Repetitive Transcranial Magnetic Stimulation of Relief of Fibromyalgia Pain
Condition: Fibromyalgia
MeSH terms: Fibromyalgia; Myofascial Pain Syndromes
Study type: Interventional

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 .
    

Intervention name(s): Conventional rTMS - study 1; Sham rTMS - study 1; Conventional rTMS - study 2; Patterned rTMS - stage 2
Intervention type(s): Procedure; Procedure; Procedure; Procedure
Intervention description(s): Patients will be undergoing to 10Hz transcranial magnetic stimulation session; Patients will be undergoing to sham transcranial magnetic stimulation session; Patients will be undergoing to 10Hz transcranial magnetic stimulation session; Patients will be undergoing to theta-burst transcranial magnetic stimulation session
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: This is an adaptive sequential trial of FM patients. In stage 1 patients were randomly allocated into two parallel arms (conventional rTMS, sham) using adaptive methodology. In stage 2, after the end of the first trial, patients will be allocated to two arms (conventional rTMS, patterned rTMS). Both stages will be conducted in a sequential methodology where an interim analysis will take place and indicate whether will take place trial is positive and of the scientific board agrees open its start.
Recruitment time will be extended by 12 months due to dropouts related to the Covid-19 pandemic. We have had dropouts due to some patients who developed Covid-19 and also due to patients who were afraid of becoming infected during hospital visits. Those patients who dropped out of the study due to the pandemic will be excluded from the main analysis and will be analyzed as a secondary outcome.
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: fibromyalgia; repetitive transcranial magnetic stimulation