In this multi-site sample of medication-free unipolar depressed patients, the painfulness of left prefrontal rTMS diminished 48% over 3 weeks of daily treatment. This fairly dramatic reduction in the painfulness of rTMS, albeit from an open label trial, appears to be independent of changes in mood and anxiety as assessed by other VAS questions. Since all data analyzed for this paper were delinked from the primary database to maintain the principal study's integrity; it is unknown which subjects received 3 weeks of rTMS in the initial blinded phase of the study and which subjects were TMS naive at the start of open label rTMS in phase II. In addition, we are not able to associate these data with observer ratings, or any other data from the trial.
To our knowledge, this is the first formal description of this accommodation to the painfulness of rTMS. We were struck by the magnitude of the reduction, as well as the fact that the painfulness continues to decline even into the second and third weeks of treatment. Furthermore, many of these subjects received 3 weeks of rTMS in the blinded phase for a total of 6 weeks of active rTMS. The exact number of subjects in this category is unknown since the blind for this study has not been compromised but the ratio is likely 1:1. In previous studies, pain was not meticulously assessed once the subject stopped complaining about discomfort during the first few days of rTMS treatment. Interestingly, Avery and colleagues' recent report suggested that rTMS reduced aches and pains after 1 and 2 weeks of treatment and then lost its durability at 3 weeks.[9
] We were thus surprised to see a continued decline in the later weeks of treatment.
There are several aspects of this small study that should be kept in mind in order to properly interpret these findings. First, this is open label and we are not able to determine if the effects are due to actual cortical brain stimulation by rTMS, or due to the stimulation of scalp receptors. We will hopefully be able to address this directly with the data from the blinded phase of the trial, with results available within 2 years.
Second, all subjects had already participated in 3 weeks of the first phase of the study. It is unclear how and to what degree 3 compared to 6 weeks of active treatment influenced these results. For example, someone with extreme pain during rTMS might have dropped out of the earlier phase and thus not be in this dataset. We wondered whether a visual examination of the initial pain ratings might show two groups, with half of the subjects having lower pain ratings from receiving 3 weeks of active treatment in the earlier blinded phase. The data however do not appear strikingly split.
Third, in order to maintain study blind integrity these data were de-linked from the clinical trial dataset and thus there is incomplete information regarding whether these pain changes are related to demographic variables, prior treatments or treatment response to rTMS. Anecdotally, we think these pain accommodation effects are separate from the clinical antidepressant effects. For example, in other studies we have had patients who respond to active rTMS, and have an accommodation to the pain. When they return several weeks later for maintenance rTMS, they have lost their accommodation to the painfulness and the procedure hurts in the same manner as when they began. Their mood however remains good. This is indirect evidence of a disconnect between the accommodation to pain and a clinical antidepressant effect. We also failed to find a correlation between the rTMS pain changes and other VAS measured mood effects.
We are unclear whether these changes in the subjective painfulness of left prefrontal rTMS in depressed patients might relate to other work showing that prefrontal rTMS can cause changes in pain perception. For example, in post-surgical patients, 4000 stimuli immediately after surgery have been shown to cause a 40% reduction in morphine use in the hospital.[10
] The time course of this effect has not been explored more than 24 hours.
The current study allowed four sheet of foam padding to be inserted between the TMS coil and the scalp. The use of the foam padding was not recorded for each session so it is unclear how well the foam reduced subjective pain. Borckardt and colleagues have shown that a single foam pad can reduce subjective pain and unpleasantness ratings by 5.3% to 8.4%.[1
] The foam padding increases the distance between the TMS coil and the scalp and thus may reduce subjective pain since the intensity of the magnetic field decreases rapidly with distance from the coil. The foam may simply cushion the weigh and vibration of the TMS coil yielding a more pleasant experience. The use of foam padding needs further study.