Effect of Non-Invasive Neuromodulation on Primary Chronic Pain, Including Post-COVID-19

Effects of Non-invasive Neuromodulation on Post-COVID-19 Syndrome: Multicenter Study

The aim of this study is to analyse whether there is an advantage in adding low-intensity electrical stimulations to the vagus nerve with electrodes in the outer ear to control pain and fatigue in people with primary chronic pain, and in people who have had COVID-19. Several studies have shown that many people with primary chronic pain and also people who have had COVID patients continue to have pain and fatigue that may be due to changes that occur in the brain and the vagus nerve that passes through the neck might cause inflammation. Therefore the aim of this study is to investigate if these electrical stimulations can help improve the condition of the brain and nerve and consequently, the inflammation so that these complaints improve.

This study will be organized as the following: It will begin with an assessment, divided into a part with questionnaires and another with specific tests. The questionnaires are aimed at understanding volunteer's characteristics, pain, fatigue, inflammation, sleep, quality of life, and the presence of symptoms of anxiety and depression. Next, the volunteer will undergo two tests to assess the behavior of his/her brain. They are performed using EEG electroencephalography and transcranial magnetic stimulation (TMS).

• Quantitative EEG at rest - In this technique, a cap with electrodes is placed on volunteer's head, in contact with hair, which are connected through a gel. The volunteer needs to remain still for 6 minutes with eyes closed, sitting in a comfortable chair.
• TMS with EEG - First, the volunteer will be asked to honestly answer the questions in the safety questionnaire for using this technique. Honest answers will eliminate the risks associated with this evaluation. Next, the volunteer's skin will be cleaned with alcohol and a special paste and place three self-adhesive electrodes on the muscle of the volunteer's hand, in a muscle called the interosseous, on the side where he/she writes. These electrodes will only capture the electrical activity of the muscle. Next, a series of magnetic pulses will be administered to the volunteer's skull, in the area that controls the hand muscle. It will contract with each pulse and, with this, so that the functioning of this connection can be understood. At the same time, the EEG device will capture the brain activities that occur during this TMS stimulation. During this exam, the volunteer may feel anything from no stimulation to muscle contractions that move his/her hand. Some people also experience redness under the electrodes, fatigue, or muscle/joint pain.

After the assessments, volunteers will be randomly selected to receive neuromodulation sessions using low-intensity electrical stimulation of the vagus nerve, using electrodes in the outer ear (active group), or sessions that only simulate this neuromodulation (sham, or placebo, group). This will occur for five consecutive days, starting on the day of the assessment. This stimulation is very weak and may not even be felt by the person receiving it. This technique is safe and the most that may occur is redness or itching of the skin. A few people may also experience tingling, a burning sensation or momentary local pain, fatigue, drowsiness, difficulty concentrating and a feeling of nervousness during or after the stimulation.

At the end of the 5 days of electrical stimulation, the same initial assessments will be repeated to see if anything has changed in the volunteer's brain, heart rate, blood pressure, pain, fatigue, inflammation, sleep, quality of life, depression, and anxiety.

Study Overview

• Status: Enrolling by invitation
• Conditions: Healthy; Chronic Pain; Post COVID Condition
• Intervention / Treatment: Device: taVNS - transauricular vagal nerve stimulation; Device: rPMS - repetitive peripheric magnetic stimulation; Device: rTMS - repetitive transcranial magnetic stimulation; Device: taVNS sham

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • Sao paulo
    • Sâo Bernardo do Campo, Sao paulo, Brazil, 09606045
      • Federal University of ABC

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Healthy individuals, both sexes, aged between 18 and 40 years (first arm).
• Diagnosis of primary chronic pain (for more than 3 months), such as fibromyalgia (chronic widespread pain), primary chronic headache and orofacial pain, chronic primary visceral pain, post-COVID pain, and chronic primary musculoskeletal pain;
• In the case of post-COVID-19 pain, the symptoms must be present for at least 12 weeks. The complaints of pain, fatigue, and/or changes in mental health should have started after infection by SARS-Cov-2.

Exclusion Criteria:

• Individuals who present dysautonomia;
• obese individuals with a high abdominal fat index characterized by a waist/hip ratio of 0.80 for women and 0.95 for men;
• heart disease;
• diabetes mellitus;
• vestibular alterations characterized by the Dix-Hallpike maneuver, supine rotation test, arc test, side-lying maneuver, and post-head-shake nystagmus;
• diagnosis of epilepsy or first-degree family history of epilepsy
• fever;
• chronic consumption of alcohol, or other recreational drugs;
• presence of contraindications for the use of non-invasive neuromodulation;
• those who become ill with COVID-19 during the data collection period;
• those who are unable to answer the evaluation questionnaires;
• those with clinical instability;
• those who have a previous history of chronic pain or fatigue before contracting COVID-19;
• those who have neuropathic pain.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Healthy subjects; Once a week, each subject will receive a random stimulation in one of the following areas: (i) the afferent portion of the vagal nerve on the Cymba Conchae of the left ear (taVNS); (ii) rPMS on an efferent portion of the vagal nerve on the neck; (iii) rTMS intermittent theta- burst on the left DLPFC; (iv) simulated taVNS (SHAM) on helix left ear or.	Device: taVNS - transauricular vagal nerve stimulation; 30 minutes of electrical stimulation on the afferent portion of the vagal nerve on the cymba conchae of the ear, in the following configuration: 30 seg ramp up, 30 seg on, 30 seg off in intensity on which the volunteer feels a light tingling.; Device: rPMS - repetitive peripheric magnetic stimulation; Magnetic stimulation on the efferent portion of the vagal nerve on the neck, on the following configuration: 20Hz, 25 pulses in the trein, in every inhalation, for 20 inhalations with 50% of machine capacity (500 pulses total).; Device: rTMS - repetitive transcranial magnetic stimulation; rTMS intermitent theta- burst on the left DLPFC, on the following configuration: 50 Hz in treins of 5Hz, with 110% of the resting motor limiar and 600 pulses in 3 minutes.; Device: taVNS sham; Simulated taVNS (SHAM) on helix left ear, that is the same as taVNS, but during only 1 minute
Experimental: Chronic Pain and post Covid Syndrom - Active; These volunteers will receive 30 minutes of taVNS on the afferent portion of the vagal nerve on the ears.	Device: taVNS - transauricular vagal nerve stimulation; 30 minutes of electrical stimulation on the afferent portion of the vagal nerve on the cymba conchae of the ear, in the following configuration: 30 seg ramp up, 30 seg on, 30 seg off in intensity on which the volunteer feels a light tingling.
Sham Comparator: Chronic Pain and post Covid Syndrom - Sham; These volunteers will receive 30 minutes of simulated taVNS on the afferent portion of the vagal nerve on the ears. For this, the equipment will be programmed to be on only for 1 minute.	Device: taVNS sham; Simulated taVNS (SHAM) on helix left ear, that is the same as taVNS, but during only 1 minute

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain	It will be assessed through the Brief Pain Inventory (BPI), that assess place and pain intensity and its impact in life and by multidimensional pain assessment instruments to evaluate pain experience and self-efficacy	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate variability and blood preasure	It will be done using a chest polar and a sphygmomanometer.	5 days
Pressure pain threshold.	Assessed through handgrip dynamometry.	5 days
TMS-Evoked potential	TMS-Evoked Potential is a measure derived from TMS stimulus on the brain which represent a brain reactivity to exogenous stimulus	5 days
Disautonomy, fatigue and mental health	Dysautonomia will be assessed through TMS-EEG. Fatigue will be assessed by physical, cognitive and psychosocial fatigue scales and fatigue perception questionnaire. Mental health will be assessed by anxiety, depression and sleep quality questionnaires. Quality of life will be assessed by a specific questionnaire.	5 days

Collaborators and Investigators

• Sponsor: Federal University of ABC
• Collaborators: University of Sao Paulo; Coordination for the Improvement of Higher Education Personnel
• Investigators: Study Chair: Tiago S Lopes, PhD, Federal University of ABC

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2024
• Primary Completion (Estimated): December 16, 2024
• Study Completion (Estimated): December 16, 2024

Study Registration Dates

• First Submitted: September 27, 2024
• First Submitted That Met QC Criteria: November 13, 2024
• First Posted (Estimated): November 14, 2024

Study Record Updates

• Last Update Posted (Estimated): November 14, 2024
• Last Update Submitted That Met QC Criteria: November 13, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: chronic pain; neuromodulation; covid-19; TMS-EEG; vagal nerve
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; Chronic Pain
• Other Study ID Numbers: U1111-1293-2751

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