Fibromyalgia has a high female predominance and research work has been focussing mainly on women. We aimed to answer (1) gender differences in pain scores and quality of life, (2) any gender-specific subgroups defined by quantitative sensory testing (QST), and (3) correlations of QST parameters with pain intensity and questionnaire scores. We evaluated clinical presentations and QST profiles from 38 male and 38 age-matched female patients. Women reported significantly higher scores in average daily pain, daily sleep interference score, average weekly pain, weekly sleep interference score, and revised fibromyalgia impact questionnaire (rFIQ). Based on LOGA classification, L0G2, mechanical allodynia or hyperalgesia without abnormal sensory loss, was the most common QST subtype which accounted for 28.9% of men and 26.3% of women. Approximately 34.2% of men and 26.3% of women displayed loss of function of small fibres with an increased cold or warm detection threshold. Cold detection threshold was negatively correlated with pain intensity and functional impairment, suggesting a peripheral mechanism. Central sensitization, defined as allodynia and hyperalgesia to thermal or mechanical stimuli, was found in two-thirds of male and female patients. Mechanical pain sensitivity was positively correlated with the severity of pain and associated symptoms in women, but not men. There was a marked gender difference in reported pain and quality of life. We have confirmed that central sensitization is a major mechanism for women. Our data suggested an important role of small fibre pathology in both men and women.
Traumatic brain injury (mTBI) is a major public health concern, with mild TBI (mTBI) constituting the vast majority of the injuries. Post-traumatic headache (PTH) is one of the most frequent symptoms that follow a mTBI, occurring in isolation with a tension-type or migraine phenotype, or more often as part of a complex neurobehavioural array of symptoms. The existence of PTH as a separate entity from the primary headaches is still a matter of debate. Classification issues and a lack of methodologically robust epidemiological and clinical studies have made it difficult to elucidate the mechanisms underlying acute and even more persistent PTH (PPTH). Furthermore, psychiatric comorbidities such as post-traumatic stress disorder (PTSD), previous history of migraine, and legal issues often reported by PPTH patients have complicated the understanding of this condition, hence treatment approaches for PTH remain problematic. Recent findings from structural and functional neuroimaging studies have attempted to describe the brain architecture of PPTH, suggesting the involvement of different networks compared to migraine. It also seems that calcitonin gene-related peptide (CGRP) levels are not particularly raised in PPTH, although CGRP monoclonal antibodies have obtained positive initial open-label evidence of efficacy in PPTH, and more trials assessing the efficacy of this class of treatments are underway. The broad overlap between PTH, migraine, and PTSD suggests that research in this field should start with a re-appraisal of the diagnostic criteria, followed by methodologically sound epidemiological and clinical studies. Preclinical research should strive to create more reliable PTH models to support human neuroimaging, neurochemical, and neurogenetic studies, aiming to underpin new pathophysiological hypotheses that may expand treatment targets and improve the management of PTH patients.
Background Non-invasive vagus nerve stimulation has initial evidence of efficacy in migraine and cluster headache. However, little is known about its role in the management of refractory chronic headaches. Methods We evaluated the preventive and abortive effects of non-invasive vagus nerve stimulation in 41 consecutive patients with refractory primary chronic headaches in an open-label prospective clinical audit. Headache diaries were used to collect clinical information. Those who obtained at least 30% reduction in headache days/episodes after three months of treatment were considered responders and were offered treatment continuation. Results Twenty-three patients with chronic migraine, 12 with chronic cluster headache, four with hemicrania continua and two with short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) were treated. Two of 23 chronic migraine patients, one of 12 chronic cluster headache patients, and two of four hemicrania continua patients were considered responders. None of the patients with SUNA benefited from the therapy. Two chronic migraine patients were able to reduce the pain severity of moderate migraines with non-invasive vagus nerve stimulation. Conclusion Non-invasive vagus nerve stimulation may not constitute an effective acute nor preventive treatment in refractory chronic primary headaches. The encouraging effect in hemicrania continua warrants further evaluation in larger studies.
OnabotulinumtoxinA (BT-A) quarterly was the first treatment approved specifically for chronic migraine (CM). It is unclear whether three cycles are better than two to assess early BT-A response. We performed a retrospective analysis on real-life prospectively collected data in 16 European headache centers. All the centers provided data on patients treated with BT-A for CM over the first three cycles of treatment. For each treatment cycle we defined patients as "good responders" if reporting a ≥ 50% reduction in monthly headache days compared with the three months before starting BT-A, "partial responders" if reporting a 30–49% reduction in monthly headache days, and "non-responders" if reporting a < 30% reduction in monthly headache days or stopping the treatment before the third cycle. We included 2879 patients. Seven hundred and eighty-four (64.6%) of the 1213 patients reporting a good response during the first and/or the second cycle had a good response during the third cycle; 309 (49.3%) of the 627 patients reporting a partial response (but no good response) during the first and/or the second cycle had a good response during the third cycle; only 65 (6.3%) of the 1039 patients who did not respond during both the first two cycles achieved a good response during the third cycle. Multivariate analyses showed that partial or good response during the first or the second cycle were independently associated with good response during the third cycle. Our data suggest that patients with CM responding to BT-A during the first two cycles will likely benefit from the third cycle of treatment, while the probability that non-responders to the first two cycles start responding during the third cycle is low. These results can help guide the individual decision to stop or continue treatment after the second cycle in patients who have not responded to the first two cycles.
Calcitonin gene-related peptide receptor antagonists are effective acute migraine treatments without the vascular contraindications associated with triptans. While it has been demonstrated that calcitonin gene-related peptide receptor antagonists act in the central nervous system, their effects in preclinical migraine models have been investigated in only the trigeminocervical complex. Migraine is a complex neurological disorder; sites in the brainstem and forebrain are clearly involved in its expression. We have performed electrophysiological recordings in thalamic neurons of rats responding to nocioceptive trigeminovascular inputs and tested the effect of olcegepant, a calcitonin gene-related peptide receptor antagonist (1 mg/kg, intravenously), on cell firing. We further tested the effect of microiontophoresed calcitonin gene-related peptide and the receptor antagonists calcitonin gene-related peptide 8-37 and olcegepant on thalamic cell firing, elicited by stimulation of the superior sagittal sinus or by microiontophoretic application of l-glutamate. Additionally, we used immunofluorescent staining to demonstrate the presence of functional calcitonin gene-related peptide receptors in the ventroposteromedial thalamic nucleus by specifically co-staining for the calcitonin gene-related peptide receptor subunits calcitonin receptor-like receptor and receptor activity modifying protein 1. Intravenously administered olcegepant significantly inhibited cell firing evoked by stimulation of the superior sagittal sinus as well as the background activity. Microiontophoresis of calcitonin gene-related peptide 8-37 also showed a significant inhibition of l-glutamate-evoked cell firing and firing evoked by stimulation of the superior sagittal sinus. Immunofluorescent staining confirmed the presence of the components of a functional calcitonin gene-related peptide receptor, the calcitonin receptor-like receptor and the receptor activity modifying protein 1, within the area of the ventroposteromedial thalamic nucleus. This is the first report on the efficacy of calcitonin gene-related peptide receptor antagonists at the level of third-order neurons in the migraine pathway, showing that the central effects of calcitonin gene-related peptide receptor antagonists extend beyond the trigeminocervical complex at least to the sensory thalamus.
Abstract Background Initial evidence have shown the short-term efficacy of sTMS in the acute and preventive treatment of migraine. It is unknown whether this treatment approach in the long-term is effective and well tolerated in difficult-to-treat migraine. Methods This is a prospective, single centre, open-label, real-world analysis conducted in difficult-to-treat patients with high-frequency episodic migraine (HFEM) and chronic migraine (CM) with and without medication overuse headache (MOH), who were exposed to sTMS therapy. Patients responding to a three-month sTMS treatment, continued the treatment and were assessed again at month 12. The cut-off outcome for treatment continuation was reduction in the monthly moderate to severe headache days (MHD) of at least 30% (headache frequency responders) and/or a ≥ 4-point reduction in headache disability using the Headache Impact test-6 (HIT-6) (headache disability responders). Results One hundred fifty-three patients were included in the analysis (F:M = 126:27, median age 43, IQR 32.3–56.8). At month 3, 93 out of 153 patients (60%) were responders to treatment. Compared to baseline, the median reduction in monthly headache days (MHD) for all patients at month 3 was 5.0 days, from 18.0 (IQR: 12.0–26.0) to 13.0 days (IQR: 5.75–24.0) ( P = 0.002, r = − 0.29) and the median reduction in monthly migraine days (MMD) was 4.0 days, from 13.0 (IQR: 8.75–22.0) to 9.0 (IQR: 4.0–15.25) ( P = 0.002, r = − 0.29). Sixty-nine out of 153 patients (45%) reported a sustained response to sTMS treatment at month 12. The percentage of patients with MOH was reduced from 52% ( N = 79/153) at baseline to 19% ( N = 29/153) at month 3, to 8% ( N = 7/87) at month 12. There was an overall median 4-point reduction in HIT-6 score, from 66 (IQR: 64–69) at baseline to 62 at month 3 (IQR: 56–65) ( P < 0.001, r = − 0.51). A total of 35 mild/moderate adverse events were reported by 23 patients (15%). One patient stopped sTMS treatment due to scalp sensitivity. Conclusions This open label analysis suggests that sTMS may be an effective, well-tolerated treatment option for the long-term prevention of difficult-to-treat CM and HFEM.
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