Short-term synaptic plasticity in chronic migraine with medication overuse

The International Classification of Headache Disorders defines medication overuse headache (MOH) as headaches occurring ≥ 15 days per month for a period of at least 3 months as the result of excessive intake of acute medications such as non-steroidal analgesic drugs (NSAIDs) and triptans. Several electrophysiological studies have investigated the pathophysiology of MOH and demonstrated that patients with MOH exhibit characteristic neurophysiological abnormalities. For example, patients with MOH show response sensitisation of the somatosensory cortex in response to different repetitive sensorial stimulations, demonstrated by an initial increase in the amplitude of evoked potentials. Patients with MOH also exhibit impaired amplitude habituation, defined as the absence of a decrease in amplitude in response to repeated stimulation. Since habituation is a basic form of learning, these findings suggested that patients with MOH experience alterations in neural plasticity and learning processes. We recently assessed neural plasticity in the motor cortex of chronic migraineurs with and without medication overuse using low- and high-frequency repetitive transcranial magnetic stimulation (rTMS). We found that, depending on the duration of overuse headache, patients did not show short-term potentiation of motor evoked potentials in response to facilitatory trains of rTMS. In contrast, chronic migraineurs without medication overuse showed normal responses to inhibitory/facilitatory trains of rTMS. These observations led us to hypothesise that medication overuse induces a dysfunctional state of brain plasticity. On this premise, we further speculated that medication-induced alterations in short-term plasticity would normalise after the discontinuation of medication overuse. Withdrawal from acute medication is the first-choice strategy in the management of MOH patients, but the mechanisms involved in clinical improvement after detoxification are not clear, even though numerous structural and functional neuroimaging studies showed that detoxification is associated to normalization of gray matter volume and connectivity of several brain areas involved in pain processing, cognition and planning strategies. The aim of this study was to examine responses of patients with MOH to both low- and high-frequency rTMS over the motor cortex before and after drug withdrawal in comparison to normal subjects in order to understand the characteristics of short-term plasticity dysfunction in MOH. We found that the dysfunctions in short term potentiation mechanisms in MOH are fully reversible after withdrawal, indicating that this strategy may achieve clinical improvement by restoring the physiological brain plasticity. This finding adds to the importance of starting a withdrawal treatment as early as possible in patients with MOH in order to facilitate normalisation of brain plasticity mechanisms.