Background/Objectives: Chronic migraine with medication-overuse headache (CM-MOH) is neurophysiologically characterized by increased cortical excitability with sensitization at both the thalamocortical and the cortical levels. It is unclear whether the increased cortical excitability could be reverted by medication withdrawal (i.e., brain state) or whether it is a brain trait of individuals predisposed to medication overuse. In this study, we aim to investigate whether withdrawal from overused drugs can influence and restore these neurophysiological abnormalities. Methods: Somatosensory evoked potentials (SSEPs) were elicited by electrical stimulation of the median nerve (M), the ulnar nerve (U), and the simultaneous stimulation of both nerves (MU) in 14 patients with CM-MOH before (T0) and after (T1) a three-week withdrawal protocol and, for comparison, in 14 healthy volunteers (HVs) of a comparable age distribution. We measured the level of thalamocortical (pre-HFO) and cortical activation (post-HFO) by analyzing the high-frequency oscillations (HFOs) embedded in parietal N20 median SSEPs. Furthermore, we calculated the habituation and the degree of cortical lateral inhibition (dLI) of N20-P25 low-frequency SSEPs. Results: After the three-week withdrawal protocol (T1), we observed a normalization of the baseline habituation deficit (T0: +0.10 ± 0.54; T1: −0.53 ± 0.8; p = 0.040) and a reduction in the amplitude for both pre-HFO (p < 0.009) and post-HFO (p = 0.042), with values comparable to those of the HVs. However, no effects were observed on the dLI (p = 0.141). Conclusions: Our findings showed that withdrawal from overused drugs could affect the increased excitability of the non-painful somatosensory system in patients with CM-MOH, reducing the level of sensitization at both the thalamocortical and the cortical levels.
