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This randomized, double-blind, sham-controlled clinical trial aims to evaluate the efficacy of non-invasive brain stimulation as an add-on treatment to standard detoxification therapy in patients with chronic migraine and medication overuse. The study also seeks to identify sensory and biochemical biomarkers predictive of treatment response.
The main study is a randomized controlled trial enrolling patients with chronic migraine and medication overuse (MoH). Participants will undergo a standardized in-hospital detoxification protocol and will be randomly assigned to one of three parallel groups to receive either sham stimulation, active repetitive transcranial magnetic stimulation (rTMS) applied over the motor cortex face representation, or active rTMS applied over the motor cortex forearm representation. Stimulation will be delivered for five consecutive days.
Clinical, sensory (Quantitative Sensory Testing, QST), and biochemical measures (plasma glutamate, serotonin, and calcitonin gene-related peptide, CGRP) will be collected at baseline and during follow-up.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active rTMS - Motor Cortex Face Representation | Experimental | Participants will undergo a standardized in-hospital detoxification protocol for medication overuse and will receive high-frequency (10 Hz) active repetitive transcranial magnetic stimulation (rTMS) applied over the primary motor cortex corresponding to the face representation. Stimulation will be administered once daily for five consecutive days during hospitalization. |
|
| Active rTMS - Motor Cortex Forearm Representation | Experimental | Participants will undergo a standardized in-hospital detoxification protocol for medication overuse and will receive high-frequency (10 Hz) active repetitive transcranial magnetic stimulation (rTMS) applied over the primary motor cortex corresponding to the forearm representation. Stimulation will be administered once daily for five consecutive days during hospitalization. |
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| Sham rTMS | Sham Comparator | Participants will undergo a standardized in-hospital detoxification protocol for medication overuse and will receive sham high-frequency (10 Hz) repetitive transcranial magnetic stimulation (rTMS). Sham stimulation will be delivered using identical stimulation parameters and session duration as active rTMS, with the coil positioned to avoid effective cortical stimulation. Treatment will be administered once daily for five consecutive days during hospitalization. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Active rTMS Motor Cortex Face | Other | Participants will undergo a standardized in-hospital detoxification protocol for medication overuse and will receive high-frequency (10 Hz) active repetitive transcranial magnetic stimulation (rTMS) applied over the primary motor cortex corresponding to the face representation. Stimulation will be administered once daily for five consecutive days during hospitalization. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of monthly days with moderate-to-severe headache | Change in the mean number of monthly days with moderate-to-severe headache during the month following treatment | 1 month post-treatment |
| Measure | Description | Time Frame |
|---|---|---|
| Number of participants converting from chronic to episodic migraine | Conversion from chronic to episodic migraine (<15 headache days/month) assessed by headache diary | Up to 3 months post-treatment |
| Change in monthly number of acute headache medication intakes |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Giuseppe Cosentino, MD | Translational Neurophysiology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Translational Neurophysiology | Pavia | 27100 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15546593 | Background | Brighina F, Piazza A, Vitello G, Aloisio A, Palermo A, Daniele O, Fierro B. rTMS of the prefrontal cortex in the treatment of chronic migraine: a pilot study. J Neurol Sci. 2004 Dec 15;227(1):67-71. doi: 10.1016/j.jns.2004.08.008. | |
| 34062145 | Background | Knotkova H, Hamani C, Sivanesan E, Le Beuffe MFE, Moon JY, Cohen SP, Huntoon MA. Neuromodulation for chronic pain. Lancet. 2021 May 29;397(10289):2111-2124. doi: 10.1016/S0140-6736(21)00794-7. |
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|
| Active rTMS - Motor Cortex Forearm | Other | Participants will undergo a standardized in-hospital detoxification protocol for medication overuse and will receive high-frequency (10 Hz) active repetitive transcranial magnetic stimulation (rTMS) applied over the primary motor cortex corresponding to the forearm representation. Stimulation will be administered once daily for five consecutive days during hospitalization. |
|
| Sham rTMS | Other | Participants will undergo a standardized in-hospital detoxification protocol for medication overuse and will receive sham high-frequency (10 Hz) repetitive transcranial magnetic stimulation (rTMS). Sham stimulation will be delivered using identical stimulation parameters and session duration as active rTMS, with the coil positioned to avoid effective cortical stimulation. Treatment will be administered once daily for five consecutive days during hospitalization. |
|
Reduction in medication overuse assessed by patient diary |
| Up to 3 months post-treatment |
| Acute headache medications | Monthly consumption of acute headache medications | Up to 3 months post-treatment |
| Number of participants initiating preventive migraine therapy | Initiation of preventive migraine therapy during follow-up | Up to 3 months post-treatment |
| Change in Quantitative Sensory Testing (QST) | Changes in sensory and pain thresholds assessed by QST. QST is a panel of diagnostic tests used to assess somatosensory function. The panel of tests examine a broad range of different sensations, including hot, cold, touch, vibration. It has both positive and negative tests (can test for increased or reduced sensitivity). QST reflects a formalisation of existing neurological tests into a standardised battery designed to detect subtle changes in sensory function. | Up to 3 months post-treatment |
| Change in plasma glutamate concentration | Changes in plasma levels of glutamate | Up to 3 months post-treatment |
| Change in plasma serotonin concentration | Changes in plasma levels of serotonin | Up to 3 months post-treatment |
| Change in plasma CGRP concentration | Changes in plasma levels of CGRP | Up to 3 months post-treatment |
| 19833552 | Background | Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009 Dec;120(12):2008-2039. doi: 10.1016/j.clinph.2009.08.016. Epub 2009 Oct 14. |
| ID | Term |
|---|---|
| D051271 | Headache Disorders, Secondary |
| D008881 | Migraine Disorders |
| ID | Term |
|---|---|
| D020773 | Headache Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D051270 | Headache Disorders, Primary |
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