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 .
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.