In general, FM patients had the same types of side effects to VNS as those reported in patients with treatment-resistant epilepsy and depression – most often stimulus-bound voice alteration, neck pain, nausea, and dyspnea; these side effects tended to dissipate with time. Dry mouth and increased fatigue were two AEs not previously reported and present in this study population. While implantation surgery was tolerated well, two patients did not complete the acute study [one due to problems tolerating stimulation and the other due to study violations]; a third patient requested device explantation due to treatment inefficacy. This non-completion rate does not differ from that reported at the end of the one year trial of VNS for major depression [270 completers of 295 implanted (14
); fishers test NS]. Eleven women completed the follow up study. No late emerging AEs were observed.
While the primary purpose of this study was to assess the safety and tolerability of VNS in FM, a secondary goal was to do a preliminary evaluation of its efficacy. We assessed the MCID and another measure added at the end of the acute study phase – the existence of the diagnosis of FM consistent with 1990 ACR FM criteria (2
), i.e., FM caseness. We had not considered loss of FM caseness (2
) as a possible outcome measure when we designed the study because no published treatment had been efficacious enough to affect diagnosis, but since we found this to occur in certain VNS-treated patients, we realized that using loss of FM caseness as an outcome variable might be useful for clinicians in judging the potential efficacy of VNS.
Both outcome measures showed substantial improvement over time. At the end of the acute study, five of the 14 participants became MCID+ and two no longer fulfilled both diagnostic criteria for the 1990 ACR FM case definition (2
). In contrast to studies using reduction in pain alone to indicate the therapeutic efficacy of a drug in treating FM, only this and one other published trial used the more demanding MCID to determine a positive therapeutic effect (12
). Importantly, no study has ever reported sufficient improvement in pain that treated patients no longer fulfill criteria for the diagnosis of FM (2
This therapeutic effect seemed to increase beyond the acute trial. At the end of the 11 month study, seven patients were MCID+ and parallel improvement was seen in terms of FM caseness (2
): five patients no longer fulfilled either the widespread pain criterion or the tender point criterion for the diagnosis of FM (2
), and a sixth patient continued to have wide spread pain but had fewer than 11 tender points (dark grey shading in ). We were surprised by the robustness and ubiquity of response to the VNS treatment. While it is true that “improvement in tender point threshold appears to be a difficult outcome to achieve” (4
), our results suggest that an FM treatment can reduce tender point threshold to the degree that the point tested is no longer tender.
However, tender point count was not a reliable predictor of continued therapeutic success over time as can be seen with #102 as an example (see ). She had widespread pain throughout the trial and had as few as five tender points at one visit; but, then, number of tender points increased thereafter. The best predictor of outcome seemed to be reduction in painful quadrants to three or lower. For every patient except #121 at her 8 month visit, this reduction in bodily pain boded well for continued clinical improvement.
The reduction in QST/psychophysical response to heat pain stimuli suggests that VNS had an effect on the sensitivity of the nociceptive system. Patients reported large decreases in pain ratings from the pre-stimulation baseline to the end of the acute study phase, and these changes persisted throughout the remaining study visits. These data suggest that VNS may tune down the pathophysiological processes responsible for central sensitization, thus providing a potential mechanism as to how VNS can reduce widespread musculoskeletal pain in FM. The results of the entire QST battery are currently being prepared as a separate manuscript.
Since this is an uncontrolled pilot study, an obvious question is whether this positive therapeutic effect is specific to VNS itself or is a placebo effect secondary to extraneous factors related to being in a treatment trial necessitating surgery, feeling a sensory stimulus throughout the day, and having high hopes for a good therapeutic outcome. Some data do exist to show that non-specific [i.e., placebo] effects can last for many months in trials requiring surgery. But studies reporting that outcome were for episodic events – syncope (15
) or angina (16
) – very different conditions from one with chronic pain. One trial on Parkinsonian patients has been cited as showing a long-lived placebo effect, but not one which improved patients’ neurological impairment or their objective function (17
); another with sham surgery for knee pain did produce a 10% reduction in pain over one year (18
). Thus, published data indicating a prolonged effect of nonspecific factors in reducing chronic symptoms are sparse.
Some evidence for an initial non-specific effect may be seen from the data of one participant, subject #124, who became MCID+ at the end of the acute study but at no time point thereafter. However, the continued improvement over time shown by some patients and the fact that more patients attained outcome criteria over time argues against a non-specific or placebo explanation for the therapeutic benefit; such an incrementing response has been reported for VNS treatment of refractory epilepsy (19
). Nevertheless, a controlled trial is needed to determine the specificity of these effects.