Effects and Mechanism of Prolonged Continuous Theta Burst 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. A noninvasive brain-stimulation method called transcranial magnetic stimulation (TMS) has garnered interest as an alternative treatment for intractable NP potentially through inducing therapeutic brain plasticity.Indeed, high-frequency (≥ 5 Hz) Repetitive TMS (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,the investigation of rTMS protocols is important for improving rTMS analgesia. Theta burst stimulation (TBS) mimics the bursts of neuronal firing which results in robust long-term potentiation. Continuous TBS (cTBS) is designed to decrease excitability, whereby prolonged cTBS (pcTBS, i.e. multiple cTBS being delivered continuously) has recently been demonstrated to increase excitability. More importantly, pcTBS was found to have comparable or even better analgesic effects than standard 10 Hz rTMS. These findings together call for more studies to validate the analgesic efficacy of pcTBS.

In this study, the investigators aim to assess and compare the efficacy of prolonged continuous theta burst stimulation (pcTBS) with 10HZ rTMS in NP patients.

Study Overview

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

Detailed Description

The investigators designed a randomized, double-blind, sham-controlled study at 1 center. fifty NP patients were randomly assigned to 3 groups. A series of 5 daily pcTBS(1200 pulses/session) or 10-Hz rTMS (1500 pulses/session) of primary motor cortex (M1) or sham stimulation was applied to each patients.

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • The second affiliated hospital of Zhejiang University hangzhou

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• (1)woman or man over 18 and under 70 years old; （2）pain fulfilling the criteria for probable or definite peripheral neuropathic pain ; (3) pain for at least 3 months, continuous pain (at least four days per week), 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: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: pcTBS; 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. 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; Participants received 10HZ rTMS protocol consisted of 5 sessions over 5 consecutive workdays; Device: Repetitive transcranial magnetic stimulation; Participants received pcTBS protocol consisted of 5 sessions over 5 consecutive workdays
Active Comparator: 10HZ rTMS; The rTMS protocol included 15 trains of 10-second stimulation given at 10 Hz to the left M1 at 80% resting motor threshold (RMT), with the inter-train interval being set to 50 seconds (1500 pulses)	Device: Repetitive transcranial magnetic stimulation; Participants received 10HZ rTMS protocol consisted of 5 sessions over 5 consecutive workdays; Device: Repetitive transcranial magnetic stimulation; Participants received pcTBS protocol consisted of 5 sessions over 5 consecutive workdays
Sham Comparator: Sham; The Sham stimulation was delivered using the same protocol, with the coil being orientated at 90° to the scalp so that the magnetic field would be delivered away from the scal	Device: Sham stimulation; Participants received Sham rTMS stimulations consisted of 5 sessions over 5 consecutive workdays

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The mean change from baseline in pain intensity measured with the visual-analogic scale (VAS)	The primary outcome measure was the mean change from baseline over the course of 5 (group by time interaction) in average pain intensity measured with the visual-analogic scale (VAS) ( 0= no pain and 10= maximal pain). Baseline average pain intensity was assessed at inclusion then on the day of randomization, just before the first rTMS session (day 1) and corresponded to the average of these two values.	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
The sensory dimension of pain and affective dimension of pain	The sensory dimension of pain (rated on 33) and affective dimension of pain (rated on 12) from the 15-items Short form of the McGill Pain questionnaire (SF-MPQ) .	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
release of neurotransmitters	Measured with magnetic resonance spectroscopy,MRS	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): February 28, 2022
• Primary Completion (Actual): December 31, 2022
• Study Completion (Actual): January 30, 2023

Study Registration Dates

• First Submitted: December 15, 2021
• First Submitted That Met QC Criteria: December 22, 2021
• First Posted (Actual): December 23, 2021

Study Record Updates

• Last Update Posted (Actual): October 31, 2023
• Last Update Submitted That Met QC Criteria: October 30, 2023
• Last Verified: January 1, 2022

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: 2021-0751

Drug and device information, study documents

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