Recent animal studies on the mechanism of migraine show that intracranial pain is accompanied by increased periorbital skin sensitivity. These findings suggest that the pathophysiology of migraine involves not only irritation of meningeal perivascular pain fibers but also a transient increase in the responsiveness (ie, sensitization) of central pain neurons that process information arising from intracranial structures and skin. The purpose of this study was to determine whether the increased skin sensitivity observed in animal also develops in humans during migraine attacks. Repeated measurements of mechanical and thermal pain thresholds of periorbital and forearm skin areas in the absence of, and during, migraine attacks enabled us to determine the occurrence of cutaneous allodynia during migraine. Cutaneous allodynia is pain resulting from a nonnoxious stimulus to normal skin. In 79% of the patients, migraine was associated with cutaneous allodynia as defined, and in 21% of the patients it was not. The cutaneous allodynia occurred either solely within the referred pain area on the ipsilateral head, or within and outside the ipsilateral head. Cutaneous allodynia in certain well‐defined regions of the skin during migraine is an as yet unreported neurological finding that points to hyperexcitability of a specific central pain pathway that subserves intracranial sensation. Ann Neurol 2000;47:614–624

Scientific evidence support the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation and sensitization of the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. Also, structural and functional alterations include the presence of subcortical white mater lesions, thickening of cortical areas involved in processing sensory information, and cortical neuroplastic changes induced by cortical spreading depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by cortical spreading depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex.

Objective-To develop and validate a questionnaire for assessing cutaneous allodynia (CA), and to estimate the prevalence and severity of CA in the migraine population. (n = 11,388) completed the Allodynia Symptom Checklist, assessing the frequency of allodynia symptoms during headache. Response options were never (0), rarely (0), less than 50% of the time (1), ≥50% of the time (2), and none (0). We used item response theory to explore how well each item discriminated CA. The relations of CA to headache features were examined. Methods-MigraineursResults-All 12 questions had excellent item properties. The greatest discrimination occurred with CA during "taking a shower" (discrimination = 2.54), wearing a necklace (2.39) or ring (2.31), and exposure to heat (2.1) or cold (2.0). The factor analysis demonstrated three factors: thermal, mechanical static, and mechanical dynamic. Based on the psychometrics, we developed a scale distinguishing no CA (scores 0-2), mild (3-5), moderate (6-8), and severe (≥9). The prevalence of allodynia among migraineurs was 63.2%. Severe CA occurred in 20.4% of migraineurs. CA was associated with migraine defining features (eg, unilateral pain: odds ratio, 2.3; 95% confidence interval, 2.0 -2.4; throbbing pain: odds ratio, 2.3; 95% confidence interval, 2.1-2.6; nausea: odds ratio, 2.3; 95% confidence interval, 2.1-2.6), as well as illness duration, attack frequency, and disability.Interpretation-The Allodynia Symptom Checklist measures overall allodynia and subtypes. CA affects 63% of migraineurs in the population and is associated with frequency, severity, disability, and associated symptoms of migraine. CA maps onto migraine biology. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptCutaneous allodynia (CA) is characterized by pain provoked by stimulation of the skin that would ordinarily not produce pain. 1 The underlying mechanism of facial CA is sensitization of the nociceptive neurons in the trigeminal nucleus caudalis, which receives convergent afferent input from the dura mater and periorbital skin. 2,3 Clinic-based studies suggest that about two thirds of migraine sufferers experience development of CA. [4][5][6] As a marker of central sensitization, allodynia has been proposed as a risk factor for progression to chronic migraine. 7-9 Therefore, CA has significant implications for our understanding of the pathophysiology of migraine attacks, for the implementation of treatment, and for assessing prognosis.CA is usually assessed by quantitative sensory testing (QST). QST requires specialized equipment, training, and testing; it is too cumbersome and costly for wide-spread use in clinical practice or epidemiological research and is subject to temporal sampling error. As a consequence, most studies on headache and CA come from a small number of headache centers and the highly selected patients treated there. 5,10,11 There is an urgent need to develop and validate simple methods for assessing CA to better characterize CA in representative samples and...

Recently, we showed that most migraine patients exhibit cutaneous allodynia inside and outside their pain-referred areas when examined during a fully developed migraine attack. In this report, we studied the way in which cutaneous allodynia develops by measuring the pain thresholds in the head and forearms bilaterally at several time points during a migraine attack in a 42-year-old male. Prior to the headache, he experienced visual, sensory, motor and speech aura. During the headache, he experienced photo-, phono- and odour-phobia, nausea and vomiting, worsening of the headache by coughing or moving his head, and cutaneous pain when shaving, combing his hair or touching his scalp. Comparisons between his pain thresholds in the absence of migraine and at 1, 2 and 4 h after the onset of migraine revealed the following. (i) After 1 h, mechanical and cold allodynia started to develop in the ipsilateral head but not in any other site. (ii) After 2 h, this allodynia increased on the ipsilateral head and spread to the contralateral head and ipsilateral forearm. (iii) After 4 h, heat allodynia was also detected while mechanical and cold allodynia continued to increase. These clinical observations suggest the following sequence of events along the trigeminovascular pain pathway of this patient. (i) A few minutes after the initial activation of his peripheral nociceptors, they became sensitized; this sensitization can mediate the symptoms of intracranial hypersensitivity. (ii) The barrage of impulses that came from the peripheral nociceptors activated second-order neurons and initiated their sensitization; this sensitization can mediate the development of cutaneous allodynia on the ipsilateral head. (iii) The barrage of impulses that came from the sensitized second-order neurons activated and eventually sensitized third-order neurons; this sensitization can mediate the development of cutaneous allodynia on the contralateral head and ipsilateral forearm at the 2-h point, over 1 h after the appearance of allodynia on the ipsilateral head. This interpretation calls for an early use of anti-migraine drugs that target peripheral nociceptors, before the development of central sensitization. If central sensitization develops, the therapeutic rationale is to suppress it. Because currently available drugs that aim to suppress central sensitization are ineffective, this study stresses the need to develop them for the treatment of migraine.