CTRI

TITLE: Safety and Efficacy of Add-On Repetitive Transcranial Magnetic Stimulation (rTMS) in Patients with Persistent Somatoform Pain Disorder: A double-blinded Randomized Controlled Trial

Name of the student: Dr. Apurva Parashar (M.D. Psychiatry PGt1)

Guide: Dr. Ram Chandra Das (Principal and Professor of Psychiatry, Kalinga Institute Of Medical Sciences, Bhubaneswar)

Co-guide: - Dr. Jigyansa I. Pattnaik (Assistant Professor, Department Of Psychiatry),

Dr. Bhumika Mishra (Assistant Professor, Department Of Psychiatry),

Dr. Barsha Baishali Parida (Assistant Professor, Department Of Physiology)

INTRODUCTION: Persistent somatoform pain disorder represents a challenging clinical entity characterized by the presence of chronic, distressing pain without adequate medical explanation despite extensive evaluation and reassurance by doctors. Pharmacotherapy with antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), has demonstrated modest benefits. Similarly, cognitive-behavioral therapy (CBT) and other psychological interventions have shown effectiveness in managing psychological aspects of pain but often fail to provide complete symptom resolution Repetitive Transcranial Magnetic Stimulation (rTMS) has emerged as a promising non-invasive neuromodulatory technique for various neuropsychiatric conditions, including chronic pain syndromes .

RESEARCH QUESTION: Is add on High-frequency rTMS targeting the right medial prefrontal cortex more effective in reducing pain intensity in patients with Persistent Somatoform Pain Disorder compared to sham stimulation?

OBJECTIVE

PRIMARY OBJECTIVE:

To assess the efficacy of add-on high-frequency rTMS targeting the right medial prefrontal cortex in reducing pain intensity (as measured by VAS, defined as equal to or more than 50 percent reduction in VAS score, remission rates defined as VAS score less than 3) in patients with persistent somatoform pain disorder compared to sham stimulation.

SECONDARY OBJECTIVES :

1.To evaluate the impact of rTMS on somatic symptom burden (SSS-8) and quality of life (WHOQOL-BREF) compared to sham stimulation.

2.To measure the effects of rTMS on anxiety (HAM-A) and depression (HAM-D) .

3. To identify potential socio-demographic and electrophysiological predictors of treatment response .

METHODOLOGY:

STUDY DESIGN- A prospective, parallel-group, double-blind, randomized, sham-controlled, trial.

STUDY SETTING- Department of Psychiatry, Kalinga Institute of Medical Sciences, Bhubaneswar.

STUDY DURATION- 24 months (including recruitment, intervention, and follow-up phases).

PICO FRAMEWORK

1. POPULATION

STUDY POPULATION- Adults aged 18 to 60 years of any gender with a diagnosis of persistent somatoform pain disorder according to DSM V criteria using SCID -5 RV.

SAMPLE SIZE- A total sample size of 52 patients (26 per group) is required.

INCLUSION AND EXCLUSION CRITERIA:

INCLUSION CRITERIA:

1) Age: 18–60 years, any gender

2) Diagnosis of persistent somatoform pain disorder according to DSM V criteria using SCID -5 RV for at least 6 months

3) Moderate to severe pain intensity (VAS score greater than or equal to 4)

4) Stable medication regimen for at least 4 weeks prior to enrollment

5) Willing and able to provide written informed consent

6) Able to comply with study procedures and follow-up visits

EXCLUSION CRITERIA:

1) Presence of diagnosable physical illness that could explain the pain symptoms

2) Severe psychiatric comorbidities (e.g., psychosis, bipolar disorder, substance dependence, severe major depressive disorder with suicidal ideation)

3) Pregnancy or lactation

4) Recent changes in psychotropic medications (<4 weeks)- Shall be put on waitlist

5) Neurological disorders (e.g., epilepsy, cerebrovascular disease, traumatic brain injury, dementia)

6) Current participation in another clinical trial 7. Inability to provide informed consent

7) Contraindications to rTMS:

Ferromagnetic metallic implants in the head/neck region
Implanted medical devices (e.g., cardiac pacemakers, cochlear implants)
History of seizures or epilepsy
Increased intracranial pressure

2. INTERVENTION

Rtms protocol:

Target: Right medial prefrontal cortex (identified using the International 10-20 EEG system)
Frequency: 10 Hz
Intensity: 100 percent of resting motor threshold (RMT)
Trains: 20 trains per session
Train duration: 5 seconds
Inter-train interval: 25 seconds
Total pulses per session: 1000
Sessions: 10 sessions (5 sessions per week for 2 weeks)
Equipment: FDA-cleared R30 rTMS system with the Accent neuro navigation module (Magstim Company Limited, UK).

TREATMENT AS USUAL (TAU)

Both groups will continue to receive standard care for persistent somatoform pain disorder, which may include:

I. Stable doses of prescribed medications (unchanged for at least 4 weeks prior to enrollment)

II. Supportive psychotherapy

III. Physical therapy if prescribed

Any changes in medication during the study period will be documented.

3. COMPARISON

STUDY ARMS - (1) active rTMS (2) sham rTMS

RANDOMIZATION AND BLINDING

1.Randomization: Participants will be randomized into one of two treatment groups (Group A or Group B) using computer generated block randomization to ensure equal group sizes throughout the study.

2.Allocation: Consultants involved in the study will perform group allocation accordingly at the time participant enrollment.

3.Administration: To ensure procedural separation and reduce bias, the administration of the intervention will be carried out by another designated team member or colleague, who will be blinded to the allocation sequence and not involved in the randomization process.

4.Eligible participants will be randomly assigned in a 1:1 ratio to either active rTMS or sham rTMS using computer-generated block randomization.

5.Both participants and outcome assessors will be blinded to treatment allocation (double-blind design)

6.The rTMS operator will not be blinded but will be instructed not to disclose the treatment condition to either participants or outcome assessors.

4. OUTCOME MEASURES

PRIMARY OUTCOME MEASURE

Change in pain intensity from baseline to end of treatment (after 2 weeks- completion of 10 sessions ,5 sessions per week) as measured by the Visual Analog Scale (VAS)- defined as less than or equal to 50 percent reduction in VAS score).

SECONDARY OUTCOME MEASURES

1. Change in somatic symptom burden as measured by the Somatic Symptom Scale-8 (SSS-8)

2. Change in quality of life as measured by the WHO Quality of Life Scale (WHOQOL-BREF)

3. Change in anxiety symptoms as measured by the Hamilton Anxiety Rating Scale (HAM-A)

4. Change in depressive symptoms as measured by the Hamilton Depression Rating Scale (HAM-D)

5. Remission rate (defined as VAS score less than 3)

6. Incidence and severity of adverse events

TOOLS:

Pain-visual analog scale (VAS), short-term Mcgill Questionnaire
Somatic Symptoms- Somatic Symptom Scale-8 (SSS-8),
Quality of life (WHO Quality Of Life Scale, WHOQOL-BREF),
Anxiety (Hamilton Anxiety Rating Scale, HAM-A)
Depression (Hamilton Depression Rating Scale, HAM-D)

ETHICAL CONSIDERATIONS

The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines.

1. Approval will be obtained from the Institutional Ethics Committee of Kalinga Institute of Medical Sciences.

2. Written informed consent will be obtained from all participants before enrollment.

3. Participants will be informed about:

Study purpose, procedures, and duration
Potential risks and benefits
Right to withdraw at any time without affecting standard care
Confidentiality protections

4. Data will be de-identified and stored securely.

5. Adverse events will be monitored throughout the study and managed appropriately.