Alterations in pain processing circuitries in episodic migraine

Background The precise underlying mechanisms of migraine remain unknown. Although we have previously shown acute orofacial pain evoked changes within the brainstem of individuals with migraine, we do not know if these brainstem alterations are driven by changes in higher cortical regions. The aim of this investigation is to extend our previous investigation to determine if higher brain centers display altered activation patterns and connectivity in migraineurs during acute orofacial noxious stimuli. Methods Functional magnetic resonance imaging was performed in 29 healthy controls and 25 migraineurs during the interictal and immediately (within 24-h) prior to migraine phases. We assessed activation of higher cortical areas during noxious orofacial heat stimulation using a thermode device and assessed whole scan and pain-related changes in connectivity. Results Despite similar overall pain intensity ratings between all three groups, migraineurs in the group immediately prior to migraine displayed greater activation of the ipsilateral nucleus accumbens, the contralateral ventrolateral prefrontal cortex and two clusters in the dorsolateral prefrontal cortex (dlPFC). Reduced whole scan dlPFC [Z + 44] connectivity with cortical/subcortical and brainstem regions involved in pain modulation such as the putamen and primary motor cortex was demonstrated in migraineurs. Pain-related changes in connectivity of the dlPFC and the hypothalamus immediately prior to migraine was also found to be reduced with brainstem pain modulatory areas such as the rostral ventromedial medulla and dorsolateral pons. Conclusions These data reveal that the modulation of brainstem pain modulatory areas by higher cortical regions may be aberrant during pain and these alterations in this descending pain modulatory pathway manifests exclusively prior to the development of a migraine attack.

Assessment of peripheral biomarkers potentially involved in episodic and chronic migraine: a case-control study with a focus on NGF, BDNF, VEGF, and PGE2

Background Several inflammatory and vascular molecules, and neurotrophins have been suggested to have a possible role in the development of migraine. However, pathophysiological events leading to migraine onset and transformation of episodic migraine (EM) to chronic migraine (CM) are not fully understood. Thus, we aimed to assess peripheral levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE2) in EM and CM patients, and controls. Methods From September 2017 to June 2020, 89 subjects were enrolled in a case-control study; 23 and 36 EM and CM patients, respectively, and 30 age and sex-matched controls. Demographic data and medical history were obtained from all patients. Headache characteristics were recorded at baseline visit and ensuing 30 days for persons with migraine disease. Serum levels of NGF, BDNF, VEGF, and PGE2 were measured once for controls and EM and CM patients, and adjusted for age, sex, and body mass index. Results Serum levels of NGF were significantly lower in EM patients compared to controls and CM patients (P-value=0.003 and 0.042, respectively). Serum levels of BDNF were significantly lower in EM and CM patients as opposed to controls (P-value<0.001), but comparable between EM and CM patients (P-value=0.715). Peripheral blood levels of VEGF were significantly higher in EM and CM patients as opposed to controls (P-value<0.001), but not different between EM and CM patients (P-value=0.859). Serum levels of PGE2 were significantly lower in EM patients compared to controls (P-value=0.011), however similar between EM and CM patients (P-value=0.086). In migraine patients, serum levels of NGF and PGE2 positively correlated with headache frequency (NGF: ρ = 0.476 and P-value<0.001; PGE2: ρ = 0.286 and P-value=0.028), while corresponding levels of BDNF and VEGF did not correlate with headache frequency (BDNF: ρ = 0.037 and P-value=0.778; VEGF: ρ= -0.025 and P-value=0.850). Conclusions Our findings suggest that NGF, BDNF, PGE2, and VEGF may play a significant role in migraine pathogenesis and/or chronification, and therefore might bear potential value for novel targeted abortive and prophylactic migraine therapy. Further prospective cohort studies with larger sample sizes can more robustly evaluate the implications of these findings.

Fremanezumab in the Prevention of High-Frequency Episodic and Chronic Migraine: A 12-Week, Multicenter, Real-Life, Cohort Study (The FRIEND Study).

Background Fremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8-14 days/month) or CM. Methods This is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9-12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥50%, ≥75% and 100% responder rates at the same time intervals. Results 67 migraine patients had received ≥1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p<0.05), MHDs (-9.4, p<0.001), MAI (-5.7, p<0.05; -11.1, p<0.001), NRS (-3.1, p<0.001; -2.5, p<0.001), and MIDAS scores (-58.3, p<0.05; -43.7; p<0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1, p<0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥50%, ≥75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR=0.91; 95% CI 0.85-0.98, p=0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason. Conclusions Fremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.

Evaluation of Serum Levels of Transient Receptor Potential Cation Channel Subfamily V Member 1, Vasoactive Intestinal Polypeptide, and Pituitary Adenylate Cyclase-Activating Polypeptide in Chronic and Episodic Migraine: The Possible Role in Migraine Transformation

Objectives: This study aimed to investigate the role of serum levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), vasoacive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) in the development and also the transformation of migraine in patients suffering from migraine.Methods: Eighty-nine participants with a mean age of 39 years were divided into 23 episodic migraine (EM), 36 chronic migraine (CM), and 30 healthy control groups. Demographic, anthropometric, and headache characteristic information, and also blood samples, was collected. Serum levels of TRPV1, VIP, and PACAP were measured using the enzyme-linked immunosorbent assay (ELISA) technique.Results: Based on our findings, the serum level of TRPV1 was significantly higher in CM compared to the control group (p &lt; 0.05), whereas serum levels of VIP (p &lt; 0.01) and PACAP (p &lt; 0.05) in the EM group were significantly more than the control group. There was no significant difference between EM and CM groups.Conclusions: An elevation in the serum levels of TRVP1 among chronic migraineurs and increments in the levels of VIP and PACAP were observed among EM patients compared to healthy subjects. However, our data failed to demonstrate the probable role of these biomarkers in migraine progression, and more studies are needed to clarify the molecular mechanisms involved in migraine progression.

Inter-individual differences in pain anticipation and pain perception in migraine: Neural correlates of migraine frequency and cortisol-to-dehydroepiandrosterone sulfate (DHEA-S) ratio

Previous studies targeting inter-individual differences in pain processing in migraine mainly focused on the perception of pain. Our main aim was to disentangle pain anticipation and perception using a classical fear conditioning task, and investigate how migraine frequency and pre-scan cortisol-to-dehydroepiandrosterone sulfate (DHEA-S) ratio as an index of neurobiological stress response would relate to neural activation in these two phases. Functional Magnetic Resonance Imaging (fMRI) data of 23 participants (18 females; mean age: 27.61± 5.36) with episodic migraine without aura were analysed. We found that migraine frequency was significantly associated with pain anticipation in brain regions comprising the midcingulate and caudate, whereas pre-scan cortisol-to DHEA-S ratio was related to pain perception in the pre-supplementary motor area (pre-SMA). Both results suggest exaggerated preparatory responses to pain or more general to stressors, which may contribute to the allostatic load caused by stressors and migraine attacks on the brain.

Erenumab for Migraine Prevention in a 1-Year Compassionate Use Program: Efficacy, Tolerability, and Differences Between Clinical Phenotypes

During a 1-year compassionate use program, 156 patients with migraine self-administered a monthly dose of erenumab 140 mg with a subcutaneous autoinjector. Main inclusion criteria were: ≥ 4 migraine days/month and ≥two prior prophylactic treatment failures. The patients covered the migraine severity spectrum from episodic migraine (EM) (n = 80) to chronic migraine (CM) (n = 76). During the 3rd month of treatment, monthly headache days decreased by 45.7% in EM and 35.5% in CM. The 50% responder rate for reduction in monthly headache days was significantly higher in EM (55%) than in CM (43%) (p = 0.05). In both the migraine subgroups, the clinical improvement vs. baseline was already significant during the 1st month of treatment (p &lt; 0.001). There were also significant reductions in mean headache severity, duration, and monthly days with acute drug intake. The 30% responder rate at 3 months was 60% in CM and 54.1% of patients reversed from CM to EM. The therapeutic effect was maintained at 12 months when 50% responder rates, considering discontinuation for lack of efficacy or adverse effects as 0% response, still were 51% in EM and 41% in CM. A total of 10 patients with EM (12.5%) and 23 patients with CM (30.3%) had discontinued treatment, considering the treatment as ineffective. At 3 months, 48% of patients reported non-serious adverse events among which the most frequent was constipation (20.5%); corresponding figures at 12 months were 30 and 15%. Discontinuation due to an adverse effect for the entire 12 month period was rare (3.8%). The lower efficacy in CM than in EM was mainly due to a very low 50% responder rate in patients with CM with continuous pain (13%) as compared to CM with pain-free periods (58%) (p &lt; 0.001). Similarly, the 50% responder rate was lower in patients with ≥two prior prophylactic treatment failures (40.5%) compared to those with two failures (70%) (p &lt; 0.05). There was no significant efficacy difference between low (4–7 migraine days/month, n = 22) and high frequency (8–14 days, n = 59) EM nor between patients with CM with (n = 50) or without (n = 26) acute medication overuse. Erenumab had no effect on the frequency of auras. Taken together, erenumab 140 mg monthly was highly effective for migraine prophylaxis over the whole severity spectrum of the disease, except in patients with continuous headaches. Its effect is significant after the first injection, quasi-maximal after the second injection, and does not wear off after 12 months. The most frequent adverse effect was constipation. These results are compared to those published for erenumab in the pivotal randomized placebo-controlled trials and to those reported in several recent real-world studies.

Cranial autonomic symptoms in episodic and chronic migraine: a cross sectional study in Iran

Background Cranial autonomic symptoms are common in migraine, with eye redness and tearing being the most common ones. Their identification can help to avoid misdiagnosis, predict the disease course, and select the appropriate treatment. Methods This was a cross-sectional study of 904 patients who presented with migraine to a headache referral clinic. The participants filled out a questionnaire about their headache characteristics, as well as the presence of cranial autonomic symptoms. A total of 904 patients, 698 women (77.2%) and 206 men (22.8%), were included in the study, with a mean (SD) age of 38.05 (11.76) years. Results About 70% of subjects with chronic migraine and 56.2% of those with episodic migraine reported one or more cranial autonomic symptoms. The two most commonly reported autonomic symptoms were eye redness (36.06%) and tearing (21.02%). Chronic migraine (43.4% vs. 29.5%), unilateral headache (56.8% vs. 48.7%), and blurred vision (20% vs. 14.7%) were significantly more frequent in migraineurs with cranial autonomic symptoms. Headache intensity and frequency in subjects with cranial autonomic symptoms were significantly higher than in those without cranial autonomic symptoms. Conclusion We found higher percentages of cranial autonomic symptoms in patients with unilateral headaches, frequent and severe attacks and blurred vision. A diagnosis of cranial autonomic symptoms accompanying migraine may predict more severe disease and the possibility of evolution into chronic migraine.

Two-year efficacy and safety of erenumab in participants with episodic migraine and 2–4 prior preventive treatment failures: results from the LIBERTY study

ObjectiveTo evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2–4 prior preventatives had failed.MethodsParticipants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could continue into an open-label extension phase (OLEP) receiving erenumab 140 mg monthly for up to 3 years. Main outcomes assessed at week 112 were: ≥50%, ≥75% and 100% reduction in monthly migraine days (MMD) as group responder rate and individual responder rates, MMD change from baseline, safety and tolerability.ResultsOverall 240/246 (97.6%) entered the OLEP (118 continuing erenumab, 122 switching from placebo). In total 181/240 (75.4%) reached 112 weeks, 24.6% discontinued, mainly due to lack of efficacy (44.0%), participant decision (37.0%) and adverse events (AEs; 12.0%). The ≥50% responder rate was 57.2% (99/173) at 112 weeks. Of ≥50% responders at the end of the DBTP, 36/52 (69.2%) remained responders at ≥50% and 22/52 (42.3%) at >80% of visits. Of the non-responders at the end of the DBTP, 60/185 (32.4%) converted to ≥50% responders in at least half the visits and 24/185 (13.0%) converted to ≥50% responders in >80% of visits. Change from baseline at 112 weeks in mean (SD) MMD was −4.2 (5.0) days. Common AEs (≥10%) were nasopharyngitis, influenza and back pain.ConclusionsEfficacy was sustained over 112 weeks in individuals with difficult-to-treat EM for whom 2–4 prior migraine preventives had failed. Erenumab treatment was safe and well tolerated, in-line with previous studies.Trial registration numberNCT03096834