Optimize the Effects of Repetitive Transcranial Magnetic Stimulation on Neuropathic Pain

Neuropathic pain (NP) is one type of refractory chronic pain condition,medical treatments for NP is limited because of its poorly response.Repetitive transcranial magnetic stimulation (rTMS) can induce neuroplastic changes which has been used to manage chronic pain conditions. Indeed, high-frequency (≥ 5 Hz) rTMS over the primary motor cortex (M1) is suggested to be able to reduce neuropathic pain in randomized controlled studies. Overall, the clinical application of rTMS in chronic pain is still limited by the response rate, whereby it is close to moderate and far from being excellent at its best. Therefore this project designed a series of clinical trials to optimize the analgesic efficacy of rTMS. According to the research results of investigators previous project, patients with neuropathic pain were divided into responders and non-responders after 5 consecutive days of 10HZ rTMS or pcTBS intervention (see project ID:2021-0751)according to the change of pain intensity, and then different trials will be applied to responders and non-responders to optimize the analgesic effect of rTMS.

Study Overview

• Status: Completed
• Conditions: Neuropathic Pain; Repetitive Transcranial Magnetic Stimulation
• Intervention / Treatment: Device: Repetitive transcranial magnetic stimulation; Device: Repetitive transcranial magnetic stimulation

Detailed Description

For non-responders (whose visuo-analogic scale (VAS) decreased less than 20 mm or T1-T0/T0×100%<30%), a feasible method is to switch stimulation targets. So the investigator will change the stimulation target from M1 to dorsolateral prefrontal cortex (DLPFC), and then delivered another 5 days consecutive interventions to assess the efficacy.

For responders (whose VAS decreased an average of 20 mm or more or T1-T0/T0×100%≥30%), the investigator further investigate the long-lasting effect of rTMS. the patients will participate a continuous trials (2 sessions weekly for 2 weeks) and 4 weeks follow up.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • The second affliated hospital of zhejiang university

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• （1）woman or man over 18 years and under 85 years; （2）Clinical diagnosis of neuropathic pain (3) pain for at least 3 months, at least moderate intensity (≥ 4/10 assessed by VAS) ; (4) stable pharmacological treatment for pain at least 2 weeks before inclusion; (5) able to cooperate in completing questionnaire.

Exclusion Criteria:

• (1)Any clinically significant or unstable ongoing medical or psychiatric disorder including major depression; (2) History of substance abuse (alcohol, drugs); (3) Past treatment with repetitive transcranial magnetic stimulation (rTMS); (4) Contraindications to rTMS (previous severe head trauma or neurosurgical intervention, past or current epilepsy, active brain tumor, intracranial hypertension, implanted ferromagnetic devices, e.g., cardiac pacemaker, neurostimulator, or cochlear implants); (5) other type of pain more severe than neuropathic pain; (6) Any difficulty to fill out questionnaires (due to language or cognitive problems); (7) impossibility to be followed during the time course of the study;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: pcTBS; The protocol is same as the previous study: pcTBS was administered to the left M1 at 80% resting motor threshold (RMT), consisting of a burst of 3 pulses given at 50 Hz repeated every 5 Hz using repetitive transcranial magnetic stimulation device . A total of 1,200 pulses were delivered with the TMS coil positioned in a posterior-anterior (PA) direction parallel to the midline.	Device: Repetitive transcranial magnetic stimulation; Magnetic stimulation was performed using a figure-eight coil connected to a Magstim Rapid2 system, All patients seat in a comfortable reclining chair and delivered pcTBS protocol using repetitive transcranial magnetic stimulation . The stimulation intensity was set to 80% of the resting motor threshold, which is measured as the minimal intensity of stimulation evoking an electromyographic response ≥50µV on the first dorsal interosseus muscle of the hand contralateral to the stimulated hemisphere in at least 5 out of 10 trials. For this measurement, a figure-of-eight coil is positioned over the hand motor hotspot and oriented perpendicular to the central sulcus (parallel to the hemispheric midline).; Device: Repetitive transcranial magnetic stimulation; Magnetic stimulation was performed using a figure-eight coil connected to a Magstim Rapid2 system, All patients seat in a comfortable reclining chair and delivered 10HZ protocol using repetitive transcranial magnetic stimulation . The stimulation intensity was set to 80% of the resting motor threshold, which is measured as the minimal intensity of stimulation evoking an electromyographic response ≥50µV on the first dorsal interosseus muscle of the hand contralateral to the stimulated hemisphere in at least 5 out of 10 trials. For this measurement, a figure-of-eight coil is positioned over the hand motor hotspot and oriented perpendicular to the central sulcus (45° away from the hemispheric midline).
Experimental: 10HZ rTMS; The protocol is same as the previous study: 10HZ rTMS included 15 trains of 10-second stimulation given at 10 Hz to the left M1 at 80% resting motor threshold (RMT) using repetitive transcranial magnetic stimulation device , with the inter-train interval being set to 50 seconds (1500 pulses)	Device: Repetitive transcranial magnetic stimulation; Magnetic stimulation was performed using a figure-eight coil connected to a Magstim Rapid2 system, All patients seat in a comfortable reclining chair and delivered pcTBS protocol using repetitive transcranial magnetic stimulation . The stimulation intensity was set to 80% of the resting motor threshold, which is measured as the minimal intensity of stimulation evoking an electromyographic response ≥50µV on the first dorsal interosseus muscle of the hand contralateral to the stimulated hemisphere in at least 5 out of 10 trials. For this measurement, a figure-of-eight coil is positioned over the hand motor hotspot and oriented perpendicular to the central sulcus (parallel to the hemispheric midline).; Device: Repetitive transcranial magnetic stimulation; Magnetic stimulation was performed using a figure-eight coil connected to a Magstim Rapid2 system, All patients seat in a comfortable reclining chair and delivered 10HZ protocol using repetitive transcranial magnetic stimulation . The stimulation intensity was set to 80% of the resting motor threshold, which is measured as the minimal intensity of stimulation evoking an electromyographic response ≥50µV on the first dorsal interosseus muscle of the hand contralateral to the stimulated hemisphere in at least 5 out of 10 trials. For this measurement, a figure-of-eight coil is positioned over the hand motor hotspot and oriented perpendicular to the central sulcus (45° away from the hemispheric midline).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pain intensity measured with the visuo-analogic scale (VAS)	For non-responders:the primary outcome measure is the mean change from baseline over the course of 5 (group by time interaction) in average pain intensity measured with the visuo-analogic scale (VAS) ( 0= no pain and 10= maximal pain). Pain intensity is further assessed immediately before each rTMS session at days 2, 3, 4, 5, and then at weeks 2, 3, 4 after the intervention. For responders: pain intensity is assessed after two sessions of rTMS session and then at weeks 2, 3, 4 after the intervention.	through study completion, an average of 8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor-evoked potential (MEP)	Corticospinal excitability was measured with MEP at rest of the first dorsal interosseous (FDI) muscle, A total of 20 single pulses were consecutively delivered to the hand region of the left M1 at 120% RMT (45° to the midline, handle pointing backward).	through study completion, an average of 8 months
Cortical silent period (CSP)	Corticospinal excitability was measured with CSP during a sustained voluntary FDI muscle contraction, A total of 20 single pulses were consecutively delivered to the hand region of the left M1 at 120% RMT (45° to the midline, handle pointing backward).	through study completion, an average of 8 months
Pain interference scale	7 items rated from 0= does not interfere to 10= complete interference, total score 70 from the Brief Pain Inventory.	through study completion, an average of 8 months
Patients global impression of change	the 7 items Patients global impression of change (PGIC) (from very much worse to very much improved)	through study completion, an average of 8 months
The depression score	ranging from 0 to 13 with higher scores indicating more severe depression from the 13 items Beck Depression Inventory (BDI)	through study completion, an average of 8 months
The sensory dimension of pain	The sensory dimension of pain (rated on 33) measured with Short form of the McGill Pain questionnaire (SF-MPQ) .	through study completion, an average of 8 months
The affective dimension of pain	The affective dimension of pain measured with Short form of the McGill Pain questionnaire (SF-MPQ) .	through study completion, an average of 8 months

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Investigators: Study Chair: min yan, prof, The second affiliated hospital of Zhejiang University hangzhou

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Actual): December 1, 2022
• Study Completion (Actual): December 31, 2022

Study Registration Dates

• First Submitted: December 16, 2021
• First Submitted That Met QC Criteria: April 19, 2022
• First Posted (Actual): April 21, 2022

Study Record Updates

• Last Update Posted (Estimate): February 16, 2023
• Last Update Submitted That Met QC Criteria: February 14, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia
• Other Study ID Numbers: 2021-0752

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: investigators do not plan to make individual participant data (IPD) available to other researchers.

Drug and device information, study documents

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