In a group of TMS naïve outpatients with fibromyalgia, we found that 10 sessions of high frequency left prefrontal TMS resulted in statistically significant reductions in daily pain over time in comparison to baseline mean pain in the treatment group. There were no significant reductions in pain over time in the sham group. However, there were no statistically significant reductions in mean pain between treatment versus sham groups in this pilot trial. Thus any conclusions of fibromyalgia pain reduction with TMS are premature until studies with larger sample sizes show differences between groups, not just pain reduction over time from baseline measures. There were few side effects and no dropouts. TMS was well tolerated. Subjects in both arms were similar across demographics. The pain reduction in the treatment arm was statistically different from baseline after day five of treatment and remained statistically different throughout the follow-up visits. Percent change in reduced pain was 29% at the end of 10 days of treatment over two weeks. Pharmaceutical clinical trials for fibromyalgia seek a 30% reduction in pain for clinical significance. The rapid onset of pain reduction in this pilot trial approximates that of pregabalin and duloxetine, although with markedly less side effects [31
Fibromyalgia Impact Questionnaire data suggest that the treatment arm experienced a significant reduction in pain compared to baseline at the end of week two of treatment. In follow up week one and two, treatment subjects continued to show a reduction in pain and improved function, however subjects that received sham additionally improved in these domains too. Overall there was no significant difference in follow up weeks one and two. It is unclear as to why sham subjects had robust improvements in these scales after, not during, sham treatment. Speculatively, subjects enrolled were not accustomed to repeat daily visits to the Brain Stimulation Lab that may have unexpectedly involved an element of behavioral activation along with a limited social engagement to the TMS device operator. These effects would occur in both arms, however the sham group received a noxious sham stimulation to simulate real TMS. When sham TMS subjects no longer received sham, they may have inadvertently recorded benefits of removing noxious stimuli along with some nonspecific benefits of behavioral activation, relative to baseline activity, needed to carry out the study. Other possibilities include delayed placebo effect, natural history, or regression to the mean. The BPI assesses pain comparisons over the past 24 hours and the FIQ measures symptom change over the past week. Both assessments possibly captured some non-specific effects but did not capture daily changes from baseline as the pain diary data could.
Secondary analyses of tender point changes are of interest. Subjects with real TMS showed a reduction in tender points in comparison to sham TMS subjects. The treatment sample mean number of tender points dropped below 11 points by the end of the session 10, technically reducing tender points below the categorical 11 of 18 tender points for a diagnosis of fibromyalgia. The tender point reduction was not seen in the placebo arm. Currently tender point counts are a topic of debate for research utility or as clinical marker of improvement in symptoms given the heterogeneity in the fibromyalgia population [46
]. In this sample, a reduction in tender points was pronounced, but potentially biased by an unblinded tender point rater later in the study.
In regards to depression, there was not a statistical difference in depression at the end of ten days of rTMS versus sham, however there was a statistical reduction in depression by HDRS in the follow up assessments in the treatment group compared to baseline. Post hoc analyses of daily pain and mood diaries revealed daily pain reduction occurred on average one day before any change in mood, supporting a change in pain before shifts in mood. Other trials have additionally seen reductions in TMS procedural pain and overall pain levels before antidepressant effects when stimulating at 10Hz, LDLPFC rTMS [6
Given antidepressant effects observed, it is relevant to note the evidence for high frequency rTMS antidepressant effects are not without ambiguity. A Cochrane review [38
], analyzing TMS antidepressant trials until 2001, concluded there is no strong evidence for efficacy of transcranial magnetic stimulation for the treatment of depression. Small sample size, lower stimulation intensities, and shorter treatment courses were the primary methodological deficiencies in those trials. Recent meta-analyses [29
] of subsequent rTMS antidepressant studies lend support to the FDA’s approval of high frequency rTMS for the treatment of unipolar, nonpsychotic, depression after failing to respond to one antidepressant. Any conclusions of antidepressant effects with TMS in patients with fibromyalgia are premature.
Fibromyalgia subjects have abnormalities in central pain modulation. They may have abnormalities in endogenous opioid systems [7
] and enhanced spontaneous pain related to enhanced insula connectivity with default mode network circuitry [34
]. Fibromyalgia subjects can have higher resting motor thresholds, motor evoked potentials, lower intracortical facilitation, and short intracortical inhibition suggesting abnormal intracortical modulation involving GABAergic and glutamatergic mechanisms [33
]. Fibromyalgia subjects have been shown to have less rostral ACC activity with pain provocation [26
], suggesting decreased activity of pain inhibition circuitry.
rTMS to DLPFC may reduce fibromyalgia pain via modulation of pain processing circuitry. Pain modulation circuitry may involve prefrontal cortex (PFC), anterior cingulate cortex, periaqueductal gray, and ventral medial medulla [37
]. The PFC may be directly involved in placebo analgesia via release of endogenous opiods in these subcortical regions, and reducing pain transmission [45
]. Placebo analgesia can be experimentally blunted with opiate antagonists [2
]. Furthermore, the placebo response can be transiently blocked with low frequency TMS to bilateral DLPFC in healthy volunteers [28
]. Speculatively, our study may be stimulating left DLPFC at high frequency and activating the same pain modulation circuitry without necessarily activating the psychological expectation. Might high frequency TMS in the DLPFC activate rostral ACC and pain control circuitry to facilitate the placebo response by endogenous opiod release? Fortunately, these are testable hypotheses.
There are several limitations to the study. As a pilot trial, the sample size is small, subjects are not matched by age or severity of symptoms, and subjects remained on medications for fibromyalgia pain. The treatment course was abbreviated (2 weeks instead of 4-6 weeks) in comparison to TMS depression clinical trials from whence the methods were derived. Between group differences were not statistically significant, rather differences were significant over time from baseline, respective to each group. Subsequent secondary functional outcome measures were limited statistically and clinically, which possibly is a function of limited therapeutic significance or premature termination of rTMS. Several pharmacotherapy clinical trials for fibromyalgia are similarly challenged with some secondary functional measures either not reaching statistical significance [5
] or modest clinical significance [18
]. LDLPFC localization methodology did not use neuroimaging to confirm anatomic site of interest or account for inter-individual neuroanatomic differences. Although subjects were blinded to treatment condition, the TMS administrator was not blind to treatment condition and potentially introduced bias in subjects, effecting treatment response. The rater measuring tender points was not blind to treatment condition throughout the study, thus serving as another source of bias. A blinded, continuous rater was employed for all other measures. Subjects were not followed for months, as part of the study, and thus is it unclear how long the treatment effects lasted. Anecdotally, one subject contacted the research team requesting another course as her fibromyalgia pain had returned after an almost fibromyalgia pain free period of eleven months. A second had called noting approximately 6 months significant fibromyalgia pain relief. Future TMS fibromyalgia research can address several methodological issues with larger samples, double blinding, neuroanatomic localization, longer duration of treatment and observation to ascertain if there are actual treatment effects observed between TMS and sham groups. Future trials may also test for changes in cortical excitability, neuroanatomic changes in PFC, ACC and insula that may preclinically correlate with symptom improvement and be used as a biomarker.