Withdrawal from acute medication normalises short-term cortical synaptic potentiation in medication overuse headache

DOI: https://doi.org/10.1007/s10072- 019- 03735- 4

Abstract-Summary To study the effects of a standard acute medication withdrawal program on short- term cortical plasticity mechanisms in patients with medication overuse head- ache (MOH).

Thirteen patients with MOH and 16 healthy volunteers underwent repetitive transcranial magnetic stimulation (rTMS) over the left motor cortex; in patients with MOH, recordings were performed before and after a 3-week medication with- drawal program.

The 5-Hz trains of rTMS inhibited rather than potentiated MEP amplitudes in

patients with MOH.

The physiological potentiating effect of 5  Hz rTMS on MEP amplitudes was restored after drug withdrawal and in proportion with the percentage reduction in monthly headache days in patients with MOH.

The results suggest that acute medication withdrawal normalises brain responses

in patients with MOH.

Medication withdrawal should be offered to patients with MOH as early as pos- sible in order to prevent the development of more pronounced alterations in brain plasticity.

Extended: Future studies in a larger cohort of patients are necessary to determine the exact relationships between neurophysiological changes and clinical variables in patients with MOH and whether the normalisation of such brain processes allow patients to regain clinical efficacy from acute and prophylactic migraine medications.

Introduction 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 [616].

We recently assessed neural plasticity in the motor cortex of chronic migraineurs with and without medication overuse using low- and high-frequency repetitive tran- scranial 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 [617].

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3 Diagnosis

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 with- drawal in comparison to normal subjects in order to understand the characteristics of short-term plasticity dysfunction in MOH.

Material and Methods We previously published the results of rTMS studies performed on the initial 8 patients [617] and have combined these data with data from 5 additional patients in order to verify the observed effect of acute medication withdrawal.

The inclusion criteria were restricted to patients with MOH as a result of NSAID use only (IHCD-III code 8.2.3.2) based on a previous study demonstrating that these patients exhibit more pronounced sensorimotor abnormalities than patients overusing acute migraine medications such as triptans [616, 618].

Patients with MOH underwent a 3-week standard acute medication withdrawal program which consisted in the advice to abruptly withdraw the overused medica- tion without any prophylactic medication [619].

Eight patients out of 13 were able to completely avoid drug intake, while one tablet was taken by three patients, two tablets by one patient and four tablets by another patient for the entire period of 3-week acute medication withdrawal program.

Results There was a significant difference in the mean slope of the linear regression of MEP amplitudes recorded in response to 5 Hz rTMS between before and after drug with- drawal (t = − 2831, p = 0.015).

The mean slope of MOH-a data was not significantly different from that for HVs

(t = 0.854, p = 0.400).

The mean days with headache per month and the mean number of tablets taken per month were also significantly decreased 1 month after withdrawal compared to baseline in patients with MOH (t  =  12.338, p < 0.001; t  =  5.252, p < 0.001 respectively).

Discussion The main finding of the present study was that a standard withdrawal program for patients overusing medication restored normal short-term synaptic potentiation in the primary motor cortex of patients with MOH.

The results of this study confirm our previous finding of dysfunctional short-term synaptic potentiation in patients with MOH [617]; in this study, trains of high- frequency rTMS induced a paradoxical decrease in amplitude in patients with MOH prior to medication withdrawal.

This conclusion was underscored by the observation that longer durations of medication overuse were associated with more pronounced dysfunction of short- term potentiation in the motor cortex [617], as previously demonstrated for the somatosensory cortex [616].

The present results expand on our previous findings by demonstrating that com- plete medication withdrawal restores normal short-term potentiation mechanisms within the motor cortex of patients with MOH.

3.5 Medication Overuse and Addiction

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We demonstrate that the dysfunction of short-term plasticity mechanisms in

patients with MOH is alleviated by the discontinuation of medication overuse.

Acknowledgement A machine generated summary based on the work of Cortese, Francesca; Pierelli, Francesco; Pauri, Flavia; Di Lorenzo, Cherubino; Lepre, Chiara; Malavolta, Giulia; Merluzzo, Chiara; Parisi, Vincenzo; Ambrosini, Anna; Serrao, Mariano; Coppola, Gianluca. 2019 in Neurological Sciences.

Treatment of withdrawal headache in patients with medication overuse headache: a pilot study