Background

Repetitive transcranial magnetic stimulation (rTMS) is an efficacious and well-tolerated intervention for treatment-resistant depression (TRD). A novel rTMS protocol, intermittent theta burst stimulation (iTBS) has been recently implemented in clinical practice, and it is essential to characterize the factors associated to pain and the trajectory of pain of iTBS compared to standard rTMS protocols.

Objective

We aimed to characterize the side effect profile and the pain trajectories of High-Frequency Left (HFL) and iTBS in TRD patients in the THREE-D trial. We also investigated factors associated to pain and the relationship between pain and clinical outcomes.

Methods

414 patients were randomized to either HFL or iTBS. Severity of pain was measured after every treatment. General Estimating Equation was used to investigate factors associated with pain. Latent class linear mixed model was used to investigate latent classes of pain trajectories over the course of rTMS.

Results

Higher level of pain was associated with older age, higher stimulation intensity, higher anxiety, female, and non-response. The severity of pain significantly declined over the course of treatments with a steeper decrease early on in the course of the treatment in both protocols, and four latent pain trajectories were identified. The less favorable pain trajectories were associated with non-response and higher stimulation intensity.

Conclusions

HFL and iTBS were associated with similar factors and pain trajectories, although iTBS was more uncomfortable. Response to rTMS was associated with less pain and more favorable pain trajectories furthering the evince base of overlapping neurobiological underpinnings of mood and pain. We translated these results into patient-oriented information to aid in the decision-making process when considering rTMS.