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NCT Number: NCT05360030

Mechanism of Analgesic Effect on Prolonged Continuous Theta Burst Stimulation

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.

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Key information

Conditions

Chronic Pain Neurologic Manifestations Pain Pathological Conditions, Signs and Symptoms Rtms Signs and Symptoms

Age range

18 year–85 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

The second affiliated hospital of Zhejiang University hangzhou

Hangzhou, Zhejiang, China

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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);

Treatment and study plan

naloxone

Drug

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

Saline

Drug

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

Ketamine Hydrochloride

Drug

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

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

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

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

Primary outcomes

  1. pain intensity at baseline

    Time frame: Baseline

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

  2. pain intensity at the posttreatment of pcTBS

    Time frame: through study completion, an average of 8 months

    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.

Secondary outcomes

  1. Motor-evoked potential (MEP)

    Time frame: through study completion, an average of 8 months

    Corticospinal excitability will be 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).

  2. Cortical silent period (CSP)

    Time frame: through study completion, an average of 8 months

    Corticospinal excitability will be 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).

  3. Maximum plasma concentration of opioid peptide at baseline

    Time frame: baseline

    plasma opioid peptide concentrations will be measured using ELISA at baseline.

  4. Maximum plasma concentration of opioid peptide at the posttreatment of pcTBS

    Time frame: through study completion, an average of 8 months

    plasma opioid peptide concentrations will be measured using ELISA at the last posttreatment of pcTBS.

Sponsors and collaborators

Lead sponsor

Second Affiliated Hospital, School of Medicine, Zhejiang University

Other

Registry information

Important dates

Study start
2022
Primary completion
2022
Study completion
2022
First posted
May 4, 2022
Registry last updated
Feb 16, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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