Mechanism of Analgesic Effect on Prolonged Continuous Theta Burst Stimulation

NCT ID: NCT05360030

Last Updated: 2023-02-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 45 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-14
• Study Completion Date: 2022-12-31

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.

Detailed Description

This study comprised 3 parallel arms corresponding to 3 types of stimulation: active stimulation of M1, active stimulation of DLPFC-pcTBS, and sham stimulation (of M1 or DLPFC). Volunteers were randomly assigned to the 3 arms. In the first part, these volunteers participated in 2 experimental sessions 1 weeks apart, in which we compared the effects of naloxone and placebo (saline), administered according to a randomized, double-blind crossover design, on pcTBS-induced analgesia. Each experimental session started with the determination of baseline pain intensity and cortical excitability as well as plasma opioid peptide concentrations. Ten minutes before pcTBS (of M1, DLPFC, or sham), the volunteer received an intravenous bolus followed by a continuous infusion of either placebo (ie, saline) or naloxone, which was continued throughout the rTMS session (2 minutes). The participant was then allowed to rest for 60 minutes. Posttreatment pain intensity, cortical excitability and plasma opioid peptide concentrations will be determined by the same procedure used at baseline.In the second part, ketamine will be delivered the same as the first part.

Conditions

Chronic Pain; rTMS

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: DOUBLE

Study Groups

active stimulation of M1

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.

Group Type: EXPERIMENTAL

Naloxone

Intervention Type: DRUG

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

Saline

Intervention Type: DRUG

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

Ketamine Hydrochloride

Intervention Type: DRUG

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

pcTBS of M1

Intervention Type: 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 DLPFC

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.

Group Type: EXPERIMENTAL

Naloxone

Intervention Type: DRUG

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

Saline

Intervention Type: DRUG

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

Ketamine Hydrochloride

Intervention Type: DRUG

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

pcTBS of DLPFC

Intervention Type: 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

SHAM stimulation

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

Group Type: SHAM_COMPARATOR

Naloxone

Intervention Type: DRUG

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

Saline

Intervention Type: DRUG

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

Ketamine Hydrochloride

Intervention Type: DRUG

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

SHAM stimulation

Intervention Type: 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

Interventions

Naloxone

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

Intervention Type: DRUG

Saline

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

Intervention Type: DRUG

Ketamine Hydrochloride

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

Intervention Type: DRUG

pcTBS of M1

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

Intervention Type: DEVICE

pcTBS of DLPFC

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

Intervention Type: DEVICE

SHAM stimulation

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

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

1）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.

Exclusion Criteria

1)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);

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Second Affiliated Hospital, School of Medicine, Zhejiang University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

min yan, prof

Role: STUDY_CHAIR

The second affiliated hospital of Zhejiang University hangzhou

Locations

The second affiliated hospital of Zhejiang University hangzhou

Hangzhou, Zhejiang, China

Countries

China

References

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.

Reference Type: DERIVED

PMID: 38537053 (View on PubMed)

Other Identifiers

RI2022089

Identifier Type: -

Identifier Source: org_study_id