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J Neurol Neurosurg Psychiatry. 2019 Mar 1. pii: jnnp-2018-320113. doi: 10.1136/jnnp-2018-320113. [Epub ahead of print]

Non-invasive neuromodulation for migraine and cluster headache: a systematic review of clinical trials.

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Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany
North American Science Associates, Minneapolis, Minnesota, USA.
electroCore, Inc, Basking Ridge, New Jersey, USA.
Headache and Craniofacial Pain Unit, Neurology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Headache Research Group, VHIR, Universitat Autònoma de Barcelona, Barcelona, Spain.


Non-invasive neuromodulation therapies for migraine and cluster headache are a practical and safe alternative to pharmacologics. Comparisons of these therapies are difficult because of the heterogeneity in study designs. In this systematic review of clinical trials, the scientific rigour and clinical relevance of the available data were assessed to inform clinical decisions about non-invasive neuromodulation. PubMed, Cochrane Library and databases and the WHO's International Clinical Trials Registry Platform were searched for relevant clinical studies of non-invasive neuromodulation devices for migraine and cluster headache (1 January 1990 to 31 January 2018), and 71 were identified. This analysis compared study designs using recommendations of the International Headache Society for pharmacological clinical trials, the only available guidelines for migraine and cluster headache. Non-invasive vagus nerve stimulation (nVNS), single-transcranial magnetic stimulation and external trigeminal nerve stimulation (all with regulatory clearance) were well studied compared with the other devices, for which studies frequently lacked proper blinding, sham controls and sufficient population sizes. nVNS studies demonstrated the most consistent adherence to available guidelines. Studies of all neuromodulation devices should strive to achieve the same high level of scientific rigour to allow for proper comparison across devices. Device-specific guidelines for migraine and cluster headache will be soon available, but adherence to current guidelines for pharmacological trials will remain a key consideration for investigators and clinicians.


evidence-based neurology; headache; migraine; randomised trials; systematic reviews

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Conflict of interest statement

Competing interests: PP-R has received honoraria as a consultant and speaker for Allergan, Amgen, Almirall, Chiesi, Eli Lilly, Janssen Cilag, Medscape, MSD, Novartis, and Teva. Her research group has received research grants from Allergan and has received funding for clinical trials from Alder, Boehringer Ingelheim, MSD, electroCore, Eli Lilly, Janssen Cilag, Novartis, and Teva. She is a trustee member of the board of the International Headache Society, a member of the Council of the European Headache Federation, and coordinator of the Spanish Headache Study Group of the Spanish Neurological Society. She is on the editorial board of Revista de Neurologia. She is an editor for Frontiers in Neurology and The Journal of Headache and Pain. She is a member of the Clinical Trials Guidelines Committee of the International Headache Society. She has edited the Guidelines for the Diagnosis and Treatment of Headache of the Spanish Neurological Society. She is the founder of She does not own stocks in any pharmaceutical company. CM is an employee of North American Science Associates, Inc. EL is an employee of electroCore, Inc., and receives stock ownership. UR has received honoraria as a consultant and speaker for Allergan, Amgen, Autonomic Technologies, Eli Lilly, electroCore, Novartis, Medscape, StreMedup, and Teva. He has participated in clinical trials from Allergan, Alder, Amgen, Autonomic Technologies, Eli Lilly, electroCore, Novartis, and Teva. He is a board member of the European Headache Federation. He is on the editorial boards of The Journal of Headache and Pain and Frontiers in Neurology.

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