The painfulness of active, but not sham, transcranial magnetic stimulation decreases rapidly over time: results from the double-blind phase of the OPT-TMS Trial

Abstract

Background: Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) over several weeks is an FDA approved treatment for major depression. Although rTMS is generally safe when administered using the FDA guidelines, there are a number of side effects that can make it difficult for patients to complete a course of rTMS. Many patients report that rTMS is painful, although patients appear to accommodate to the initial painfulness. The reduction in pain is hypothesized to be due to prefrontal stimulation and is not solely explained by accommodation to the stimulation.

Methods: In a recent 4 site randomized controlled trial (using an active electrical sham stimulation system) investigating the antidepressant effects of daily left dorsolateral prefrontal rTMS (Optimization of TMS, or OPT-TMS), the procedural painfulness of TMS was assessed before and after each treatment session. Computerized visual analog scale ratings were gathered before and after each TMS session in the OPT-TMS trial. Stimulation was delivered with an iron core figure-8 coil (Neuronetics) with the following parameters: 10 Hz, 120% MT (EMG-defined), 4 s pulse train, 26 s inter-train interval, 3000 pulses per session, one 37.5 min session per day. After each session, procedural pain (pain at the beginning of the TMS session, pain toward the middle, and pain toward then end of the session) ratings were collected at all 4 sites. From the 199 patients randomized, we had usable data from 142 subjects for the initial 15 TMS sessions (double-blind phase) delivered over 3 weeks (142 × 2 × 15 = 4260 rating sessions).

Results: The painfulness of real TMS was initially higher than that of the active sham condition. Over the 15 treatment sessions, subjective reports of the painfulness of rTMS (during the beginning, middle and end of the session) decreased significantly 37% from baseline in those receiving active TMS, with no change in painfulness in those receiving sham. This reduction, although greatest in the first few days, continued steadily over the 3 weeks. Overall, there was a decay rate of 1.56 VAS points per session in subjective painfulness of the procedure in those receiving active TMS.

Discussion: The procedural pain of left, prefrontal rTMS decreases over time, independently of other emotional changes, and only in those receiving active TMS. These data suggest that actual TMS stimulation of prefrontal cortex maybe related to the reduction in pain, and that it is not a non-specific accommodation to pain. This painfulness reduction softly corresponds with later clinical outcome. Further work is needed to better understand this phenomenon and whether acute within-session or over time painfulness changes might be used as short-term biomarkers of antidepressant response.

Trial registration: ClinicalTrials.gov NCT00149838.

Keywords: Clinical trial; Depression; OPT-TMS; Pain; Sham; TMS; Transcranial magnetic stimulation.

Conflict of interest statement

Conflicts of Interest: Full disclosures and listings for all authors are at the end of the manuscript. For the specific interests of this clinical trial, Dr. George, the study chair, has received no compensation from any TMS manufacturer for the past 5 years, and owns no equity stake in any device or pharmaceutical company. Following a competitive bid and request involving all known TMS manufacturers at the time, Neuronetics was selected and loaned the TMS device, head-holder and coils used in the trial and allowed the use of the safety IDE of their device, but has otherwise been uninvolved in trial conduct or analysis. The TMS sham equipment was purchased from the MECTA Corporation and the James Long Company.

Copyright © 2013 Elsevier Inc. All rights reserved.

Figures

Figure 1

Graph of painfulness changes over time (beginning, middle and end of treatment) separated by active and sham groups. Note that only in the active group is there a reduction over time. Note also that the two groups differed in their overall painfulness ratings.