen 600mg was study.; Other Names: Lower third molar surgery with ibuprofen for pharmacogenetic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of changes in the postsurgical pain during the first 24 hours until 96 hours after the procedure	Subjective evaluation of postsurgical pain, which was annotated by the volunteer after the surgery, in a Visual Analogue Scale (VAS, 0-100 mm). The subjective pain evaluations will be performed by patients at the following times after administration of the drug [0, 15, 30 and 45 min, 1; 1.5; 2; 3; 4; 5; 6; 7; 8; 10; 12; 16; 24 hr, 48, 72 and 96 h]. What will be taken into account on this outcome is the representation of the postsurgical pain, that will be noted on the Visual Analogue Scale (in millimeters) in respective moments.	Seventh postoperative day
Quality of anesthesia	Quality of anesthesia during surgery based on a category 3point scale: 1) the patient reported no discomfort; 2) the patient reported discomfort, without the need to supplement the anesthesia; 3) reported some discomfort by the patient, requiring anesthesia complementation. Intraoral bleeding that will be evaluated by the surgeon according to a 3point scale (1: minimal, 2: normal and 3: Maximum), immediately after the following steps: injection of the first cartridge anesthesia, incision, mucoperiosteal detachment, osteotomies, tooth section, extraction, cleaning and suturing.	During the surgical procedure
Intraoperative bleeding during the surgeries steps	Intraoperative bleeding, rated by the surgeon according to a 3 point category rating scale (1 minimal bleeding; 2 normal bleeding; 3 excessive bleeding) (SISK, 1986), immediately after the following steps: injection of the first cartridge of articaine, tissue incision, flap reflection, bone removal (when this procedure was necessary), tooth extraction, cleaning of the operated site, and completion of suturing.	During the surgical procedure
Blood pressure variability during the surgeries steps	Systolic blood pressure, diastolic, and mean to be verified and recorded at surgical moments previously described (injection of the first cartridge anesthesia, incision, mucoperiosteal detachment, osteotomies, tooth section, extraction, cleaning and suturing), carried out with the aid of a system for monitoring hemodynamic parameters.	During the surgical procedure
Heart rate variability during the surgeries steps	Heart rate to be verified and recorded surgical at moments described above, carried out with the aid of a system for monitoring hemodynamic parameters.	During the surgical procedure
Oxygen saturation variability during the surgeries steps	Oxygen saturation to be verified and recorded at surgical moments described above, carried out with the aid of a system for monitoring hemodynamic parameters.	During the surgical procedure
Subjective evaluation of postsurgical pain at the moment of the rescue medication utilization	Subjective evaluation of postsurgical pain at the moment of the rescue medication consumption which was annotated by the volunteer after the surgery, in a Visual Analogue Scale (VAS, 0-100 mm).	Seventh postoperative day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative mouth opening	Mouth opening (mm) between the mesial-incisal corners of the upper and lower right central incisors at maximum opening of the jaws was measured and recorded before the surgery and during the second and seventh postoperative days.	Second and Seventh postoperative days
Onset and duration of surgery after administration of local anesthetic	Will only be considered those surgeries in which there is no difference in the duration time of the procedure between the patients. This time count will be started after the administration of the first local anesthetic. Unit of mesure used will be hours.	During the surgery
Incidence, type and severity of adverse reactions after the surgery	Will be considered as adverse reactions: gastrointestinal irritation, nausea, vomiting, bleeding, allergy, headache, dizziness, drowsiness or any other type of reaction presented after surgery.	Seventh postoperative day
Total amount of rescue medication	The total amount of rescue medication that was used by the patient during the postoperative period (Acetominophen- 750 mg) will be analyzed.	Seventh postoperative day
Measurement the facial edema	It will apply the method used by Ustun et al. (2003), which takes into account the sum of the following measures (obtained with flexible tape measure): A) distance between the lateral corner of the eye and the gonion, B) away from the tragus corner of the mouth and C) away from the tragus to the soft tissue of pogonion. Preoperative sum of three measures will be considered as the baseline that way. The difference between the values obtained in the postoperative period and baseline indicate the facial edema in the 2nd and 7th days.	On the second day after surgery and on the seventh day after surgery.

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Investigators: Principal Investigator: Giovana M Weckwerth, DDS, 416.016.638-54

Publications and helpful links

General Publications

• Weckwerth GM, Dionisio TJ, Costa YM, Zupelari-Goncalves P, Oliveira GM, Torres EA, Bonjardim LR, Faria FAC, Calvo AM, Moore T, Absher DM, Santos CF. Multifocal Analysis of Acute Pain After Third Molar Removal. Front Pharmacol. 2021 Apr 15;12:643874. doi: 10.3389/fphar.2021.643874. eCollection 2021.
• Weckwerth GM, Dionísio TJ, Costa YM, Colombini-Ishiquiriama BL, Oliveira GM, Torres EA, Bonjardim LR, Calvo AM, Moore T, Absher DM, Santos CF. CYP450 polymorphisms and clinical pharmacogenetics of ibuprofen after lower third molar extraction. Eur J Clin Pharmacol. 2021 May;77(5):697-707. doi: 10.1007/s00228-020-03046-0. Epub 2020 Nov 17.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): July 30, 2018
• Study Completion (Anticipated): July 1, 2020

Study Registration Dates

• First Submitted: March 16, 2017
• First Submitted That Met QC Criteria: May 24, 2017
• First Posted (Actual): May 30, 2017

Study Record Updates

• Last Update Posted (Actual): July 12, 2019
• Last Update Submitted That Met QC Criteria: July 11, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Ibuprofen; Lower third molar; Oral Surgery
• Additional Relevant MeSH Terms: Stomatognathic Diseases; Tooth Diseases; Tooth, Impacted; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ibuprofen
• Other Study ID Numbers: 59807716.9.0000.5417

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No