REVIEW published: 21 January 2022 doi: 10.3389/fneur.2021.831035 Cutaneous Allodynia in Migraine: A Narrative Review Ane Mínguez-Olaondo 1,2,3,4,5 , Sonia Quintas 6 , Noemí Morollón Sánchez-Mateos 7 , Alba López-Bravo 8,9 , Marta Vila-Pueyo 10 , Vesselina Grozeva 11 , Robert Belvís 7 , Sonia Santos-Lasaosa 9,12 and Pablo Irimia 5* 1 Neurology Department, Hospital Universitario Donostia, San Sebastián, Spain, 2 Athenea Neuroclinics, Policlínica Guipúzcoa, Grupo Quirón Salud Donostia, San Sebastián, Spain, 3 Neuroscience Area, Biodonostia Health Institute, Donostia, Spain, 4 Medicine Faculty, University of Deusto, Bilbao, Spain, 5 Clínica Universidad de Navarra, Pamplona, Spain, 6 Hospital Universitario de la Princesa, Madrid, Spain, 7 Headache and Neuralgia Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 8 Hospital Reina Sofía, Tudela, Spain, 9 Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain, 10 Headache and Neurological Pain Research Group, Department of Medicine, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain, 11 Private Neurology Practice, Sofia, Bulgaria, 12 Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain Objective: In the present work, we conduct a narrative review of the most relevant Edited by: literature on cutaneous allodynia (CA) in migraine. Simona Sacco, Background: CA is regarded as the perception of pain in response to non-noxious skin University of L’Aquila, Italy stimulation. The number of research studies relating to CA and migraine has increased Reviewed by: Gianluca Coppola, strikingly over the last few decades. Therefore, the clinician treating migraine patients Sapienza University of Rome, Italy must recognize this common symptom and have up-to-date knowledge of its importance Giuseppe Cosentino, University of Pavia, Italy from the pathophysiological, diagnostic, prognostic and therapeutic point of view. *Correspondence: Methods: We performed a comprehensive narrative review to analyze existing literature Pablo Irimia regarding CA in migraine, with a special focus on epidemiology, pathophysiology, pirimia@unav.es assessment methods, risk for chronification, diagnosis and management. PubMed and Specialty section: the Cochrane databases were used for the literature search. This article was submitted to Headache and Neurogenic Pain, Results: The prevalence of CA in patients with migraine is approximately 60%. a section of the journal The mechanisms underlying CA in migraine are not completely clarified but include a Frontiers in Neurology sensitization phenomenon at different levels of the trigemino-talamo-cortical nociceptive Received: 07 December 2021 pathway and dysfunction of brainstem and cortical areas that modulate thalamocortical Accepted: 29 December 2021 Published: 21 January 2022 inputs. The gold standard for the assessment of CA is quantitative sensory testing (QST), Citation: but the validated Allodynia 12-item questionnaire is preferred in clinical setting. The Mínguez-Olaondo A, Quintas S, presence of CA is associated with an increased risk of migraine chronification and has Morollón Sánchez-Mateos N, López-Bravo A, Vila-Pueyo M, therapeutic implications. Grozeva V, Belvís R, Conclusions: CA is a marker of central sensitization in patients with migraine Santos-Lasaosa S and Irimia P (2022) Cutaneous Allodynia in Migraine: A that has been associated with an increased risk of chronification and may influence Narrative Review. therapeutic decisions. Front. Neurol. 12:831035. doi: 10.3389/fneur.2021.831035 Keywords: cutaneous allodynia, migraine, migraine chronification, risk factors, treatment Frontiers in Neurology | www.frontiersin.org 1 January 2022 | Volume 12 | Article 831035 Mínguez-Olaondo et al. Cutaneous Allodynia in Migraine INTRODUCTION and sociodemographic variables on the appearance of CA. In this sense, a higher prevalence of CA has been observed in Cutaneous allodynia (CA) is defined as pain resulting from women, in patients with frequent migraine and in those with application of a non-noxious stimulus to normal skin (1, 2), anxiety and/or depression, and acute medication overuse (36, and is classified according to either the sensory modality 37, 44). Some studies also found that CA increased with body that is used to elicit the sensation (thermal, mechanical mass index (BMI) (34, 45, 46). Furthermore, Louter et al. (26) dynamic, and mechanical static allodynia) or by the developed a study with a similar design in the Netherlands location of the symptom (cephalic and extracephalic). The and found a 70% prevalence of CA in patients with migraine. presence of CA in patients with migraine was described The risk factors identified for developing CA, included lifetime more than 100 years ago (3), but only recently a growing depression, female gender, low age at onset, and high migraine number of studies began to highlight the importance of this attack frequency, but not BMI. Other investigators have studied common and bothersome symptom (2, 4–6). Therefore, the the prevalence of migraine in cohorts of patients recruited clinician treating migraine patients must recognize CA (7) from a single-center and with a limited number of subjects and have up-to-date knowledge of CA importance from (Table 1), which makes it difficult to generalize the results and pathophysiological, diagnostic, prognostic and therapeutic point explain, at least in part, the wide range found in the prevalence of view. of CA. In the present work, we performed a comprehensive One of the findings that is consistently observed in most narrative review to analyze the most relevant literature on studies is that CA increased with headache frequency suggesting CA in migraine, with a special focus on epidemiology, that repeated migraine attacks lead to the development of pathophysiology, assessment methods, risk for chronification, allodynia. Some studies also describe that the presence of AC is diagnosis, and management. more frequent in patients with migraine with aura (37) and in those who overuse analgesics (44). In the coming years, the widespread use of the ASC-12 scale METHODS will allow us to have more data on the prevalence of CA. It would We conducted a non-systematic literature search in PubMed be very useful to have data obtained in large series of patients, and Cochrane databases for published manuscripts on allodynia attended in different centers, in which the diagnosis of migraine and migraine in October 2021, with no date limits. Search has been made by a specialist in a face-to-face interview. terms were limited to migraine and allodynia. The articles were selected independently by the authors based on the intrinsic characteristics and value of the studies. Articles PATHOPHYSIOLOGY OF ALLODYNIA IN addressing epidemiology, pathophysiology, evaluation tools, risk MIGRAINE for chronification, diagnosis and management in patients with CA were included. The search included publications in English The mechanisms underlying CA in migraine are still not and Spanish. completely understood but include a sensitization phenomenon at different levels of the trigemino-vascular system and ascending projections, and a dysfunction of the different EPIDEMIOLOGY OF ALLODYNIA IN brainstem and cortical areas that modulate thalamocortical MIGRAINE inputs (47, 48) (Figure 1). The trigeminal ganglion (TG) gives rise to pseudo-unipolar trigeminal primary afferents that The prevalence of CA in migraine is highly variable (8, 43) project to peripheral and central sites. In the periphery, in the literature (Table 1), although it can be considered that the nociceptive fibers from TG neurons innervate the between 40 and 70% of the patients with migraine experience meninges, dural blood vessels, middle meningeal artery, this symptom, according to population-based studies (26, 36, and large cerebral arteries. Activation and sensitization of these 37). Several factors influence these differences including the peripheral structures occurs by the local release of vasoactive heterogeneity of the populations in each study (population- peptides, such as calcitonin gene-related peptide (CGRP), based nationwide studies, cross-sectional studies or prospective amylin, substance P and pituitary adenylate cyclase-activating case series) and the methodology used for the identification of peptide (PACAP) (49–52), and inflammatory mediators (49). CA (8–43). Sensitization of peripheral afferent TG fibers, or peripheral Two of the largest population-based studies were conducted sensitization, explains the characteristic throbbing pain that in the United States to assess the prevalence of CA in patients worsens with physical activity during migraine attacks (49). with migraine (36, 37). Prevalence rates range from 39 to 63% Peripheral sensitization also implies that the threshold needed (36, 37). In both studies, migraine diagnosis was made using by these first-order neurons of the TG to respond to a validated questionnaires, not through a medical consultation, stimulus decreases and that the magnitude of the response is and 12-item Allodynia Symptom Checklist (ASC-12) was used to increased (47). detect CA. The population studies published to date have large There are central afferent projections from the TG neurons sample sizes that allow the analysis of patients by subgroups to the trigeminal nucleus caudalis (TNC) and the upper and facilitate the study of the influence of different clinical cervical spinal cord (C1–C2) (53). The TNC receives repetitive, Frontiers in Neurology | www.frontiersin.org 2 January 2022 | Volume 12 | Article 831035 Mínguez-Olaondo et al. Cutaneous Allodynia in Migraine TABLE 1 | Most relevant studies regarding different epidemiological aspects of CA in migraine. References Year Number Country Type of study Type of Medication Age range % of Evaluation of migraine overuse patients method patients with CA Han et al. (8) 2021 289 Korea Cross-sectional study PM Not specified >18 years 17% ASC-12 Akarsu et al. (9) 2019 871 Turkey Nationwide Migraine Not specified >17 years 57.5% Not described population-based study Munjal et al. (10) 2019 6,045 U.S. Cross-sectional Migraine Not specified 18–65 years 61.1% ASC-12 observational Lipton et al. (11) 2019 8,658 U.S. Longitudinal, internet-based EM Included, >17 years 36.7% ASC-12 panel 19% Young et al. (12) 2019 716 U.S., Multicenter, open-label, CM Icluded, Not described 44.4% ASC-12 Australia prospective study 11.9% and South Korea Seo et al. (13) 2019 312 South Cross-sectional study Migraine Independently Not described 39.9% ASC-12 Korea assessed, 20.7% Vs 11.9% in those with allodynia Lipton et al. (14) 2018 18,353 U.S. Longitudinal, internet-based Migraine Not specified >17 years 40.4% ASC-12 panel Lipton et al. (15) 2018 12,810 U.S. Longitudinal, internet-based CM and EM Included 15–70 years 18.6% ASC-12 panel Levinstky et al. 2019 119 Israel Retrospective transversal Migraine 3 – 18 Included, >17 years 39.9% ASC-12 (16) study years 2.8% De Tommasso et 2017 151 Italy Observational CM, EM 8 - Included, Not described 47% ASC-12 al. (17) cross-sectional study 15years 15% Kim et al. (18) 2016 140 South Prospective consecutive CM, EM Not specified 3–18 years 31.1% ASC-12 Korea patients Mathew et al. 2016 44 US Consecutive patients CM Not specified 8–15 years 96.6% ASC-12 (19) Mendonça et al. 2016 98 Portugal Cross - sectional study EM Included, 15–75 years 14.5% ASC-12 (20) 19.5% Baykan et al. 2016 871 Turkey Population-based Migraine Not specified Not described 91% Standard (21) nationwide, home-based questions prevalence study in adults Lovati et al. (22) 2015 673 Milan, Prospective consecutive CM and EM Not specified Not described 77% Standard Italy patients questions Park et al. (23) 2015 220 Korea Cross-sectional study CM, EM and Independently Not described 61.1% ASC-12 MOH assessed, higher in those with allodynia (10.3% Vs 4.7%) Raieli et al. (24) 2015 202 Italy Retrospective study Migraine Not specified Not described 50% Brief Children questionnaire and teenagers Baldacci et al. 2015 200 Italy Cross-sectional study Migraine Included, 15 - 73 years 47.3% ASC-12 (25) 23.6% Louter et al. (26) 2013 2,331 The Population-based Migraine Not specified Children and 37.1% ASC-12 Netherlands nationwide survey teenagers Kao et al. (27) 2014 434 Taiwan Cross-sectional study Migraine Excluded >17 years 79% ASC-12 Menon et al. (28) 2013 422 India Cross-sectional study in Migraine Included 18–74 years 70% Not described medical students Lovati et al. (29) 2013 456 Italy Prospective consecutive CM and EM Not specified Not described 48.4% Semi- patients structured ad hoc questionnaire (Continued) Frontiers in Neurology | www.frontiersin.org 3 January 2022 | Volume 12 | Article 831035 Mínguez-Olaondo et al. Cutaneous Allodynia in Migraine TABLE 1 | Continued References Year Number Country Type of study Type of Medication Age range % of Evaluation of migraine overuse patients method patients with CA Misra et al. (30) 2013 448 India Prospective consecutive Migraine Included, Not described 23% Own check patients 27% list Güven et al. (31) 2013 168 Turkey Prospective consecutive EM Excluded Not described 54.4% ASC-12 patients Díaz-Insa et al. 2011 1,036 Europe Randomized Migraine Not specified 10–62 years 71.4% Not described (32) placebo-controlled trial Chou et al. (33) 2010 100 Taiwan Cross-sectional study CM and EM Not specified >18 years 61.3% Self-reported brushing allodynia Tietjen et al. (34) 2009 1,413 U.S. Cross-sectional study Migraine Not specified Not described 39% Questionnaire Friedmann et al. 2009 182 U.S. Multicenter ED-based Migraine in the Not specified 17–65 years 17% BA (35) clinical trial emergency department Bigal et al. (36) 2008 11,094 U.S. Population-based TM and EM Included, 6% >17 years 60% ASC-12 nationwide survey AMPP Lipton et al. (37) 2008 11,388 U.S. Population-based Migraine Not specified Not described 14% ASC-12 nationwide study Lovati et al. (38) 2007 221 Italy Consecutive patients EM and CM Not specified >17 years 68.3% Not described and 63.25 Ashkenazi et al. 2007 151 U.S. Cross-sectional study EM Not specified >17 years 63% QST (39) Ashkenazi et al. 2007 89 U.S. Cross-sectional study CM Included Not described >40% BA (40) LoPinto et al. 2006 55 U.S. Cross-sectional study Migraine Not specified 12–60 years 77% Cutaneous (41) stimulation (BA) And pressure alllodynia (PA) Raieli et al. (42) 2005 55 Italy Cross-sectional study Migraine 6 - 18 Not specified >15 years 42.7% Not described years Mathew et al. 2004 295 U.S. Cross-sectional study Migraine Not specified Not described 32.7% Semi- (43) structured ad hoc questionnaire 14.5% 53.3% ASC-12, allodynia symptom checklist; BA, brushing allodynia; CM, chronic migraine; EM, episodic migraine; PM, probable migraine (fulfills all but one criterion of migraine); QST, quantitative sensory test; TM, transformed migraine. nociceptive inputs from the periphery and become sensitized to Additionally, functional MRI studies also show that the further stimulus. Central sensitization refers to a condition in activation pattern of cortical structures after a painful stimulus which central neurons in the trigeminal nociceptive pathway, is different in patients with migraine and allodynia. These mainly TNC second-order neurons or third-order neurons in findings support the existence of a dysfunction of the trigeminal- the thalamus, are sensitized and exhibit increased excitability thalamus-cortical nociceptive pathway, which could specifically (2, 43). Sensitization of second-order neurons of the TNC affect the cortical areas that modulate thalamocortical inputs explain the appearance of cephalic allodynia in patients with (48, 55). migraine (47, 49). It has been observed that once the sensitization Apart from noxious stimuli, sensitization can be of second order trigeminovascular neurons is established, it activated other mechanisms. Experimentally, it has been becomes activity independent, and it maintains itself in the observed that CSD is capable of activating peripheral and absence of sensory input (54). central trigeminovascular neurons (56). Also, fat excess, Subsequently, nociceptive information ascends from the TNC may promote chronic release of different inflammatory toward the thalamus. Sensitization of third-order thalamic mediators that decrease the threshold for the onset of a neurons (especially those located in the pulvinar region) is the migraine attack and contribute to central sensitization (46). mechanism that explains extracephalic allodynia (2, 47, 49). Finally, central sensitization may also be facilitated by the Frontiers in Neurology | www.frontiersin.org 4 January 2022 | Volume 12 | Article 831035 Mínguez-Olaondo et al. Cutaneous Allodynia in Migraine impairment of descending inhibitory pain mechanisms on USE OF ALLODYNIA AS A READOUT OF the trigeminovascular system observed in patients with MIGRAINE-LIKE PAIN IN PRECLINICAL migraine (57). MODELS Preclinical models have greatly enhanced our current ASSESSMENT OF ALLODYNIA IN understanding of migraine; hence they are considered an MIGRAINE PATIENTS invaluable tool for investigating this disorder. One of the most used and easiest to quantify readout in preclinical models of CA is usually classified according to the type of stimulus that migraine is CA (64), which indicates the importance attributed causes the sensation of pain. At least three types of CA have been to CA within the field of migraine research. CA can be measured consistently described: thermal allodynia, dynamic mechanical, in preclinical models by using either mechanical or thermal and static mechanical (1, 7). Thermal allodynia is mediated sensory nociceptive thresholds, which have been shown to be by nociceptive fibers C and Aδ (1, 7) and is usually assessed reliable markers of migraine pathophysiology (65). with Quantitative Sensory Testing (QST). Dynamic mechanical Mechanical allodynia is the most used method for studying allodynia is mediated by Aβ mechanoreceptive and Aβ fibers pain-like behavior in preclinical models of headache, and insensitive to capsaicin (7) and is assessed by brushing the skin. it is assessed with the von Frey test. This method uses Finally, static mechanical allodynia is mediated by Aδ nociceptive calibrated von Frey filaments which are applied to the periorbital fibers (58) and evaluated using von Frey hair filaments. region (cephalic) or hind paw (extracephalic) of rodents to QST is the gold standard method for assessing allodynia. determine evoked response thresholds (64). Von Frey test is However, this neurophysiological test requires special used to assess responses to different substances, such as the equipment, is time-consuming and costly for use in clinical dural inflammatory soup and the administration of algogenic settings. Therefore, initial studies on CA were conducted in very substances, nytroglicerin, CGRP, amylin or pituitary adenylate few centers and included highly selected patients (2, 59, 60). In cyclase-activating polypeptide (PACAP), among others (66, 67). order to have a method for measuring CA in clinical practice, The translational utility of this test has been crucial to investigate Lipton et al. developed and validated a questionnaire for the underlying mechanisms of several migraine treatments and assessing CA. The Allodynia Symptom Checklist or ASC-12 (37), to predict the efficacy of new therapies. Some of the treatments was developed by modifying Jakubowski et al. instrument (7) to positively tested to date include triptans (68, 69), which in provide graded allodynia response options, as CA is not an all or turn are also used as a positive control in these tests; gepants none phenomenon. Based on clinical interview, different types (69); CGRP monoclonal antibodies (69); ditans (70); and opioid of allodynic symptoms could be studied during or immediately receptor agonists (71). after the migraine attacks including cephalic (scalp, face, neck, Although most preclinical studies are focused on assessing ears) and extracephalic symptoms (limbs, trunk) (43). The aim mechanical allodynia, thermal allodynia (cold and hot) can also was to quantify CA in general based on clinical symptoms and be easily assessed, and both measures can complement each other determine if there were natural subtypes of CA (37). ASC-12 has to enhance our understanding of the mechanisms involved in high reliability in detecting patients with CA but low reliability migraine pathophysiology. Thermal allodynia can be measured in detecting patients without CA (7). Perhaps the addition of with different methodologies including the Hargreaves’ test (73), questions aimed at improving this aspect could give the tool even based on applying a heat stimulus to the hind paws or tail greater value. Nevertheless, this questionnaire helps neurologists of the animal to measure their withdrawal latency; and the identify patients with CA within the time frame of a routine acetone evaporation test, which measures the aversive behaviors office visit even when the patient is free of migraine (7). elicited by evaporative cooling both in cephalic or extracephalic The ASC-12 includes 12 questions on the frequency of various regions (74). These tests have been used in preclinical models symptoms of CA in association with a headache attack. For of migraine, where the administration of nitroglycerin and people with more than one type of headache, questions are algogenic substances have shown to increase thermal allodynia focused on the “most severe type of headache,” as it is likely to (67, 68), and the nasocilary nerve ligation to increase sensitization be migraine (61). The response categories are “never,” “rarely,” to acetone evaporation (75). “less than half the time,” and “half the time or more.” According Basic science has proven to be a fundamental pillar for the to previous studies, the option “rarely” is considered a negative development of knowledge in migraine and in the relevance of answer and the objective of its presence is to reduce false positives CA in it. Hence the value of continuing to use animal models that (37, 62, 63). Additionally, subjects can also indicate that an item resemble the human and thus be able to deepen the knowledge on “does not apply to me” that option is for someone who has never this area. shaved their face or someone who has never worn a ponytail. The ASC-12 items are scored as 0 (that is, never, rarely, or do not apply to me), 1 (less than half the time), and 2 (half the time or ALLODYNIA AND MIGRAINE more), so the score can range from 0 to 24 and in its validation CHRONIFICATION the following categories are defined based on the total scores obtained, being: non-allodynia 0–2, mild allodynia 3–5, moderate The presence of CA is currently considered as a possible marker allodynia 6–8 and severe allodynia ≥ 9 (37). and a risk factor for migraine chronification (19, 26) (Table 2). Frontiers in Neurology | www.frontiersin.org 5 January 2022 | Volume 12 | Article 831035 Mínguez-Olaondo et al. Cutaneous Allodynia in Migraine TABLE 2 | Summary of the studies analyzing the prevalence of CA in Episodic Migraine (EM) vs. Chronic Migraine (CM) (in %) and those identifying CA as a risk factor for migraine chronification (NA, Not Applicable; TTH, Tension Type Headache; HTTH, Chronic Tension Type Headache). References Year Number of Country CA as a risk Type of migraine CA prevalence CA prevalence patients factor for in EM % in CM % chronification Russo et al. (55) 2020 50 Italy YES Migraine NA NA Mathew et al. (19) 2016 44 U.S. YES CM – ∼90% Louter et al. (26) 2013 3,029 Netherlands YES Migraine – – Tietjen et al. (34) 2009 1,413 U.S. NA Migraine – – FIGURE 1 | Schematic representation of the sensitization of central trigeminovascular neurons in the thalamus believed to mediate the extracephalic CA trigeminal and nucleus caudalis believed to mediate cephalic CA during migraine. NR, Neuron. Adapted from Noseda and Burstein (72). Biorender.com CA is more common in patients with frequent attacks, and patients with migraine and CA (19). When tested with long-lasting disease (19, 26, 34, 36, 37). The increased headache a functional magnetic resonance imaging (MRI) study frequency, disability, and longer duration of illness indicate that using blood oxygen-level-dependent (BOLD) contrast- either CA is a marker for a more severe migraine disorder or that sensitive sequences, the patients with migraine with CA repeated attacks over a long period can lead to development of showed more prominent periaqueductal gray and nucleus CA (26, 34). cuneiformis resting state connectivity with other brainstem, The association between CA and migraine frequency may thalamic, insula, and cerebellar regions that process pain be explained by the repetitive activation of trigemino-talamo- when compared to patients with migraine with no-CA cortical nociceptive pathway. Recurrent migraine attacks with (19). Resting state connectivity in this population was also CA leads to a decreased threshold for subsequent migraine found to be stronger, with frontal and temporal regions attacks (76) but may also induce functional changes in different suggesting differences in higher-order pain modulation structures involved in pain modulation, such as periaqueductal (78). These thermal threshold and MRI BOLD imaging gray (26, 36), the spinal trigeminal nucleus and posterior data further clarify that the presence of CA is probably a thalamus (77). Rome et al. give another explanation using a risk factor for the transformation from episodic to chronic nociception-induced plasticity model suggesting that a noxious migraine (19). A deeper understanding of CA and how it is stimulus may, under certain conditions, lead to a sensitized related to chronification of migraine may elucidate the exact corticolimbic state, and pain chronification (26). pathophysiological mechanisms and can provide a rationale On the other hand, lower thermal pain thresholds on for adequate treatment of this difficult to manage migraine cutaneous testing have been noted during an attack among form (76). Frontiers in Neurology | www.frontiersin.org 6 January 2022 | Volume 12 | Article 831035 Mínguez-Olaondo et al. Cutaneous Allodynia in Migraine IMPLICATIONS OF ALLODYNIA FOR of our study, we analyzed an important quantity of articles MIGRAINE TREATMENT highlighting the most relevant research on CA and migraine. The efficacy of the treatment of migraine attacks is reduced in SUGGESTIONS FOR FUTURE STUDIES ON patients with CA (79). Data from the AMPP study observed that CA has been associated with an increased likelihood of an ALLODYNIA inadequate response to triptans, non-steroidal anti-inflammatory Many questions remain to be clarified about CA and migraine. drugs, opioids, and barbiturates in comparison with patients First, it is very relevant to have a deeper knowledge about without CA (80). However, randomized controlled trials did the pathophysiology of CA to understand why some patients not confirm these findings (81, 82). The impact of CA on develop CA and others do not. Second, if the longer duration of treatment outcomes in the patients with acute migraine treated migraine indicates that CA is a marker for more severe disease, with almotriptan was analyzed in the “Act when Mild” study. and patients with CA start to have migraine at younger age The presence of CA did not alter the efficacy of almotriptan (32), it can be speculated that children and adolescents with administered for early/mild pain in terms of 2-h pain-free rates CA and migraine are more prone to chronification at a later or sustained pain-free rates. CA impaired the effectiveness of stage of their lives. However, this has not been proved, yet and almotriptan in patients with moderate to severe pain in terms more studies on CA and migraine are needed to verify such of longer migraine duration. Therefore, the data from this study correlation in the younger population. Third, the detection of suggest that pain intensity is the main driver of triptan response, CA can be done easily in clinical practice and therefore the use and not the presence of CA (32). of ASC-12 should be promoted. Furthermore, the presence of Available data are not finally conclusive regarding the role CA may have implications from the diagnostic point of view due of CA in triptan response (81, 82). A fundamental question to its association with other comorbidities such as depression may be the distinction between developing CA, in which central or medication overuse. It is not known whether treatment of sensitization depends on incoming pain signals from peripheral risk factors reduces the risk of CA. On the other hand, it is nociceptors, and established CA, where sensitization becomes also important to define the best strategy to effectively treat independent of pain signals coming from the dura mater (83). acute migraine attacks in patients with CA. Finally, if the risk The influence of CA on the response to preventive treatment of migraine progression increases in patients with CA, perhaps is currently unknown. Some authors suggest that the effectiveness the use of preventive drugs should be promoted in patients with of oral preventatives is reduced in patients with CA (84). In this symptom. the same line, the COMPEL study demonstrated that the effect of onabotulinumtoxinA on the reduction of headache days was lower in patients with CA (12). However, the effect of CONCLUSIONS onabotulinumtoxinA on other efficacy measures was similar in patients with and without CA, and the improvement of the CA is common in patients with migraine, reflects the presence of MIDAS scale was significantly higher in the former (12). Data central sensitization, and is associated with migraine progression. available to date do not allow us to conclude with certainty The mechanisms underlying CA in migraine are not completely whether the efficacy of preventive treatment is reduced in patients clarified but include a sensitization phenomenon at different with CA. More studies are needed to clarify this hypothesis. It is levels of the trigemino-talamo-cortical nociceptive pathway and possible that in the future, treatments may be personalized based dysfunction of brainstem and cortical areas that modulate on clinical variables that include the presence of CA. thalamocortical inputs. The gold standard for the assessment of Considering that main site of action of monoclonal antibodies CA is QST, but the validated ASC-12 questionnaire is preferred targeting the CGRP pathway is outside the central nervous in clinical setting and epidemiological research. CA may increase system, it is reasonable to hypothesize that these treatments may the probability of a deficient response to acute treatments, not be effective in patients with migraine and CA. However, but the influence of CA on the effectiveness of preventive recent studies in migraine patients treated with erenumab for medication is uncertain. Clinicians should consider that patients migraine prevention, showed that the presence of CA does not with severe or frequent attacks, who overuse analgesics or with appear to negatively impact on erenumab effectiveness, and the depression, are more likely to develop CA. Addressing these risk treatment could even reduce the symptoms of allodynia (85, 86). factors, may reduce the likelihood of having CA and prevent migraine chronification. Future studies are necessary to better understand the pathophysiology of CA and to determine how to treat patients with migraine and CA and thus prevent disease progression. LIMITATIONS AND STRENGTHS Some limitations need to be acknowledged in the interpretation AUTHOR CONTRIBUTIONS of our results. First, this is not a systematic review. We limited our scope to selected articles which we believed could be the AM-O: literature review, data processing and analyses, results most representative ones. Secondly, we relied on PubMed and interpretation, language editing, review and drafting of the first Cochrane only for our search strategy, which has potentially manuscript, and results interpretation. SQ, NM, AL-B, VG, hampered the scope of our narrative review. Among the strengths and MV-P: literature review, data processing and analyses, and Frontiers in Neurology | www.frontiersin.org 7 January 2022 | Volume 12 | Article 831035 Mínguez-Olaondo et al. Cutaneous Allodynia in Migraine results interpretation. RB and SS-L: critical revision of the ACKNOWLEDGMENTS manuscript. PI: conception and article design, literature review, results interpretation, and critical revision of the manuscript. We would like to thank to M. F. Olaondo-Preboste and J. D. All authors contributed to the article and approved the Mínguez-Carrasco and P. Mínguez-Olaondo for their support submitted version. and close collaboration. REFERENCES 18. Kim SY, Park SP. Cutaneous allodynia and its risk factors in korean patients with migraine: a survey of two tertiary care hospitals. J Oral Facial Pain 1. Woolf CJ. Relative effectiveness of C primary afferent fibers of different origins Headache. (2016) 30:323–9. doi: 10.11607/ofph.1687 in evoking a prolonged facilitation of the flexor reflex in the rat. J Neurosci. 19. Mathew PG, Cutrer FM, Garza I. A touchy subject: an assessment of (1986) 6:1433–42. doi: 10.1523/JNEUROSCI.06-05-01433.1986 cutaneous allodynia in a chronic migraine population. J Pain Res. (2016) 2. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. 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Bigal ME, Buse DC, Chen YT, Golden W, Serrano D, Chu MK, et al. Rates and predictors of starting a triptan: results from the American endorsed by the publisher. Migraine Prevalence and Prevention Study. Headache. (2010) 50:1440– 8. doi: 10.1111/j.1526-4610.2010.01703.x Copyright © 2022 Mínguez-Olaondo, Quintas, Morollón Sánchez-Mateos, López- 81. Tfelt-Hansen P. Maximum effect of triptans in migraine? Bravo, Vila-Pueyo, Grozeva, Belvís, Santos-Lasaosa and Irimia. This is an open- A comment. Cephalalgia. (2008) 28:767–8. doi: 10.1111/ access article distributed under the terms of the Creative Commons Attribution j.1468-2982.2007.01415.x License (CC BY). The use, distribution or reproduction in other forums is permitted, 82. Goadsby PJ, Zanchin G, Geraud GA, De Klippel N, Diaz-Insa S, Gobel H, et provided the original author(s) and the copyright owner(s) are credited and that the al. Early vs. nonearly intervention in acute migraine- Act when Mild (AwM). original publication in this journal is cited, in accordance with accepted academic A double-blind, placebo-controlled trial of almotriptan. Cephalalgia. (2008) practice. No use, distribution or reproduction is permitted which does not comply 28:383–91. doi: 10.1111/j.1468-2982.2008.01546.x with these terms. Frontiers in Neurology | www.frontiersin.org 10 January 2022 | Volume 12 | Article 831035