Effect of Nebulized Dexmedetomidine on Central Sensitization and Chronification in Migraine

Chronic migraine: This is defined as a headache that occurs on 15 or more days in a month for more than 3 months, with migraine features present on at least 8 or more days in a month. Episodic syndromes that may be associated with migraine include recurrent gastrointestinal disturbances, involving recurrent attacks of abdominal pain, discomfort, nausea, and vomiting that may be associated with migraines; benign paroxysmal vertigo involving brief, recurrent attacks of vertigo, or benign paroxysmal torticollis is characterized by recurrent episodes of head tilt to one side.

Migraine chronification is strongly associated with central sensitization of the trigeminovascular system, a process mediated by the upregulation of calcitonin gene-related peptide (CGRP) and enhanced excitability of both brainstem and cortical pain-processing structures. Elevated CGRP plays a pivotal role in migraine pathophysiology by promoting vasodilation, neurogenic inflammation, and nociceptive facilitation.

Calcitonin gene-related peptide is a 37-amino acid neuropeptide and a potent vasodilator produced by neurons in both the central and peripheral nervous systems. Activation of CGRP-R in the trigeminovascular system plays a critical role in peripheral and central events that ultimately lead to the experience of migraine pain .

Following nerve stimulation, CGRP is released from its storage vesicles through the process of calcium-dependent exocytosis.This peripheral release of CGRP from trigeminal nerve endings is thought to trigger multiple responses induced by CGRP-R binding, which eventually lead to the sensitization of nociceptor trigeminal neurons.

The stimulation of peripheral nociceptive trigeminal neurons is hypothesized to relay the migraine pain signal through the brainstem into the brain, ultimately leading to the experience of migraine pain.

Central effects of CGRP may involve pain transmission through sensitization and activation of central processes (eg, feedback from a sensitized brain).

Objective neurophysiological biomarkers such as the nociceptive blink reflex (nBR) and trigeminal somatosensory evoked potentials (TSSEP) allow non-invasive assessment of central sensitisation through analysis of brainstem and cortical excitability. Impaired habituation in nBR and latency shifts in TSSEP have been consistently observed in migraineurs, particularly in those with chronic features.

The nociceptive blink reflex is a trigeminofacial brain-stem reflex which is used in pain research to evaluate the modulation of pain processing. Lack of habituation is a reproducible abnormality found in migraine between attacks, and attains to a model of behavior and a learning process that seem to predispose to attack occurrence. There is strong evidence that lack of habituation during stimulus repetition, despite an initial normal or low response amplitude, is a functional, probably genetically determined, hallmark of the migrainous brain between attacks.

In addition, incapacity to progressively reduce pain-related responses under repetitive stimulation. may favor mechanisms of central sensitization.

Inclusion criteria

• Diagnosis of Early chronic migraine (<6 months of ≥15 headache days/month), per ICHD-3 criteria.
• No preventive migraine therapy in the prior 8 weeks.

Exclusion criteria

• Presence of cardiopulmonary, psychiatric, or neurological comorbidities.
• Current use of sedatives, opioids, or CGRP-targeting therapies.
• Pregnancy or breastfeeding.