Pharmacological Treatment on the Recovery of Neurosensory Disturbance After Bilateral Sagittal Split Osteotomy

Pharmacological Treatment on the Recovery of Neurosensory Disturbance After Bilateral Sagittal Split Osteotomy: a Randomized, Double-blind Trial

The bilateral sagittal split osteotomy (BSSO) of the mandible is one of the most used surgical techniques to achieve a harmonious jaw relation in the context of orthognathic surgery. Nevertheless, one of its main complications is neurosensory damage to the inferior alveolar nerve, which can cause severe impact in the quality of life on patients who suffer from it permanently. The purpose of this randomized clinical trial is to provide rigorous scientific evidence of the pharmacological effect of 1) Melatonin, 2) combination uridine triphosphate (UTP), cytidine monophosphate (CMP), and hydroxycobalamin (UTP/CMP/hydroxycobalamin) and 3) hydroxycobalamin regarding neurosensory disturbances incidence and persistence after BSSO.

Study Overview

• Status: Not yet recruiting
• Conditions: Orthognathic Surgery; Prognathism; Neurosensory Disorder; Retrognathism
• Intervention / Treatment: Procedure: Orthognathic Surgery; Drug: Centrum; Drug: Melatonin 10 MG Oral Tablet; Drug: Hydroxycobalamin

Detailed Description

The study will be done according to the international standards of the Helsinki convention for medical research and approved by the scientific ethics committee of Universidad de los Andes Clinic.

All subjects will give their signed consent to participate of this clinical research.

This clinical randomized trial will be double-blinded as both the patient and the surgeon will not know the treatment used until the experiment is over. The randomization will be done using "random.org" software to assign participants into 4 groups. Groups A, B and C will receive the medication, whereas the Group P will receive a placebo.

• Study Type: Interventional
• Enrollment (Anticipated): 220
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Pedro Sole, DMD, OMFS; Phone Number: +56 9 9235 2728; Email: psole@uic.es
• Study Contact Backup: Name: Maximiliano Bravo, DMD; Phone Number: +56 9 7690 0878; Email: mabravo9@uc.cl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria: Patients with dentomaxillofacial anomalies who present a complete mandibular dental arch and who have not undergone previous mandibular surgery.

Exclusion Criteria:

patients who:

• do not have sufficient information in their clinical records
• cannot be contacted
• do not attend their check-ups (for at least 24 postoperative months in cases with DNS)
• have refused consent to the use of their information for purposes of research.
• already undergoing Orthognathic Surgery
• with systemic conditions prone to alter recovery patterns or serious systemic diseases (decompensated metabolic disorders; neoplasms; osteodysplasias; neuropathies).
• pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Citoneurone; Groups A will receive the pharmacology treatment with 1.5 mg uridine triphosphate, 2.5 mg cytidine monophosphate and 1 mg hydroxycobalamin (Citoneurone). One capsule orally three times a day for 60 days as suggested by the manufacturer for patients with trauma - compressive peripheral neural disorders.	Procedure: Orthognathic Surgery; Prognathism/Retrognathism correction through surgical procedures; Other Names: Bilateral Sagittal Split Osteotomy; Drug: Centrum; Groups A will receive the pharmacology treatment with 1.5 mg uridine triphosphate, 2.5 mg cytidine monophosphate and 1 mg hydroxycobalamin (Citoneuron). One capsule orally three times a day for 60 days as suggested by the manufacturer for patients with trauma - compressive peripheral neural disorders.; Other Names: Citoneurone [Cytidine + Hydroxocobalamin, + Uridine]
Experimental: Melatonin; Group B will receive the pharmacology treatment with 10 mg Melatonin. One capsule orally at night for 60 days.	Procedure: Orthognathic Surgery; Prognathism/Retrognathism correction through surgical procedures; Other Names: Bilateral Sagittal Split Osteotomy; Drug: Melatonin 10 MG Oral Tablet; Group B will receive the pharmacology treatment with 10 mg Melatonin. One capsule orally at night for 60 days.
Experimental: Hydroxycobalamin; Group C will receive the pharmacology treatment with 1 mg hydroxycobalamin (vitamin B12). One capsule daily for 60 days.	Procedure: Orthognathic Surgery; Prognathism/Retrognathism correction through surgical procedures; Other Names: Bilateral Sagittal Split Osteotomy; Drug: Hydroxycobalamin; Group C will receive the pharmacology treatment with 1 mg hydroxycobalamin (vitamin B12). One capsule daily for 60 days.
Placebo Comparator: Placebo; The controls will receive 1 capsule placebo containing 5 mg starch to be taken once daily.	Procedure: Orthognathic Surgery; Prognathism/Retrognathism correction through surgical procedures; Other Names: Bilateral Sagittal Split Osteotomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurosensory Activity	Presence or absense of symptoms and signs such as hypoesthesia, pain, anesthesia, numbness, among others	pre-operative
Neurosensory Activity	Presence or absense of symptoms and signs such as hypoesthesia, pain, anesthesia, numbness, among others	1 day postoperative
Neurosensory Activity	Presence or absense of symptoms and signs such as hypoesthesia, pain, anesthesia, numbness, among others	3 day postoperative
Neurosensory Activity	Presence or absense of symptoms and signs such as hypoesthesia, pain, anesthesia, numbness, among others	2 weeks postoperative.
Neurosensory Activity	Presence or absense of symptoms and signs such as hypoesthesia, pain, anesthesia, numbness, among others	1 month postoperative
Neurosensory Activity	Presence or absense of symptoms and signs such as hypoesthesia, pain, anesthesia, numbness, among others	2 month postoperative
Neurosensory Activity	Presence or absense of symptoms and signs such as hypoesthesia, pain, anesthesia, numbness, among others	6 month postoperative
Neurosensory Activity	Presence or absense of symptoms and signs such as hypoesthesia, pain, anesthesia, numbness, among others	12 month postoperative
Neurosensory Activity	Presence or absense of symptoms and signs such as hypoesthesia, pain, anesthesia, numbness, among others	18 month postoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective Test	Subjective testing using a questionnaire and visual analogue scale. 0 = normal sensation, 10= more severe sensory deficit.	pre-operative, at day 1 and 3, at week 2, and at month 1, 2, 6, 12 and 18 after surgery.
Objetive Test	The Semmes-Weinstein (SW) test of sensitivity to touch/pressure will be used.	pre-operative, at day 1 and 3, at week 2, and at month 1, 2, 6, 12 and 18 after surgery.

Collaborators and Investigators

• Sponsor: Universitat Internacional de Catalunya
• Collaborators: Universidad de los Andes, Chile
• Investigators: Principal Investigator: Pedro Sole, DMD, OMFS, Universidad De Los Andes

Publications and helpful links

General Publications

• Ylikontiola L, Kinnunen J, Oikarinen K. Factors affecting neurosensory disturbance after mandibular bilateral sagittal split osteotomy. J Oral Maxillofac Surg. 2000 Nov;58(11):1234-9; discussion 1239-40. doi: 10.1053/joms.2000.16621.
• Colella G, Cannavale R, Vicidomini A, Lanza A. Neurosensory disturbance of the inferior alveolar nerve after bilateral sagittal split osteotomy: a systematic review. J Oral Maxillofac Surg. 2007 Sep;65(9):1707-15. doi: 10.1016/j.joms.2007.05.009.
• Alolayan AB, Leung YY. Resolution of neurosensory deficit after mandibular orthognathic surgery: A prospective longitudinal study. J Craniomaxillofac Surg. 2017 May;45(5):755-761. doi: 10.1016/j.jcms.2017.01.032. Epub 2017 Feb 12.
• Teerijoki-Oksa T, Jaaskelainen SK, Forssell K, Forssell H, Vahatalo K, Tammisalo T, Virtanen A. Risk factors of nerve injury during mandibular sagittal split osteotomy. Int J Oral Maxillofac Surg. 2002 Feb;31(1):33-9. doi: 10.1054/ijom.2001.0157.
• da Costa Senior O, Gemels B, Van der Cruyssen F, Agbaje JO, De Temmerman G, Shaheen E, Lambrichts I, Politis C. Long-term neurosensory disturbances after modified sagittal split osteotomy. Br J Oral Maxillofac Surg. 2020 Oct;58(8):986-991. doi: 10.1016/j.bjoms.2020.05.010. Epub 2020 Jul 4.
• Seddon HJ. A Classification of Nerve Injuries. Br Med J. 1942 Aug 29;2(4260):237-9. doi: 10.1136/bmj.2.4260.237. No abstract available.
• Schlund M, Grall P, Ferri J, Nicot R. Effect of modified bilateral sagittal split osteotomy on inferior alveolar nerve neurosensory disturbance. Br J Oral Maxillofac Surg. 2022 Oct;60(8):1086-1091. doi: 10.1016/j.bjoms.2022.04.001. Epub 2022 Apr 13.
• Yoshioka I, Tanaka T, Khanal A, Habu M, Kito S, Kodama M, Oda M, Wakasugi-Sato N, Matsumoto-Takeda S, Seta Y, Tominaga K, Sakoda S, Morimoto Y. Correlation of mandibular bone quality with neurosensory disturbance after sagittal split ramus osteotomy. Br J Oral Maxillofac Surg. 2011 Oct;49(7):552-6. doi: 10.1016/j.bjoms.2010.09.014. Epub 2010 Nov 10.
• van Merkesteyn JP, Zweers A, Corputty JE. Neurosensory disturbances one year after bilateral sagittal split mandibular ramus osteotomy performed with separators. J Craniomaxillofac Surg. 2007 Jun-Jul;35(4-5):222-6. doi: 10.1016/j.jcms.2007.04.006. Epub 2007 Jul 30.
• Panula K, Finne K, Oikarinen K. Neurosensory deficits after bilateral sagittal split ramus osteotomy of the mandible--influence of soft tissue handling medial to the ascending ramus. Int J Oral Maxillofac Surg. 2004 Sep;33(6):543-8. doi: 10.1016/j.ijom.2003.11.005.

Study record dates

Study Major Dates

• Study Start (Anticipated): September 30, 2022
• Primary Completion (Anticipated): June 30, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: September 1, 2022
• First Submitted That Met QC Criteria: September 8, 2022
• First Posted (Actual): September 13, 2022

Study Record Updates

• Last Update Posted (Actual): September 13, 2022
• Last Update Submitted That Met QC Criteria: September 8, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Bilateral Sagittal Split Osteotomy; Neurosensory Disturbances
• Additional Relevant MeSH Terms: Congenital Abnormalities; Musculoskeletal Diseases; Stomatognathic Diseases; Stomatognathic System Abnormalities; Jaw Abnormalities; Jaw Diseases; Maxillofacial Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Mandibular Diseases; Retrognathia; Prognathism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin B Complex; Hematinics; Melatonin; Vitamin B 12; Hydroxocobalamin
• Other Study ID Numbers: PISV01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be available due to anonymity and ethical considerations.

Drug and device information, study documents

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