Mechanism of Analgesic Effect on Prolonged Continuous Theta Burst Stimulation

NCT05360030 | Completed DMC

• 1 other identifier: RI2022089
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 1

Brief Summary

It has been shown that prolonged continuous theta burst stimulation (pcTBS) , a relatively new repetitive transcranial magnetic simulation (rTMS) protocol, of the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) decreases pain in healthy volunteers, in various experimental models. In addition, rTMS of M1 has also been shown to have analgesic effects in various chronic pain conditions, including neuropathic pain.The mechanisms underlying rTMS-induced analgesia remain unclear. Functional neuroimaging studies have shown that rTMS of M1 and DLPFC induces changes in the activity of cortical and subcortical structures involved in pain processing and modulation. Endogenous opioids and e N-methyl-D-aspartate (NMDA) receptor are known to play a major role in these processes. The investigator hypothesized that the endogenous opioids systems (EOS) and NMDA receptor might be involved in the analgesic action of pcTBS. In the first part,the investigator compares the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) stimulation before and after naloxone or placebo treatment, the intensity of pain induced by capsaicin were used to evaluate the analgesic effects of pcTBS. If naloxone does not reverse the analgesic effect of pcTBS,The volunteers will be invited to participant the second part of the study, which the investigator compares the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) stimulation before and after Ketamine treatment.

Conditions

Chronic Pain; rTMS

Outcome Measures

Primary Outcomes (2)

• pain intensity at baseline

  pain intensity on a 10-cm visual analogue scale (VAS) extending from 0 (no pain) to 100 (maximal pain possible) at baseline.

  Baseline

• pain intensity at the posttreatment of pcTBS

  pain intensity on a 10-cm visual analogue scale (VAS) extending from 0 (no pain) to 100 (maximal pain possible) at the posttreatment of pcTBS.

  through study completion, an average of 8 months

Secondary Outcomes (4)

• Motor-evoked potential (MEP)

  through study completion, an average of 8 months

• Cortical silent period (CSP)

  through study completion, an average of 8 months

• Maximum plasma concentration of opioid peptide at baseline

  baseline

• Maximum plasma concentration of opioid peptide at the posttreatment of pcTBS

  through study completion, an average of 8 months

Study Arms (3)

active stimulation of M1

EXPERIMENTAL

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.

Drug: Naloxone; Drug: Saline; Drug: Ketamine Hydrochloride; Device: pcTBS of M1

active stimulation of DLPFC

EXPERIMENTAL

pcTBS was administered to the left DLPFC 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.

Drug: Naloxone; Drug: Saline; Drug: Ketamine Hydrochloride; Device: pcTBS of DLPFC

SHAM stimulation

SHAM COMPARATOR

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

Drug: Naloxone; Drug: Saline; Drug: Ketamine Hydrochloride; Device: SHAM stimulation

Interventions

Naloxone DRUG

The volunteer received an intravenous bolus followed by a continuous infusion of naloxone, which was continued throughout the pcTBS session

SHAM stimulation; active stimulation of DLPFC; active stimulation of M1

Saline DRUG

The volunteer received an intravenous bolus followed by a continuous infusion of placebo (saline), which was continued throughout the pcTBS session

SHAM stimulation; active stimulation of DLPFC; active stimulation of M1

Ketamine Hydrochloride DRUG

The volunteer received an intravenous bolus followed by a continuous infusion of ketamine, which was continued throughout the pcTBS session

SHAM stimulation; active stimulation of DLPFC; active stimulation of M1

pcTBS of M1 DEVICE

Prolonged continuous theta-burst stimulation (pcTBS) was administered to the left M1 at 80% 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

active stimulation of M1

pcTBS of DLPFC DEVICE

Prolonged continuous theta-burst stimulation (pcTBS) was administered to the left DLPFC at 80% 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

active stimulation of DLPFC

SHAM stimulation DEVICE

The Sham stimulation was delivered using the same pcTBS protocol, with the coil being flipped 90◦to the scalp so that the magnetic field would be delivered away from the scalp

SHAM stimulation

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ）woman or man over 18 and under 85 years old; 2）Clinical diagnosis of physical and mental health people; 3) able to cooperate in completing questionnaire.

You may not qualify if:

• )Clinical diagnosis of 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) Any difficulty to fill out questionnaires (due to language or cognitive problems);

Sponsors & Collaborators

• Second Affiliated Hospital, School of Medicine, Zhejiang University: lead

Study Sites (1)

The second affiliated hospital of Zhejiang University hangzhou

Hangzhou, Zhejiang, China

Location

Related Publications (1)

• Liu Y, Sun J, Wu C, Ren J, He Y, Sun N, Huang H, Chen Q, Liu D, Huang Y, Xu F, Yu L, Fitzgibbon BM, Cash RFH, Fitzgerald PB, Yan M, Che X. Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: a randomized controlled trial. Pain. 2024 Sep 1;165(9):2035-2043. doi: 10.1097/j.pain.0000000000003220. Epub 2024 Mar 26.

  PMID: 38537053 DERIVED

MeSH Terms

Conditions

Chronic Pain

Interventions

Naloxone; Sodium Chloride; Ketamine

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals

Study Officials

• min yan, prof

  The second affiliated hospital of Zhejiang University hangzhou

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 19, 2022
• First Posted: May 4, 2022
• Study Start: May 14, 2022
• Primary Completion: December 1, 2022
• Study Completion: December 31, 2022
• Last Updated: February 16, 2023

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)