On the importance of placebo timing in rTMS studies for pain relief

The efficacy of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex for neuropathic pain relief is founded on double-blind studies versus placebo. In these studies, however, the analgesic effect of active interventions remained modest compared with the placebo effect. This observation led us to re-evaluate the intrinsic placebo action on pain relief according to the relative timing of active and sham rTMS interventions. In a randomized controlled study including 45 patients, we compared the analgesic effect of sham rTMS that either preceded or followed an active rTMS, which could be itself either successful or unsuccessful. Placebo analgesia differed significantly when the sham rTMS session followed a successful or an unsuccessful active rTMS. Placebo sessions induced significant analgesia when they followed a successful rTMS (mean pain decrease of 11%), whereas they tended to worsen pain when following an unsuccessful rTMS (pain increase of 6%). Only when the sham intervention was applied before any active rTMS were placebo scores unchanged from the baseline. These results probably reflect an unconscious conditioned learning. The timing of placebo relative to active interventions should be taken into account in rTMS studies for pain relief, and possibly in other conditions too. The fact that placebo effects could be enhanced by a previous rTMS with an analgesic effect as low as 10% suggests that a 30% pain decrease threshold in therapeutic trials may be too severe because smaller analgesic effects may have a clinical significance too. Sham rTMS induces significant analgesia only when preceded by a successful active stimulation. Such a placebo modulation is probably related to an unconscious conditioned learning.