Classical, Spaced, or Accelerated Transcranial Magnetic Stimulation of Motor Cortex for Treating Neuropathic Pain: a 3-arm Parallel Non-inferiority Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Interference Scale of the short form of the Brief Pain Inventory (BPI)
研究概览
简要总结
Neuropathic pain is frequent and drugs relieves only 50% of the patients. Repetitive transcranial magnetic stimulation (rTMS) at high frequency (HF, usually 10Hz) applied on the primary motor cortex (M1) is an effective treatment of neuropathic pain. For the treatment of chronic pain, the 'classical' HF-rTMS protocol (CHF-rTMS) include one daily session for one or two weeks as an induction phase of treatment followed by a weekly session to produce analgesic effects. However, another type of protocol is based on a more spaced repetition of HF-rTMS sessions (SHF-rTMS), including intervals of several days or weeks between two sessions, but also resulting in a significant pain relief. However, CHF-rTMS and SHF-rTMS have never been compared regarding their analgesic efficacy.
Alongside with pain, depression is the other clinical condition for which HF-rTMS is proposed as an effective therapeutic strategy. Another type of rTMS paradigm, called "accelerated intermittent theta burst stimulation" (ACC-iTBS) protocol has been recently proposed for the treatment of depression, combining a high number of pulses delivered per session and a high number of short-duration sessions grouped into a few days of stimulation. However, this type of protocol has never been applied for the treatment of chronic pain patients.
Thus, for the first time we propose to compare in a pilot study the efficacy of three different rTMS protocols for the treatment of chronic neuropathic: CHF-rTMS, SHF-rTMS, and ACC-iTBS. In this study, two protocols two rTMS protocols (CHF-rTMS and ACC-iTBS) will share the same high total number of TMS pulses (i.e. 30 000 pulses) versus an rTMS protocol (SHF-rTMS) based on a lower total number of TMS pulses (i.e. 6 400 pulses), while one protocol (CHF-rTMS) will include a higher number of days of stimulation (i.e. 10 days) compared to the two other protocols (ACC-iTBS and SHF-rTMS) (i.e. 4 days). In all cases, the motor cortical target and the intensity of stimulation will the same.
Thus, this study will be able to appraise the respective influence of the number of pulses delivered (the higher the number, the greater the effect) and the number of sessions (the higher the number, the more restrictive the implementation of treatment). That is to say that the new ACC-iTBS protocol could be an optimal compromise of a more efficacious and more easy-to-perform rTMS protocol for the treatment of patients with chronic pain.
详细描述
Description of the research proceedings and study design This is a 3-parallel-group monocentric randomized study, in which 36 patients, aged between 18 and 80 years, suffering from painful peripheral neuropathy (DN4 and NRS pain scores ≥4/10), will be randomly assigned to one of three rTMS protocols: CHF-rTMS, SHF-rTMS, and ACC-iTBS. The group allocation of the patients will be performed by one investigator not involved in the experimental task or clinical assessment. Patients will be recruited in the Clinical Neurophysiology department of the Henri Mondor University Hospital, Créteil, France, where the research will take place
Screening and inclusion visits During a routine medical visit, the study will be explained and proposed to the eligible patients and a letter of information about the protocol will be given to them. The list of the patients receiving the letter of information will be collected to determine the ratio between the number of patients definitively included and the number of patients screened. After a delay of reflection of at least a week, patients who agree to perform this research will be convened for an inclusion visit. After checking the inclusion/exclusion criteria, the informed consent form will be completed and signed by the participant and duly countersigned by the investigator.
During this inclusion visit, performed two weeks after the rTMS intervention, information regarding demographic data (age, gender), medical history and the list of drug treatments will be collected. A pain diary of 13 pages will be given to the patient with one page per week presenting a 0-10 numeric pain intensity rating scale (NRS) per day and a box to indicate the number of pain attacks and analgesic pills taken in addition to the usual treatment for each day of the week (cf. Appendix). Finally a code will be assigned to the patient (first 3 letters of the surname and the inclusion number) and this code will be sent to the person responsible for the randomization between the three types of stimulation protocol (CHF-rTMS / SHF-rTMS / ACC-iTBS).
First assessment visit One week after the inclusion visit (i.e. one week before the rTMS intervention), the first complete assessment visit will be managed to record all the clinical and neurophysiological outcome measures assessed in this study.
Clinical outcome measures: Scales and questionnaires
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(1) existence of a definite peripheral neuropathy on both clinical and neurophysiological grounds, present for at least 6 months;
- •(2) neuropathic pain clearly related to the neuropathy, as defined by a score ≥ 4/10 on the questionnaire "Douleur Neuropathique en 4 Questions" (DN4) ;
- •(3) a score ≥ 4/10 on a 0-10 numerical rating scale (NRS) concerning the average intensity of daily ongoing pain;
- •(4) age between 18 and 80 years;
- •(5) affiliation with the social security system;
- •(6) ability to provide signed informed consent.
排除标准
- •(1) concomitant neurological (neurodegenerative disorders, migraine, epilepsy, stroke, tumor) or psychiatric illness;
- •(2) contraindications related to TMS (intracranial ferromagnetic material);
- •(3) drug-resistant or active epilepsy.
研究组 & 干预措施
Classical HF-rTMS (CHF-rTMS)
Stimulation was applied over the hand knob area of the primary motor cortex (M1), contralateral to the pain side, corresponding to the left hemisphere. The stimulation intensity was set at 80% of the resting motor threshold.
Each session consisted of 30 trains of 100 pulses, delivered at a frequency of 10 Hz for 10 seconds per train, with an inter-train interval (ITI) of 20 seconds. This resulted in a total of 3,000 pulses per session, delivered over approximately 15 minutes.
The treatment protocol included one session per day for 5 consecutive days during the first week. Subsequently, one session per week was performed during weeks 2, 3, 4, 5, and 7.
In total, the protocol consisted of 10 sessions delivered over 7 weeks, with a cumulative number of 30,000 pulses.
干预措施: transcranial magnetic stimulation (TMS) (Device)
Spaced HF-rTMS (SHF-rTMS)
Stimulation was applied over the hand knob area of the primary motor cortex (M1), contralateral to the pain side, corresponding to the left hemisphere. The stimulation intensity was set at 80% of the resting motor threshold.
Each session consisted of 20 trains of 80 pulses, delivered at a frequency of 20 Hz for 4 seconds per train, with an inter-train interval (ITI) of 80 seconds. This resulted in a total of 1,600 pulses per session, delivered over approximately 28 minutes.
The treatment protocol included one session per week during weeks 1, 3, 5, and 7.
In total, the protocol consisted of 4 sessions delivered over 4 weeks, with a cumulative number of 6,400 pulses.
干预措施: transcranial magnetic stimulation (TMS) (Device)
Accelerated iTBS (ACC-iTBS)
Stimulation was applied over the hand knob area of the primary motor cortex (M1), contralateral to the pain side, corresponding to the left hemisphere. The stimulation intensity was set at 80% of the resting motor threshold.
Each session consisted of 50 trains of 30 pulses, corresponding to 10 bursts (delivered at 5 Hz over 2 seconds), with each burst containing 3 pulses at 50 Hz (lasting 60 milliseconds). The inter-train interval (ITI) was 8 seconds. This resulted in a total of 1,500 pulses per session, delivered over approximately 8 minutes.
The treatment protocol included 5 sessions per day, with an interval of 45 minutes between sessions, for 2 consecutive days during each stimulation week (from week 1 to week 7).
In total, the protocol consisted of 20 sessions delivered over 4 days, with a cumulative number of 30,000 pulses.
干预措施: transcranial magnetic stimulation (TMS) (Device)
结局指标
主要结局
Interference Scale of the short form of the Brief Pain Inventory (BPI)
时间窗: From enrollment to 5 weeks after the last TMS session
The 7-item Interference Scale of the short form of the Brief Pain Inventory measures how much pain has interfered with seven daily activities, including general activity, walking, work, mood, enjoyment of life, relations with others, and sleep. It uses a 0 to 10 numeric rating scales for each item rating. The minimum score is 0 (no interference of pain on daily living activities, ie better outcome) and the maximum score is 70 (maximal interference of pain on daily living activities, ie worse outcome).
次要结局
- Average intensity of daily ongoing pain on a 0-10 numeric rating scale (NRS)(From enrollment to 5 weeks after the last TMS session)
- Average intensity of daily ongoing pain on a 0-5 verbal rating scale (VRS)(From enrollment to 5 weeks after the last TMS session)
- Patient global impression of change (PGIC)(From enrollment to 5 weeks after the last TMS session)
- Symptomatic profile of neuropathic pain on the Neuropathic Pain Symptom Inventory (NPSI)(From enrollment to 1 weeks after the last TMS session)
- Tendency to catastrophizing on the Pain Catastrophizing Scale (PCS)(From enrollment to 1 weeks after the last TMS session)
- Anxiety and depression on the Hospital Anxiety and Depression scale (HAD)(From enrollment to 1 weeks after the last TMS session)
- Fatigue on the Fatigue Severity Scale (FSS)(From enrollment to 1 weeks after the last TMS session)
- Quality of sleep on the Leeds Sleep Evaluation Questionnaire (LSEQ).(From enrollment to 1 weeks after the last TMS session)
- Absolute PSD from EEG recording(From enrollment to 1 weeks after the last TMS session)
- Relative PSD from EEG recording(From enrollment to 1 weeks after the last TMS session)
- TMS-EEG evoked potentials(From enrollment to 1 weeks after the last TMS session)
- Global mean field power(From enrollment to 1 weeks after the last TMS session)
- TMS-EEG evoked potientals spreading(From enrollment to 1 weeks after the last TMS session)
- Event-related spectral perturbation(From enrollment to 1 weeks after the last TMS session)
- Maximum MEP inhibition from T-SICI recording(From enrollment to 1 weeks after the last TMS session)
- ISI value from maximum MEP inhibition(From enrollment to 1 weeks after the last TMS session)
- area under the T-SICI curve(From enrollment to 1 weeks after the last TMS session)
- TMS-EEG evoked potentials during second nTMS-EEG set(From enrollment to 1 weeks after the last TMS session)
- Global mean field power during second nTMS-EEG set(From enrollment to 1 weeks after the last TMS session)
- TMS-EEG evoked potientals spreading during second nTMS-EEG set(From enrollment to 1 weeks after the last TMS session)
研究者
François Vialatte
Director of PiPsy Institute
Institut pour la Pratique et l'Innovation en PSYchologie appliquée (Institut Pi-Psy)