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J Pain. 2018 Sep;19(9):1040-1048. doi: 10.1016/j.jpain.2018.03.015. Epub 2018 Apr 12.

Trait- and Frequency-Dependent Dysfunctional Habituation to Trigeminal Nociceptive Stimulation in Trigeminal Autonomic Cephalalgias.

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IRCCS Neuromed, Pozzilli, IS, Italy. Electronic address:
G.B. Bietti Foundation IRCCS, Research Unit of Neurophysiology of Vision and Neurophthalmology, Rome, Italy.
IRCCS Neuromed, Pozzilli, IS, Italy; Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy.
C. Mondino National Neurological Institute, Department of Brain and Behavioral Sciences, University of Pavia, Italy.
IRCCS Neuromed, Pozzilli, IS, Italy.
Unit of Neurorehabilitation, Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, ICOT, Latina, Italy.
Istituto di Anestesiologia, Rianimazione e Terapia del Dolore, Università Cattolica del Sacro Cuore/CIC, Rome, Italy.
IRCCS Neuromed, Pozzilli, IS, Italy; Unit of Neurorehabilitation, Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, ICOT, Latina, Italy.


We investigated whether the stimulation frequency (SF), the pain phases, and different diagnoses of trigeminal autonomic cephalalgias (TACs) may influence the habituation to pain. We studied the habituation of the nociceptive blink reflex R2 responses at different SFs (.05, .1, .2, .3, .5, and 1 Hz), in 28 episodic cluster headache (ECH) patients, 16 during and 12 outside the bout; they were compared with 16 episodic paroxysmal hemicrania (EPH) during the bout and 21 healthy subjects. We delivered 26 electrical stimuli and subdivided stimuli 2 to 26 in 5 blocks of 5 responses for each SF. Habituation values for each SF were expressed as the percentages of the mean area value of second through fifth blocks with respect to the first one. A significant lower mean percentage decrease of the R2 area across all blocks was found at .2 to 1 Hz SF during ECH, outside of the ECH, and EPH compared with healthy subjects. We showed a common frequency-dependent deficit of habituation of trigeminal nociceptive responses at higher SFs in ECH and EPH patients, independently from the disease phase. This abnormal temporal pattern of pain processing may suggest a trait-dependent dysfunction of some underlying pain-related subcortical structures, rather than a state-dependent functional abnormality due to the recurrence of the headache attacks during the active period.


TACs showed a frequency-related defective habituation of nociceptive trigeminal responses at the higher SFs, irrespectively of the diagnosis and/or the disease phase. We showed that the clinical similarities in the different subtypes of TACs are in parallel with a trait-dependent dysfunction in pain processing.


Cluster headache; habituation; nociceptive blink reflex; paroxysmal hemicrania

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