Repetitive Transcranial Magnetic Stimulation of Relief of Fibromyalgia Pain

Not Applicable

Completed

• Conditions: Fibromyalgia
• Interventions: Procedure: Conventional rTMS - study 1; Procedure: Sham rTMS - study 1; Procedure: Conventional rTMS - study 2; Procedure: Patterned rTMS - stage 2

• Registration Number: NCT03658694
• Lead Sponsor: University of Sao Paulo

Brief Summary

There are currently several points concerning rTMS for pain relief that have a huge impact in the practical application of rTMS in clinical practice, but which have not been approached by previous studies. Also, an even more important issue is the frequency of the sessions in each treatment protocol. The idea of performing stimulation in chronic pain patients on a consecutive daily basis for long-term treatments seem unrealistic and potentially costly. However, it has been reported in animals, healthy subjects and FM patients that the analgesic effects of rTMS can outlast the stimulation session for several minutes and even days. This has led to the proposal that pain treatment with rTMS could be performed in consecutive daily induction sessions, followed by spaced (weekly, fortnightly and even monthly) maintenance sessions. This approach is similar to what is performed routinely in patients with major depression treated by rTMS to the dorsolateral prefrontal cortex, and has successfully been tested in FM patients in a single- center study. Should this approach prove effective in larger prospective multicentric studies, rTMS could enter the armamentarium of non-invasive, non- pharmacological, low-adverse event therapeutic options to relieve fibromyalgia- related pain and associate symptoms. Hence, our aim is to conduct a multicentric international clinical trial on the influence of rTMS in the control of pain in a consecutive adaptive trial design where conventional rTMS (10Hz) and patterned rTMS (theta-burst) will be studied. Stimulations will be performed in a clinical practice-friendly approach, where daily maintenance sessions will be followed by weekly, and fortnightly stimulation sessions. There have been very scarce adaptive trials in the pain and non-invasive stimulation fields. This methodological approach allows for the use of lower number of patients in consecutive trials and, among other qualities, it allows for the imputation of data from the first trial into the second one, thus decreasing the duration of the studies and the number of participants.

Detailed Description

There are currently several points concerning rTMS for pain relief that have a huge impact in the practical application of rTMS in clinical practice, but which have not been approached by previous studies. One of them refers to dosing of the treatment. rTMS sessions have been proposed to comprise from 1000 to 3000 pulses of stimulation in each session, which means that treatment sessions may last from 7 to 20 minutes. While there are positive studies reporting different numbers of pulses, the actual stimulation protocol chosen may impact not only the efficacy of the treatment, but also the duration of the stimulation session, the time patients stay at the health-care facility, and, thus, cost and compliance to treatment. Also, an even more important issue is the frequency of the sessions in each treatment protocol. The idea of performing stimulation in chronic pain patients on a consecutive daily basis for long-term treatments seem unrealistic and potentially costly. However, it has been reported in animals, healthy subjects and FM patients that the analgesic effects of rTMS can outlast the stimulation session for several minutes and even days. This has led to the proposal that pain treatment with rTMS could be performed in consecutive daily induction sessions, followed by spaced (weekly, fortnightly and even monthly) maintenance sessions. This approach is similar to what is performed routinely in patients with major depression treated by rTMS to the dorsolateral prefrontal cortex, and has successfully been tested in FM patients in a single- center study. Should this approach prove effective in larger prospective multicentric studies, rTMS could enter the armamentarium of non-invasive, non- pharmacological, low-adverse event therapeutic options to relieve fibromyalgia- related pain and associate symptoms. Hence, our aim is to conduct a multicentric international clinical trial on the influence of rTMS in the control of pain in a consecutive adaptive trial design where conventional rTMS and patterned rTMS will be studied. Stimulations will be performed in a clinical practice-friendly approach, where daily maintenance sessions will be followed by weekly, and fortnightly stimulation sessions. There have been very scarce adaptive trials in the pain and non-invasive stimulation fields. This methodological approach allows for the use of lower number of patients in consecutive trials and, among other qualities, it allows for the imputation of data from the first trial into the second one, thus decreasing the duration of the studies and the number of participants. Similarly, this technical approach allows for pre-planned interim analyses to be performed during data collection, allowing for the sample size to be readjusted during the trial, and, more importantly, allowing for trial termination due to futility or due to achievement of the primary endpoint before the end of the original preplanned data collection period, with lower risk of bias. Here, the adaptive approach will allow one not only to compare conventional rTMS (10Hz) to sham stimulation, but also, on second consecutive study, it will provide the first head-to-head study on rTMS to date comparing the analgesic effects of conventional (10Hz) and patterned (theta-burst) rTMS .

Study Timeline

• Study First Submitted: 2018-09-03
• Study First Submitted QC: 2018-09-03
• Study First Posted: 2018-09-05
• Study Start: 2019-04-01
• Primary Completion: 2023-03-01
• Study Completion: 2023-03-01
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-11
• Last Update Posted: 2023-10-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 80

Inclusion Criteria

1. Female patients with diagnosis fibromyalgia according to the ACR 2016 criteria (patient satisfies modified 2016 fibromyalgia criteria if the following 3 conditions are met: 1) widespread pain index (WPI) ≥ 7 and symptom severity scale (SSS) score 5 OR WPI of 4-6 and SSS score ≥ 9. 2) Generalized pain, defined as pain in at least 4 of 5 regions, must be present. Jaw, chest, and abdominal pain are not included in generalized pain definition. 3) Symptoms have been generally present for at least 3 months. 4) A diagnosis of fibromyalgia is valid irrespective of other diagnoses. A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses).
2. Age ≥18 years;
3. Be able to understand study protocol and give signed, written informed consent
4. Not under opioids
5. VAS score ≥ 40/100 mm;

Exclusion Criteria

1. Known abuse of alcohol or illicit drugs
2. Known psychiatric conditions
3. Contraindications to rTMS (42) (Head trauma or concussion, metal implants in the skull, pregnancy, cardiac pacemaker, medication infusion devices, previous troubles with TMS or MRI);
4. Not being under chronic contraceptive use (intrauterine dispositive or oral contraceptive)
5. Other medical conditions demand hospitalization;
6. Participation in other clinical studies at the same time

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Conventional rTMS - study 1	Conventional rTMS - study 1	In study 1 patients were randomly allocated to receive conventional repetitive transcranial magnetic stimulation (10Hz).
Sham rTMS - study 1	Sham rTMS - study 1	In study 1 patients were randomly allocated to receive sham repetitive transcranial magnetic stimulation.
Conventional rTMS - study 2	Conventional rTMS - study 2	In study 2, after the end of the first trial will be allocated to receive conventional of repetitive transcranial magnetic stimulation (10Hz).
Patterned rTMS - study 2	Patterned rTMS - stage 2	In study 2, after the end of the first trial will be allocated to receive patterned of repetitive transcranial magnetic stimulation (Theta-burst).

Primary Outcome Measures

Name	Time	Method
Analgesic effects of motor cortex stimulation	8th week of treatment	Percentage of responders based on the reduction of ≥50% in pain intensity (numerical rating scale 0-10) at the end of the study compared to baseline.

Secondary Outcome Measures

Name	Time	Method
Interference in daily activites	8th week of treatment	Measured by brief pain inventory
Adverse events	8th and 16th week of treatment	Assess of adverse events by standardized questionnaire\'
Global impression of change	8th and 16th weeks of treatment	Assess % of very much and much improved
Impact of fibromyalgia daily	8th and 16th week of treatment	Assess by fibromyalgia impact questionnaire
Pain intensity	At the end of the induction period (10th day) and 16th week	Measured by VAS (0 no pain -10 worst pain)
Mood	8th week of treatment	Assess mood by hospital anxiety and depression scale
Medication use	8th week of treatment	Measured by Brief Pain Inventory
Phenotypical markers of analgesic response	8th and 16th week of treatment	Assessment of phenotypical markers of analgesic response

Trial Locations

Locations (6)

Universidade Federal de Pernambuco; 🇧🇷 Recife, Pernambuco, Brazil

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC/FMUSP); 🇧🇷 São Paulo, SP, Brazil

Federal University of ABC; 🇧🇷 São Bernardo Do Campo, Brazil

Ambulatório de Fisioterapia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo; 🇧🇷 São Paulo, Brazil

Centre d'Evaluation et de Traitement de la Douleur Hôpital Ambroise Paré; 🇫🇷 Paris, France

Department of Neuromodulation Osaka University; 🇯🇵 Osaka, Japan