Comparison of Vortioxetine Versus Other Antidepressants With Pregabalin Augmentation in Burning Mouth Syndrome

Comparative Evaluation of Vortioxetine Versus Other Antidepressants With Pregabalin Augmentation in Treatment-resistant Burning Mouth Syndrome: a Prospective Longitudinal Clinical Trial With Treatment Response Prediction

Background: The treatment of Burning Mouth Syndrome (BMS) presents a challenge in tailoring appropriate medication for individual patients. Antidepressants have demonstrated efficacy in alleviating symptoms in most cases; however, a subset of patients exhibit limited or no response to these treatments. The augmentation with pregabalin to conventional treatment has shown promising outcomes in relieving pain and improving quality of life in chronic pain conditions. This study aimed to compare the efficacy of vortioxetine with other antidepressants (SSRIs/SNRIs) in combination with pregabalin in a cohort of unresponsive BMS patients and to predict treatment response using clinical data.

Methods: A 52-week randomized, open-label, active-controlled study was conducted, enrolling 203 BMS patients previously treated with one antidepressant for 12 weeks and non-responder to the treatment. The study sample have included two groups: Group A (136) received vortioxetine, while Group B (67) received SSRIs/SNRIs. Pregabalin (75mg/day) was added to both groups, with a potential dosage increase to 150mg/day for inadequate responders after 12 weeks.

Treatment response was assessed by measuring reduction in VAS and SF-MPQ scores (>50 or 1-2) and HAM-A and HAM-D scores (>50% or ≤7) at 12, 24, 36 and 52 weeks. Classical logistic regression with a stepwise algorithm and Random Forest machine learning models were used to predict treatment response.

Study Overview

• Status: Recruiting
• Conditions: Burning Mouth Syndrome
• Intervention / Treatment: Drug: Vortioxetine 20Mg Tab; Drug: Pregabalin 75mg; Drug: Paroxetine 20 Mg Oral Tablet; Drug: Sertraline 50 MG; Drug: Citalopram 20mg; Drug: Escitalopram 10mg; Drug: Duloxetine 60 MG

• Study Type: Interventional
• Enrollment (Estimated): 203
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Daniela Adamo; Phone Number: +39 3925253864; Email: danielaadamo.it@gmail.com

Study Locations

• Italy
  • Italia
    • Napoli, Italia, Italy, 80131
      • Recruiting
      • University of Naples Federico II
      • Contact: Daniela Adamo; Phone Number: +39 3925253864; Email: danielaadamo.it@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• patients with a confirmed diagnosis of BMS based on the International Classification of Orofacial Pain, 1st edition [International Classification of Orofacial Pain, 1st edition (ICOP) Cephalalgia, 2020]
• patients of any race or gender; complaining of oral burning recurring daily for >2 h per day for >3 months;
• normal blood test findings (including blood count, blood glucose levels, glycated hemoglobin, serum iron, ferritin and transferrin).
• BMS patients previously treated with one antidepressant for 12 weeks and non-responder to the treatment

Exclusion Criteria:

• the presence of any disease that could be recognized as a causative factor of BMS,
• a history of a psychiatric disorder or a neurological or organic brain disorder,
• a history of alcohol or substance abuse,
• the presence of Obstructive Sleep Apnea Syndrome (OSAS)
• uncontrolled hypertension, diabetes, HIV, narrow-angle glaucoma, or participants enrolled in other investigational studies.
• participants requiring continued treatment with medications that adversely interact with the study medications (eg, quinolone antibiotics, warfarin, agents inhibiting serotonin reuptake) or with hereditary problems of fructose intolerance, glucose galactose malabsorption, or sucrose isomaltase insufficiency
• pregnancy and lactation were exclusion criteria, and women of childbearing potential were required to receive a highly effective form of contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vortioxetine+Pregabalin; VO group(20mg)+ PGB (75mg) N= 136 Vortioxetine 20 mg, encapsulated tablets, orally, once daily, then pregabalin 75 mg, encapsulated tablets, orally, once daily. Pregabalin (75mg/day) was added, with a potential dosage increase to 150mg/day for inadequate responders after 12 weeks	Drug: Vortioxetine 20Mg Tab; Encapsulated vortioxetine immediate release tablets, once daily; Other Names: Brintellix; Drug: Pregabalin 75mg; Encapsulated pregabalin tablets, once daily
Active Comparator: Paroxetine+Pregabalin; P group (20mg) + PGB (75mg); N= 10 Paroxetine 20 mg, encapsulated tablets, orally, once daily, then pregabalin 75 mg, encapsulated tablets, orally, once daily. Pregabalin (75mg/day) was added, with a potential dosage increase to 150mg/day for inadequate responders after 12 weeks	Drug: Pregabalin 75mg; Encapsulated pregabalin tablets, once daily; Drug: Paroxetine 20 Mg Oral Tablet; Encapsulated paroxetine tablets, once daily
Active Comparator: Sertraline+Pregabalin; S group (50mg) + PGB (75mg); N= 8 Sertraline 50 mg, encapsulated tablets, orally, once daily, then pregabalin 75 mg, encapsulated tablets, orally, once daily. Pregabalin (75mg/day) was added, with a potential dosage increase to 150mg/day for inadequate responders after 12 weeks	Drug: Pregabalin 75mg; Encapsulated pregabalin tablets, once daily; Drug: Sertraline 50 MG; Encapsulated sertraline tablets, once daily
Active Comparator: Citalopram+Pregabalin; C group (20mg)+ PGB (75mg) N= 8 Citalopram 20 mg, encapsulated tablets, orally, once daily, then pregabalin 75 mg, encapsulated tablets, orally, once daily. Pregabalin (75mg/day) was added, with a potential dosage increase to 150mg/day for inadequate responders after 12 weeks	Drug: Pregabalin 75mg; Encapsulated pregabalin tablets, once daily; Drug: Citalopram 20mg; Encapsulated citalopram tablets, once daily
Active Comparator: Escitalopram+Pregabalin; E group (10mg) + PGB (75mg); N= 8 Escitalopram 10 mg, encapsulated tablets, orally, once daily, then pregabalin 75 mg, encapsulated tablets, orally, once daily. Pregabalin (75mg/day) was added, with a potential dosage increase to 150mg/day for inadequate responders after 12 weeks	Drug: Pregabalin 75mg; Encapsulated pregabalin tablets, once daily; Drug: Escitalopram 10mg; Encapsulated escitalopram tablets, once daily
Active Comparator: Duloxetine+Pregabalin; D group (60mg)+ PGB (75mg) N= 33 Duloxetine 60 mg, encapsulated tablets, orally, once daily, then pregabalin 75 mg, encapsulated tablets, orally, once daily. Pregabalin (75mg/day) was added, with a potential dosage increase to 150mg/day for inadequate responders after 12 weeks	Drug: Pregabalin 75mg; Encapsulated pregabalin tablets, once daily; Drug: Duloxetine 60 MG; Encapsulated duloxetine tablets, once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analog Scale (VAS)	The Visual Analog Scale (VAS) (Hayes and Patterson, 1921) is a well-validated unidimensional instrument for the measure of pain intensity (Hawker et al., 2011). The score is determined by measuring the distance on the line between the "no pain" and the mark of a patient mark, providing a range of scores from 0 to 10 (0 = no oral symptoms and 10 = the worst imaginable discomfort).	4 times evaluation: time 0: 0 week; time 1: 12 weeks; time 2: 24 weeks; time 3: 36 weeks; time 4: 52 weeks
Short-form McGill Pain Questionnaire (SF-MPQ)	the short form of the McGill Pain Questionnaire (SF-MPQ) is a measure of the quality of pain and is a multidimensional pain questionnaire, which measures the sensory, affective, and evaluative aspects of the perceived pain (Hawker et al., 2011). It comprises 15 items from the original MPQ, each scored from 0 (none) to 3 (severe). The SF-MPQ score is obtained by summing the item scores (range 0-45). There are no established critical cutoff points for the interpretation of the scores and, as for the MPQ, a higher score indicates the worse pain.	4 times evaluation: time 0: 0 week; time 1: 12 weeks; time 2: 24 weeks; time 3: 36 weeks; time 4: 52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hamilton rating scale for Depression (HAM-D)	The HAM-D is a clinician-administered depression assessment scale; it contains 21 items pertaining to the affective field. The scores can range from 0 to 54. A score > 7 indicates an impairment. The scores in the range of 7-17 indicate a mild depression, the scores between 18 and 24 indicate a moderate depression, and the scores >24 indicate a severe depression	4 times evaluation: time 0: 0 week; time 1: 12 weeks; time 2: 24 weeks; time 3: 36 weeks; time 4: 52 weeks
Hamilton rating scale for Anxiety (HAM-A)	The HAM-A (Hamilton, 1959) is a clinician-administered anxiety assessment scale. It comprises 14 items to measure both psychic anxiety and somatic anxiety. Each item is scored on a scale of 0-4, a total score <17 indicates a mild severity, 18-24 mild to moderate, and 25-30 moderate to severe (Hamilton, 1967).	4 times evaluation: time 0: 0 week; time 1: 12 weeks; time 2: 24 weeks; time 3: 36 weeks; time 4: 52 weeks
Pittsburgh Sleep Quality Index (PSQI)	The PSQI (Buysse et al., 1989) explores the quality of sleep over a 1-month time interval generating seven "component" scores (0-3): subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication and daytime dysfunction (Carpenter and Andrykowski, 1998). The total score is obtained by the sum of all the sub-scores and ranges between 0 and 21. A total score greater than five discriminates poor sleepers from good sleepers with a high sensitivity (90%-99%) and specificity (84%-87%) (Curcio et al., 2013).	4 times evaluation: time 0: 0 week; time 1: 12 weeks; time 2: 24 weeks; time 3: 36 weeks; time 4: 52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Global Impression Scale - Improvement (CGI-I) and Severity (CGI-S)	CGI-I scale assesses the participant's improvement (or worsening) as assessed by the clinician relative to Baseline on a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. Clinical Global Impression Scale-Severity of Illness (CGI-S) score-by-week as fixed effects.	3 times evaluation: time 1: 12 weeks; time 2: 24 weeks; time 3: 36 weeks; time 4: 52 weeks

Collaborators and Investigators

• Sponsor: Federico II University

Publications and helpful links

General Publications

• Adamo D, Calabria E, Coppola N, Pecoraro G, Mignogna MD. Vortioxetine as a new frontier in the treatment of chronic neuropathic pain: a review and update. Ther Adv Psychopharmacol. 2021 Sep 3;11:20451253211034320. doi: 10.1177/20451253211034320. eCollection 2021.
• Adamo D, Pecoraro G, Coppola N, Calabria E, Aria M, Mignogna M. Vortioxetine versus other antidepressants in the treatment of burning mouth syndrome: An open-label randomized trial. Oral Dis. 2021 May;27(4):1022-1041. doi: 10.1111/odi.13602. Epub 2020 Sep 15.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): October 30, 2023
• Study Completion (Estimated): July 24, 2024

Study Registration Dates

• First Submitted: August 29, 2023
• First Submitted That Met QC Criteria: August 29, 2023
• First Posted (Actual): September 6, 2023

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: August 29, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Drug Therapy; pregabalin; vortioxetine; Burning mouth syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Wounds and Injuries; Disease; Stomatognathic Diseases; Mouth Diseases; Syndrome; Burns; Burning Mouth Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Serotonin Antagonists; Anti-Anxiety Agents; Cytochrome P-450 Enzyme Inhibitors; Anticonvulsants; Antidepressive Agents, Second-Generation; Serotonin and Noradrenaline Reuptake Inhibitors; Cytochrome P-450 CYP2D6 Inhibitors; Serotonin 5-HT3 Receptor Antagonists; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Selective Serotonin Reuptake Inhibitors; Sertraline; Duloxetine Hydrochloride; Citalopram; Paroxetine; Vortioxetine; Pregabalin; Escitalopram
• Other Study ID Numbers: 251/19

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