An exploratory analysis of clinical and sociodemographic factors in CGRP-induced migraine attacks: A REFORM study.

OBJECTIVE: To investigate whether clinical and sociodemographic factors are associated with calcitonin gene-related peptide (CGRP) induced migraine attacks. METHODS: A total of 139 participants with migraine received a 20-minute intravenous infusion of CGRP (1.5 µg/min) on a single experiment day. The incidence of CGRP-induced migraine attacks was recorded using a headache diary during the 12-hour observational period post-infusion. Univariable and multivariable regression analyses were conducted to examine potential predictors' relationship with CGRP-induced migraine attacks. RESULTS: CGRP-induced migraine attacks were reported in 110 (79%) of 139 participants. Univariable analysis revealed that participants with cutaneous allodynia had higher odds of developing CGRP-induced migraine attacks, compared with those without allodynia (OR, 2.97, 95% CI, 1.28 to 7.43). The subsequent multivariable analysis confirmed this association (OR, 3.26, 95% CI, 1.32 to 8.69) and also found that participants with migraine with aura had lower odds of developing CGRP-induced migraine attacks (OR, 0.32, 95% CI, 0.12 to 0.84). CONCLUSION: Our results suggest that cutaneous allodynia and aura play a role in CGRP-induced migraine attacks, while other clinical and sociodemographic factors do not seem to have any noticeable impact. This indicates that the CGRP provocation model is robust, as the CGRP hypersensitivity remained unaffected despite differences among a heterogeneous migraine population.Trial Registration: ClinicalTrials.gov Identifier: NCT04592952.

Perceived severity of Visual Snow Syndrome is associated with visual allodynia.

OBJECTIVE: To investigate whether sensory sensitivity is associated with the perceived severity of Visual Snow Syndrome (VSS) symptoms. BACKGROUND: Visual Snow (VS) is a perceptual anomaly which manifests as flashing pinpricks of light throughout the visual field. VSS has an estimated population prevalence of 2.2% and is thought to be at least moderately debilitating for all who experience it. However, some people who meet the criteria for VSS have no awareness of it. This may be because they have lower sensory sensitivity, allowing them to ignore their visual phenomena. METHOD: Our study used a cross-sectional design. We recruited two distinct samples of people with VSS: a sample of people with confirmed VSS; and a sample of people who met the criteria for the condition but had no prior knowledge of it (latent VSS). The latter group was recruited and screened for symptoms via an online crowd-sourcing platform. In total, 100 participants with VSS (49 with confirmed VSS, 51 with latent VSS) completed the Visual Snow Handicap Index and three measures of sensory hypersensitivity. RESULTS: The 100 participants (52 female, 47 male, 1 non-binary) had a mean age of 35.1 years (SD = 12.2). Leiden Visual Sensitivity Scale scores were associated with both the perceived severity of VSS, ß = 0.35, p = 0.003, and the number of VSS symptoms endorsed, ß = 0.45, p < 0.001. On average, participants with VSS experienced elevated sensory hypersensitivity across all measures. Furthermore, longer duration of VSS was associated with lower perceived severity, F(1, 98) = 11.37, p = 0.001, R2  = 0.103. CONCLUSIONS: Our results suggest that sensory hypersensitivity may be prevalent in people with VSS and indicate that visual allodynia is associated with increased severity of VSS. Additionally, our findings indicate that inclusion of cases of latent VSS in future research may be important for researchers to develop a more complete understanding of the perceptual experiences of people with VSS.

Oral combined hormonal contraceptive associated with protection against allodynia in migraine in a cross-sectional study.

INTRODUCTION: For the most part, migraine afflicts young women who often need to use the hormonal contraceptive method. OBJECTIVE: To evaluate the effects of using exogenous estrogen, present in combined hormonal contraceptives (CHC) and progestin-only methods on the prevalence of allodynia in women with migraine. METHODS: Study comprising women diagnosed with migraine, with or without aura, who were not pregnant, breastfeeding, or menopausal. The study was conducted via the digital platform. Data were collected relating to demographics, contraceptive method, anthropometric information, smoking habits, and migraine-related symptoms. The participants then answered the following validated, self-administered questionnaires: Migraine Disability Assessment (MIDAS), Allodynia Symptom Checklist, Generalized Anxiety Disorder (GAD-7), and Beck's Depression Inventory (BDI). In order to determine the variables associated with allodynia, two binary logistic regression models were used. RESULTS: Four hundred eighty-six women took part in the study. Of these, 205 used CHC, 89 used a progestin-only method, and 192 participants did not use any form of hormonal contraception. Allodynia was identified in 411 (84.6%) participants. Allodynia was linked to the presence of aura (OR = 2.76; CI 95% 1.55-4.91; p = 0.001), menstrually related migraine (OR = 2.14; CI 95% 1.28-3.57; p = 0.004), greater disability (MIDAS score 23 vs. 8; p < 0.001), depression (BDI score 14 vs. 10; p < 0.001), and anxiety (GAD-7 score 11 vs. 8; p < 0.001). In adjusted analysis, CHC was associated to protection against allodynia when jointly evaluated all CHC regimens (OR = 0.49 CI 95% 0.26-0.92; p = 0.028), as well as oral CHC individually (OR = 0.48 CI 95% 0.25-0.92; p = 0.027). CONCLUSION: CHC reduced the chances of women with migraine getting allodynia.

Cutaneous allodynia and thermal thresholds in chronic migraine: The effect of onabotulinumtoxinA.

OBJECTIVE: Cutaneous allodynia (CA) is a common symptom in migraine. Its incidence is more frequent in the chronic migraine (CM). CA usually occurs during pain attacks. However, it can also be interictal and its frequency and severity seem to be correlated with the duration of the disease. Several quantitative sensory testing (QST) studies have revealed variable results about mechanical and thermal allodynia accompanying migraine. This study aimed to investigate the effects of CA and onabotulinumtoxinA (BoNT-A) injection on the thermal thresholds measured by QST in patients with CM. The effects of BoNT-A on headaches, CA, and other accompanying symptoms of migraine were also evaluated. METHODS: Single BoNT-A injections were performed in 22 female cases (mean age: 38.1 ± 7.2 years) with CM. Patients were evaluated at 1-7 days before, 28-35, and 84-91 days after the injection. The 22 healthy women in the control group (mean age: 36.6 ± 7.6 years) were examined once. Headache and its characteristics, medication intake, allodynia, presence of anxiety, and depression symptoms were evaluated through relevant scales. The heat (HDT) and cold (CDT) detection thresholds on the forehead and hand were measured bilaterally with QST. The presence of brush allodynia for patients was examined by applying a 4 × 4 gauze pad over the same areas. RESULTS: The patients in the CM group had migraine for an average of 22.5 ± 6.1 years and CM for 6.1 ± 3.2 years. The average number of painful days per month was 22.1 ± 4.0 days. All the patients had migraine attacks with CA (mean 5.6/month). The average allodynia symptom checklist (ASC-12) score was 7.8 ± 6.2. Thermal thresholds measured in the patients with CM were similar to those of the controls. Thermal thresholds did not show significant differences between the symptomatic and the asymptomatic sides at the last migraine attack. There was also no correlation between the allodynia revealed by the physical examination and the thermal thresholds detected by QST. The ASC-12 score decreased significantly with BoNT-A injection (p = 0.030), but no significant change was observed in thermal thresholds after this treatment. CONCLUSION: There was no significant correlation between CA and thermal thresholds. BoNT-A was successful in relieving headache and other associated symptoms, including CA, but had no significant effect on QST parameters.

Cutaneous allodynia in pediatric and adolescent patients and their mothers: A comparative study.

BACKGROUND: Allodynia in adults with migraine is related to disease duration. In pediatric patients with migraine, the same proportion reported allodynia in the first six months of migraine presentation as in prolonged disease. This study examined a possible association between migraine pediatric allodynia and maternal allodynia. METHODS: We interviewed children with migraine first, and then their mothers, regarding allodynia and headache symptoms. We reviewed hospital charts on pediatric medical background and headache symptoms. Mothers and children older than 11 years filled the Strengths and Difficulties Questionnaire. RESULTS: Ninety-eight children with migraine, mean age 13.49 ± 3.1 years, and their mothers, mean age 43.5 ± 6.2 years were recruited to the study. Pediatric allodynia was associated with maternal allodynia; the latter was reported in 82.8% of children with allodynia versus 35.3% of children without allodynia (p < 0.001). Maternal migraine was reported in 44 (68.7%) of children with allodynia versus 16.3% without allodynia, p < 0.001. No difference was found in Strengths and Difficulties Questionnaire scores, between children with and without allodynia. CONCLUSIONS: Pediatric allodynia is associated with maternal migraine. Genetic and environmental factors such as maternal behavior may contribute to reduced pain threshold.

Photophobia and allodynia in persistent post-traumatic headache are associated with higher disease burden.

OBJECTIVE: To assess photophobia and allodynia in subjects with post-traumatic headache and examine how these sensory hypersensitivities associate with clinical measures of disease burden. BACKGROUND: Post-traumatic headache is the most frequent and disabling long-term consequence of mild traumatic brain injury. There is evidence of sensory dysfunction in acute post-traumatic headache, and it is known from other headache conditions that sensory amplifications correlate with more severe disease. However, systematic studies in post-traumatic headache are surprisingly scarce. METHODS: We tested light and tactile sensitivity, along with measures of disease burden, in 30 persistent post-traumatic headache subjects and 35 controls. RESULTS: In all, 79% of post-traumatic headache subjects exhibited sensory hypersensitivity based on psychophysical assessment. Of those exhibiting hypersensitivity, 54% exhibited both light and tactile sensitivity. Finally, sensory thresholds were correlated across modalities, as well as with headache attack frequency. CONCLUSIONS: In this study, post-traumatic headache subjects with both light and tactile sensitivity had significantly higher headache frequencies and lower sensitivity thresholds to both modalities, compared to those with single or no sensory hypersensitivity. This pattern suggests that hypersensitivity across multiple modalities may be functionally synergistic, reflect a higher disease burden, and may serve as candidate markers of disease.

Prevalence and characteristics of cutaneous allodynia in probable migraine.

Cutaneous allodynia (CA) is a pain in response to non-nociceptive stimulation and a marker of central sensitisation. Probable migraine (PM) is a migraine subtype that fulfils all but one criterion of migraine. Headache intensity and the disability of individuals with PM are similar or lower than individuals with migraine. This study compared CA prevalence and characteristics of PM and migraine using a nationally representative sample in Korea. The Allodynia Symptom Checklist-12 (ASC-12) was used to assess CA (ASC-12 score ≥ 3). PM and migraine prevalence were 11.6% and 5.0%, respectively. CA prevalence did not significantly differ between PM and migraine (14.5% vs. 16.0%, p = 0.701). Participants with PM with CA reported a higher monthly headache frequency (3.3 ± 4.3 vs. 1.8 ± 3.6, p = 0.044), more severe headache intensity (Visuals Analogue Scale, 6.0 [4.0-7.0] vs. 5.0 [3.0-6.0], p = 0.002), and higher impact of headache (Headache Impact Test-6, 56.3 ± 7.2 vs. 48.3 ± 8.0, p < 0.001) than those without CA. Multiple regression analyses revealed that headache frequency and intensity, anxiety, and depression were significant factors for CA in participants with PM. In conclusion, CA prevalence among participants with PM and migraine were comparable. Anxiety, depression, and headache frequency and intensity were significant factors for CA in participants with PM.

Facemask headache: a new nosographic entity among healthcare providers in COVID-19 era.

BACKGROUND: SARS-CoV-2 is a novel infectious agent causing coronavirus disease 2019, which has been declared as pandemic in March 2020. Personal protective equipment has been mandatory for healthcare workers in order to contain the outbreak of pandemic disease. Mild neurological disturbances such as headache have been related to the extensive utilization of facemask. This study aims to examine headache variations related to the intensive utilization of facemask among a cohort of healthcare professionals in a setting of low-medium risk of exposure to SARS-CoV-2. METHODS: This is a cross-sectional study among healthcare providers from different hospital and clinics in Italy. Each participant completed a specifically designed self-administered questionnaire. Headache features and outcome measures' change from baseline were evaluated over a 4-month period, in which wearing facemask has become mandatory for Italian healthcare workers. RESULTS: A total of 400 healthcare providers completed the questionnaire, 383 of them met the inclusion criteria. The majority were doctors, with a mean age of 33.4 ± 9.2 years old. Among 166/383 subjects, who were headache free at baseline, 44 (26.5%) developed de novo headache. Furthermore, 217/383 reported a previous diagnosis of primary headache disorder: 137 were affected by migraine and 80 had tension-type headache. A proportion (31.3%) of these primary headache sufferers experienced worsening of their pre-existing headache disorder, mainly for migraine frequency and attack mean duration. CONCLUSIONS: Our data showed the appearance of de novo associated facemask headache in previous headache-free subjects and an exacerbation of pre-existing primary headache disorders, mostly experienced by people with migraine disease.

An Adapted Chronic Constriction Injury of the Sciatic Nerve Produces Sensory, Affective, and Cognitive Impairments: A Peripheral Mononeuropathy Model for the Study of Comorbid Neuropsychiatric Disorders Associated with Neuropathic Pain in Rats.

BACKGROUND: Chronic constriction injury (CCI) is a model of neuropathic pain induced by four loose ligatures around the sciatic nerve. This work aimed to investigate the sensory, affective, cognitive, and motor changes induced by an adaptation of the CCI model by applying a single ligature around the sciatic nerve. METHODS: Mechanical allodynia was measured from day 1 to day 28 postsurgery by the von Frey test. The beam walking test (BWT) was conducted weekly until 28 days after surgery. Anxiety- and depression-like behaviors, and cognitive performance were assessed through the open field (OF), forced swimming (FS), and novel object recognition (NOR) tests, respectively, 21 days after surgery. RESULTS: The two CCI models, both Bennett and Xie's model (four ligatures of the sciatic nerve) and a modification of it (one ligature), induced mechanical allodynia, increased immobility in the FS, and reduced recognition index in the NOR. The exploratory behavior and time spent in the central part of the arena decreased, while the defensive behavior increased in the OF. The animals subjected to the two CCI models showed motor alterations in the BWT; however, autotomy was observed only in the group with four ligatures and not in the group with a single ligature. CONCLUSIONS: Overall these results demonstrate that our adapted CCI model, using a single ligature around the sciatic nerve, induces sensory, affective, cognitive, and motor alterations comparable to the CCI model with four ligatures without generating autotomy. This adaptation to the CCI model may therefore represent an appropriate and more easily performed model for inducing neuropathic pain and study underlying mechanisms and effective treatments.

Allodynia and Disability in Migraine: The Mediating Role of Stress.

OBJECTIVE: This study sought to investigate the relationship between allodynia, psychological variables, and disability among individuals with migraine. BACKGROUND: A growing body of research views migraine as a condition of stress-related physiological dysregulation. Cutaneous allodynia is one manifestation of this dysregulation and affects a majority of individuals with migraine, though it is typically discussed in the context of headache pathophysiology. Stress, like allodynia, is implicated in the development of central sensitization and migraine progression. However, the contributions of stress and related psychological factors in allodynia and resulting disability remain largely unknown. METHODS: A cross-sectional study at a Southern U.S. university queried young adults with migraine regarding headache symptoms, disability, allodynia symptom frequency, and psychological variables using validated measures. Relations among allodynia and psychological variables of relevance were examined, including the association between allodynia and disability after controlling for pain severity. Subsequently, we assessed whether stress mediated the relationship between allodynia and disability. RESULTS: The final sample consisted of 147 young adults (87.8% [129/147] female, mean age = 19.0 ± 2.4) with an average headache frequency of 9.9 days per month (SD = 5.9). Increases in allodynia showed small associations with increases in stress, (r = 0.26, P = .001), fear of pain (r = 0.22, P = .008), and headache-related disability (r = 0.18, P = .003); and a small association with reduced self-efficacy (r = -0.16, P = .049). Allodynia significantly predicted disability even after controlling for pain severity (∆R2  = 0.02, P = .040), and the allodynia-disability relationship was mediated by stress (point estimate = 0.10, 95% CI [0.02-0.21]), such that as allodynia severity increased, stress increased and subsequent disability worsened. CONCLUSIONS: This study establishes meaningful relationships between allodynia and psychological variables of importance to headache self-management and adaptive coping. Allodynia exerts some effect on disability independent of pain itself, and this relationship is partially driven by stress. This study highlights the potential role of the stress response among those with allodynia, and further research is needed to determine if migraine interventions that target maladaptive stress responses may reduce disability by impeding the feedforward loop of allostatic load.

Edema, hyperalgesia and myonecrosis induced by Brazilian bothropic venoms: overview of the last decade.

Snakebite accidents are considered serious public health problems. They are often neglected, and individuals who have received insufficient treatment are subjected to various disabling alterations. Snake venoms are secretions composed of biologically active molecules capable of triggering local and systemic effects in envenomation victims. Bothropic snakes are responsible for most of the ophidian accidents in Brazil; their venoms are mainly related to local manifestations, due to a composition that is especially rich in proteases and phospholipases A2. The most common local damages are inflammation, with consequent cellular activation and release of inflammatory mediators, hemorrhage, edema, pain and (myo)necrosis, which may lead to amputation of the affected areas. Antivenom therapy is the main treatment for snakebites. However, the efficiency is mainly due to the neutralization of the toxins responsible for the systemic alterations. Thus, the local damages can evolve to markedly compromise the tissue. The complexity of these local effects associated with the toxicity of the snake venom components of the genus Bothrops, arouse interest in the study of the biochemical and pathophysiological mechanisms involved with the actions caused by toxins of the venom. Therefore, this review aims to analyze the edematogenic, hyperalgesic and myotoxic effects caused by Brazilian bothropic venoms in order to contribute to the study and elucidation of the mechanisms of action of its components and, consequently, enable discoveries of more effective combined therapies in the treatment of local damages resulting from envenoming.

Social stress as a trigger for depressive-like behavior and persistent hyperalgesia in mice: study of the comorbidity between depression and chronic pain.

BACKGROUND: There is great comorbidity and similarity between chronic pain and major depressive disorders. We have recently shown that 10 days of social defeat stress (SDS) induces hyperalgesia regardless depressive-like behavior in mice. Here we aimed to investigate whether social stress predisposes to chronic pain and, inversely, whether chronic pain predisposes to stress-induced depression. METHODS: Firstly, we used the 10 days SDS paradigm in mice followed by a mild protocol of repetitive inflammatory stimulus to evaluate if SDS would predispose to persistent hyperalgesia development. Secondly, we used the intense protocol of repetitive inflammatory stimulus followed by a subthreshold SDS to evaluate if persistent hyperalgesia would predispose to depressive-like behavior of social avoidance. RESULTS: Our results showed that SDS predispose to chronic pain, since stressed mice injected with PGE2 for 7 days (mild protocol), stimuli normally not sufficient to trigger chronic pain, showed persistent hyperalgesia. Also, we showed that persistent hyperalgesia induced by repetitive inflammatory stimuli predispose to long-lasting depressive-like behavior of social avoidance induced by subthreshold SDS. LIMITATIONS: We did not analyze molecular mechanism associated with chronic pain and depressive-like behavior induced by SDS. However, we hypothesized that SDS and 14 days of PGE2 would generate neuroplasticity on brain areas shared by chronic pain and depression, predisposing to pain chronification and depressive-like behavior, respectively. CONCLUSIONS: We can conclude social stress as a key and a common factor for chronic pain and depression. We can also conclude that SDS predisposes to chronic pain and, inversely, chronic pain predisposes to depressive-like behavior.

Neuropeptide and cytokine regulation of pain in the context of substance use disorders.

Substance use disorders (SUDs) are frequently accompanied by affective symptoms that promote negative reinforcement mechanisms contributing to SUD maintenance or progression. Despite their widespread use as analgesics, chronic or excessive exposure to alcohol, opioids, and nicotine produces heightened nociceptive sensitivity, termed hyperalgesia. This review focuses on the contributions of neuropeptide (CRF, melanocortin, opioid peptide) and cytokine (IL-1ß, TNF-α, chemokine) systems in the development and maintenance of substance-induced hyperalgesia. Few effective therapies exist for either chronic pain or SUD, and the common interaction of these disease states likely complicates their effective treatment. Here we highlight promising new discoveries as well as identify gaps in research that could lead to more effective and even simultaneous treatment of SUDs and co-morbid hyperalgesia symptoms.

Migraine in children under 6 years of age: A long-term follow-up study.

BACKGROUND: Early starting of migraine seems predictive for less favorable outcome in later ages, however follow-up investigations are very few and all with short-term prospective period. We report here the longest follow-up study in a population of children presenting with migraine under the age of 6. METHODS: We followed-up 74 children under 6 years of age, referred for headache to our department between 1997 and 2003. The study was carried out between October 2016 and March 2018. Headache diagnoses were made according to the IHS criteria. RESULTS: 23/74 patients, 31% of the original cohort, were found at follow-up in a period ranging between 15 to 21 years after the first visit. Seven of them were headache free. The remaining 16 patients had migraine. In the migraine group, the localization of pain changed in 75% of the subjects, 11/16 (68.7%) had allodynia and 9/16 (56.25%) had cranial autonomic symptoms. CONCLUSIONS: Our results suggest that the onset of migraine at very young age represents unfavorable prognostic factor for persistence of the disease at later ages. Some clinical features may change during clinical course, and the active persistence of the disorder may lead to an increase in allodynia.

Co-occurrence of pain syndromes.

Many pain conditions in patients tend to co-occur, influencing the clinical expressions of each other in various ways. This paper summarizes the main concurrent pain conditions by analyzing the major interactions observed. In particular, co-occurrence will be examined in: visceral pain (especially ischemic heart disease, irritable bowel syndrome, dysmenorrhea/endometriosis and urinary pain), fibromyalgia, musculoskeletal pain and headache. Two concurrent visceral pains from internal organs sharing at least part of their central sensory projection can give rise to viscero-visceral hyperalgesia, i.e., enhancement of typical pain symptoms from both districts. Visceral pain, headache and musculoskeletal pains (myofascial pain from trigger points, joint pain) can enhance pain and hyperalgesia from fibromyalgia. Myofascial pain from trigger points can perpetuate pain symptoms from visceral pain conditions and trigger migraine attacks when located in the referred pain area from an internal organ or in cervico-facial areas, respectively. The pathophysiology of these pain associations is complex and probably multifactorial; among the possible processes underlying the mutual influence of symptoms recorded in the associations is modulation of central sensitization phenomena by nociceptive inputs from one or the other condition. A strong message in these pain syndrome co-occurrence is that effective treatment of one of the conditions can also improve symptoms from the other, thus suggesting a systematic and thorough evaluation of the pain patient for a global effective management of his/her suffering.

Myofascial pain, widespread pressure hypersensitivity, and hyperalgesia in the face, neck, and shoulder regions, in survivors of head and neck cancer.

PURPOSE: Medical treatment for head and neck cancer may induce the presence of inflammation, pain, and dysfunction. The purpose of the current study was to assess the presence of myofascial trigger points (TrPs) and their relationship with widespread pressure hypersensitivity and hyperalgesia in survivors of head and neck cancer (sHNC). METHODS: TrPs and pressure-pain thresholds (PPTs) were quantified in different muscles/joints in the head and neck of 30 sHNC (59.45 ± 13.13 years) and 28 age- and sex-matched controls (58.11 ± 12.67 years). RESULTS: The sHNC had more TrPs in all muscles on the affected side (p < 0.05) than did the healthy controls, and in the temporalis, masseter, and suboccipitalis muscles on the unaffected side (p < 0.05). They also had lower PPTs in all places (p < 0.05) except for the temporalis muscle (p = 0.114) and C5-C6 joint (p = 0.977). The intensity of cervical pain correlated positively with the presence of upper trapezius TrPs. CONCLUSIONS: sHNC suffering cervical and/or temporomandibular joint pain have multiple active TrPs and experience widespread pressure hypersensitivity and hyperalgesia, suggestive of peripheral and central sensitization.

TRPM8 genetic variant is associated with chronic migraine and allodynia.

BACKGROUND: Many single nucleotide polymorphisms (SNPs) have been reported to be associated with migraine susceptibility. However, evidences for their associations with migraine endophenotypes or subtypes are scarce. We aimed to investigate the associations of pre-identified migraine susceptibility loci in Taiwanese with migraine endophenotypes or subtypes, including chronic migraine and allodynia. METHODS: The associations of six SNPs identified from our previous study, including TRPM8 rs10166942, LRP1 rs1172113, DLG2 rs655484, GFRA1 rs3781545, UPP2 rs7565931, and GPR39 rs10803531, and migraine endophenotypes, including chronic migraine and allodynia were tested. Significant associations in the discovery cohort were validated in the replication cohort. The adjusted odds ratios (aOR) were calculated after controlling for confounders. RESULTS: In total, 1904 patients (mean age 37.5 ± 12.2 years old, female ratio: 77.7%) including 1077 in the discovery cohort and 827 in the replication cohort were recruited. Of them, 584 (30.7%) had chronic migraine. Of the 6 investigated SNPs, TRPM8 rs10166942 T allele-carrying patients were more likely to have chronic migraine than non-T allele carriers in both discovery and replication cohorts and combined samples (33.7% vs. 25.8%, p = 0.004, aOR = 1.62). In addition, T allele carriers reported more allodynic symptoms than non-T allele carriers (3.5 ± 3.7 vs. 2.6 ± 2.8, p < 0.001). However, allodynia severity did not differ between episodic and chronic migraine patients. No further correlations between genetic variants and endophenotypes were noted for the other SNPs. CONCLUSIONS: TRPM8 may contribute to the pathogenesis of chronic migraine. However, our study did not support allodynia as a link between them. The underlying mechanisms deserve further investigations.

Proximal myofascial pain in patients with distal complex regional pain syndrome of the upper limb.

BACKGROUND: Patients suffering from complex regional pain syndrome (CRPS) endure myofascial-related pain in at least 50% of cases. AIMS: To evaluate the association of upper limb CRPS with myofascial pain in muscles that might influence arm or hand pain, and to evaluate whether the paraspinal skin and subcutaneous layers' tenderness and allodynia are associated with CRPS. METHODS: A case-control study comprising 20 patients presenting with upper limb CRPS, and 20 healthy controls matched for sex and age, were evaluated in the thoracic paraspinal area and myofascial trigger points (MTrPs) (infraspinatus, rhomboids, subclavius, serratus posterior superior and pectoralis minor) via a skin rolling test. RESULTS: The prevalence of MTrPs in the affected extremity of the subjects was significantly higher than in the right limb of the controls: 45% exhibited active and latent MTrPs in the infraspinatus muscle (χ2 = 11.613, p = 0.001); 60% in active and latent MTrPs in the subclavius muscle (χ2 = 17.143, p < 0.001); and in the pectoralis minor muscle (χ2 = 13.786, p < 0.001). In addition, 55% of the cases exhibited active and latent MTrPs in the serratus posterior superior muscle (χ2 = 15.172, p < 0.001). Significant differences between the groups in skin texture and pain levels (p = 0.01, p < 0.001, respectively) demonstrated that CRPS patients felt more pain, and their skin and subcutaneous layers were much tighter than in the healthy controls. CONCLUSION: There is a high prevalence of MTrPs in the shoulder and upper thoracic area muscles in subjects who suffer from CRPS. We recommend adding an MTrPs evaluation to the standardized examination of these patients.

Is the presence of neck pain associated with more severe clinical presentation in patients with migraine? A cross-sectional study.

OBJECTIVE: To investigate the association between the presence of self-reported neck pain in patients with migraine and clinical features, upper cervical mobility, and neck muscle performance. METHODS: A total of 142 patients with migraine were recruited and stratified by the presence (n = 99) or absence of self-reported neck pain (n = 43). The clinical examination included the Migraine Disability Assessment, the 12-item Allodynia Symptom Checklist, a flexion rotation test, and the Craniocervical Flexion Test. RESULTS: Migraine-related disability was reported by more than 80% in both groups (p = 0.82). However, there was a greater prevalence and severity of cutaneous allodynia observed in the group with neck pain (p < 0.001). Reduced upper cervical mobility was verified in 67% of the patients with neck pain and in 41% of those without neck pain (p = 0.005). In addition, 67% of the patients with neck pain and 40% without neck pain were not able to maintain the third stage of the Craniocervical Flexion Test without compensation (p = 0.003). CONCLUSIONS: The presence of self-reported neck pain in patients with migraine was associated with a poor clinical presentation regarding cutaneous allodynia, neck mobility, and muscle function. However, there were no differences in migraine-related disability.

Hyperalgesia and Central Sensitization Signs in Patients with Cluster Headache: A Cross-Sectional Study.

OBJECTIVE: To investigate central sensitization (CS) in cluster headache (CH) and to evaluate its relationship with disease characteristics and psychological comorbidities. DESIGN: Cross-sectional study. SETTINGS: Whether CS occurs in CH, as it does in other primary headaches, is a subject of debate. Few studies have evaluated the presence of CS and its relationship with psychological comorbidities in patients with CH. SUBJECTS: Twenty patients with episodic or chronic CH and 16 healthy controls were recruited. METHODS: The variables evaluated included frequency, intensity and duration of headache attacks, pressure pain thresholds (PPTs) and wind-up (WU) ratios of pain bilaterally measured over trigeminal and extratrigeminal areas, and results of questionnaires regarding anxiety and depression (Hospital Anxiety and Depression Scale [HADS], Beck Depression Inventory [BDI], State-Trait Anxiety Inventory [STAI]), quality of life (Short Form-36 [SF-36]), headache impact (Headache Impact Test [HIT-6]), and allodynia (Allodynia Symptom Checklist [ASC]). RESULTS: PPT levels were significantly lower in the CH group compared with the healthy participants (all tested points, P < 0.001). No differences were found in WU ratios between groups. However, differences in HADS (P < 0.01), BDI (P < 0.01), STAI (P < 0.01), SF-36 (P < 0.01), HIT-6 (P < 0.001), and ASC (P < 0.01) were observed between groups. The healthy group showed a moderate negative correlation between SF-36 and BDI (rho = -0.59, P = 0.03). Likewise, the CH group showed a moderate negative correlation between frequency and BDI (rho = -0.52, P = 0.03), a strong positive correlation between duration and HADS (rho = 0.86, P < 0.01), and a moderate negative correlation between intensity and PPT over symptomatic V1 (rho = -0.66, P < 0.01) and over asymptomatic V1 (rho = -0.65, P < 0.01). The CH group also showed a moderate negative correlation between SF-36 and anxiety and depression variables. CONCLUSIONS: Our findings show that patients with CH have lower PPT levels at cranial and extracranial points, suggesting, as in other primary headaches, the presence of CS. We have also found a high prevalence of psychiatric comorbidities that correlate with the length and frequency of attacks. These findings highlight the importance of a multidisciplinary approach to the treatment of patients with CH.