Migraine Pain Research Articles

Practice guideline update summary: Acute treatment of migraine in children and adolescents: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society.

To provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine. We performed a systematic review of the literature and rated risk of bias of included studies according to the American Academy of Neurology classification of evidence criteria. A multidisciplinary panel developed practice recommendations, integrating findings from the systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence. There is evidence to support the efficacy of the use of ibuprofen, acetaminophen (in children and adolescents), and triptans (mainly in adolescents) for the relief of migraine pain, although confidence in the evidence varies between agents. There is high confidence that adolescents receiving oral sumatriptan/naproxen and zolmitriptan nasal spray are more likely to be headache free at 2 hours than those receiving placebo. No acute treatments were effective for migraine-related nausea or vomiting; some triptans were effective for migraine-related phonophobia and photophobia. Recommendations for the treatment of acute migraine in children and adolescents focus on the importance of early treatment, choosing the route of administration best suited to the characteristics of the individual migraine attack, and providing counselling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse.

Facial presentations of migraine, TACs, and other paroxysmal facial pain syndromes.

To assess the prevalence of facial pain (V2 and/or V3) presentations among nearly 3,000 patients with headache treated in a university tertiary care center. Between 2010 and 2018, we routinely assessed the prevalence of facial pain presentations of all patients with primary headaches. Of 2,912 patient datasets, 291 patients reported facial pain either as an independent or as an additional symptom. Among patients with migraine, 2.3% (44 of 1,935) reported a facial involvement, most commonly in V2. Of these, 18 patients (40.9%) experienced the pain predominantly in the face. In patients with cluster headache, 14.8% (42 of 283) reported a facial involvement, of which 31.0% perceived the pain predominantly in the face. A facial involvement was seen in 45.0% of patients with paroxysmal hemicrania (9 of 20), 21.4% of patients with hemicrania continua (9 of 42), and 20.0% of patients with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (3 of 15). In addition, we present 6 patients who reported a constant side-locked facial pain with superseded well-defined facial pain attacks of 10- to 30-minute duration that appeared several times per day. Our data suggest that a facial involvement in primary headaches is infrequent but not uncommon. A sole facial presentation of primary headache symptomatology seems to be exceptionally rare. We describe 3 different types of facial pain involvement and, in this context, distinguish patients with paroxysmal orofacial pain syndromes that have not been previously described. These patients may represent a new entity that could tentatively be called constant unilateral facial pain with added attacks.

A reanalysis of a randomized trial on meditation for migraine headaches: Distraction is not enough but meditation takes time

Objective: Migraine headaches affect about approximately 15% of the population and some notable efforts have been made to develop meditation interventions to address pain and mood among this population. However, key active ingredients and the necessary duration of meditation interventions to produce an effect are still unknown. The purpose of this study is to assess key meditation ingredients that positively impact mood and headache factors across different meditation techniques and to establish an initial time or” dose” needed to reach proactive treatment efficacy. Method: In this longitudinal study, three active management forms of meditation were compared to a cognitive distraction meditation to assess the effects on migraine headaches and emotions over a 30 day period when practiced 20 min per day. Results: The active group showed significant decreases in anger (p = .005) and migraine pain (p = .002) over time. Further analysis showed that the bulk of the change for the active management group occurred in the final 10 days, after 20 days of practice of the technique (p < .05). Conclusion: This suggests that cognitively active forms of meditation are more effective in reducing migraine headache pain and negative mood than distraction techniques. However, individuals engaging in these strategies need to consistently practice these techniques for approximately 20 days to proactively reduce migraine headache pain and negative mood.

Practice guideline update summary: Acute treatment of migraine in children and adolescents: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society.

To provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine. We performed a systematic review of the literature and rated risk of bias of included studies according to the American Academy of Neurology classification of evidence criteria. A multidisciplinary panel developed practice recommendations, integrating findings from the systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence. There is evidence to support the efficacy of the use of ibuprofen, acetaminophen (in children and adolescents), and triptans (mainly in adolescents) for the relief of migraine pain, although confidence in the evidence varies between agents. There is high confidence that adolescents receiving oral sumatriptan/naproxen and zolmitriptan nasal spray are more likely to be headache-free at 2 hours than those receiving placebo. No acute treatments were effective for migraine-related nausea or vomiting; some triptans were effective for migraine-related phonophobia and photophobia. Recommendations for the treatment of acute migraine in children and adolescents focus on the importance of early treatment, choosing the route of administration best suited to the characteristics of the individual migraine attack, and providing counseling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse.

Effect of a rescue or recurrence dose of lasmiditan on efficacy and safety in the acute treatment of migraine: findings from the phase 3 trials (SAMURAI and SPARTAN)

BackgroundWe studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine.MethodsSAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan.ResultsThe proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo.ConclusionsA second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo.Trial registrationSAMURAI (NCT02439320) [April 2015]. SPARTAN (NCT02605174) [May 2016].

Extensor/flexor ratio of neck muscle strength and electromyographic activity of individuals with migraine: a cross-sectional study.

Neck pain is considered a common characteristic of migraine attacks. The relationship between neck pain and migraine can be explained by central sensitization of the trigeminocervical complex, where superior cervical afferents and the trigeminal nerve converge. However, few studies have evaluated motor control of cervical muscles in individuals with migraine. Thus, the purpose of the present study was to determine the extensor/flexor ratio of neck muscle strength and electromyographic activity during a test of maximal voluntary isometric contraction and craniocervical flexion in individuals with migraine and individuals without history of migraine or other headaches. Fifty-two women with the disease and 52 women with neither a history of migraine nor neck pain, between 18 and 55years old, were included in the study. The electromyographic activities of the sternocleidomastoid, anterior scalene, splenius capitis, and upper trapezius muscles were evaluated during a test of maximal voluntary isometric contraction and craniocervical flexion. The migraine group presented lower flexor muscle strength and a higher extensor/flexor muscle strength ratio than the control group. In addition, the migraine group showed a reduced electromyographic extensor/flexor muscle ratio during maximal voluntary isometric contraction in flexion. The results demonstrated worse performance in the craniocervical flexion test of the migraine group and a lower electromyographic ratio of extensor/flexor neck muscles in the last stage of the test. Altogether, the migraine group presented an imbalance in cervical muscles verified not only during force production, but also during muscle activity. These slides can be retrieved under Electronic Supplementary Material.

Effects of Anti-Calcitonin Gene-Related Peptide for Migraines: A Systematic Review with Meta-Analysis of Randomized Clinical Trials.

We aimed to evaluate the response rate of migraines by using anti-calcitonin gene-related peptide (anti-CGRP) for patients with migraines. We searched three main medical databases up to 29 March 2019. No restriction on language and publication time were applied. Eligible trials included randomized clinical trials investigating a 50%, 75%, and 100% response rate of migraine patients after anti-CGRP intervention. The collected data were dichotomous, and risk ratios (RRs) with a 95% confidence interval (CI) were used to present the quantitative synthesis results. The systematic review identified 16 eligible randomized clinical trials (RCTs) with 9439 patients. Eight of the 16 trials with 2516 patients reported a 50% response rate, and the pooled results showed a significant benefit from anti-CGRP. However, the effects seem to gradually reduce from the first month (RR 1.99, 95% CI 1.59 to 2.49) to the third month (RR 1.48, 95% CI 1.26 to 1.75) of treatment. The magnitude of effect was influenced by the type of anti-CGRP, according to the test for differences between subgroups (I-square = 53%). The funnel plots and Egger’s tests did not show serious small study effects in the results. In conclusion, the current evidences confirmed that anti-CGRP treatment can reduce migraine pain in the short term (within three months), but the long-term effect should be investigated in the future. Moreover, its effects may be influenced by the type and dose of anti-CGRP. Therefore, future studies should make direct comparisons among anti-CGRP medications.

Trigeminal Pain Responses in Obese ob/ob Mice Are Modality-Specific

How obesity exacerbates migraine and other pain disorders remains unknown. Trigeminal nociceptive processing, crucial in migraine pathophysiology, is abnormal in mice with diet induced obesity. However, it is not known if this is also true in genetic models of obesity. We hypothesized that obese mice, regardless of the model, have trigeminal hyperalgesia. To test this, we first evaluated trigeminal thermal nociception in leptin deficient (ob/ob) and control mice using an operant thermal assay. Unexpectedly, we found significant hypoalgesia in ob/ob mice. Because thermal hypoalgesia also occurs in mice lacking the transient receptor potential vanilloid 1 channel (TRPV1), we tested capsaicin-evoked trigeminal nociception. Ob/ob and control mice had similar capsaicin-evoked nocifensive behaviors, but ob/ob mice were significantly less active after a facial injection of capsaicin than were diet-induced obese mice or lean controls. Conditioned place aversion in response to trigeminal stimulation with capsaicin was similar in both genotypes, indicating normal negative affect and pain avoidance. Supporting this, we found no difference in TRPV1 expression in the trigeminal ganglia of ob/ob and control mice. Finally, we assessed the possible contribution of hyperphagia, a hallmark of leptin deficiency, to the behavior observed in the operant assay. Ob/ob and lean control mice had similar reduction of intake when quinine or capsaicin was added to the sweetened milk, excluding a significant contribution of hyperphagia. In summary, ob/ob mice, unlike mice with diet-induced obesity, have trigeminal thermal hypoalgesia but normal responses to capsaicin, suggesting specificity in the mechanisms by which leptin acts in pain processing.

State and trait anger and its expression in cluster headache compared with migraine: a cross-sectional study.

Anger is involved in the emotional experience of pain. Individuals with migraine are more likely to hold their anger-in than controls. However, only one study evaluated anger in cluster headache (CH). The objective is to compare anger between migraine and CH patients. One hundred thirty-five migraine and 108 CH patients completed the State Trait Anger Expression Inventory (STAXI-2), composed of 7 subscales. State Anger measures the intensity of the individual's angry feelings at the time of testing. Trait Anger evaluates general predisposition to become angry. Anger Expression Out and Anger Expression In measure the extent to which anger could be overtly expressed or suppressed. Anger Control Out and Anger Control In evaluate how individual try to control the outward or inward expression of anger. Anger Expression Index is a general index. CH patients have higher median scores than migraine patients in State Anger (46 vs 44, p = 0.012). CH patients have lower scores in Anger Control Out (44 vs 50, p = 0.016). In subgroup analysis, CH patients during the cluster period have higher scores than chronic migraine patients in State Anger (47 vs 44, p = 0.035), while CH patients in headache-free period did not differ from migraine patients. Migraine and CH patients differ in state anger, indicating that CH patients experienced higher intensity of anger during the time of testing. These data add new information about emotional regulation in headache patients and could support the hypothesis of different emotional and behavioral responses to pain in migraine and CH patients.

Hsa-miR-34a-5p and hsa-miR-375 as Biomarkers for Monitoring the Effects of Drug Treatment for Migraine Pain in Children and Adolescents: A Pilot Study.

MicroRNAs (miRs) have emerged as biomarkers of migraine disease in both adults and children. In this study we evaluated the expression of hsa-miR-34a-5p and hsa-miR-375 in serum and saliva of young subjects (age 11 ± 3.467 years) with migraine without aura (MWA), while some underwent pharmacological treatment, and healthy young subjects were used as controls. miRs were determined using the qRT-PCR method, and gene targets of hsa-miR-34a-5p and hsa-miR-375 linked to pain-migraine were found by in silico analysis. qRT-PCR revealed comparable levels of hsa-miRs in both blood and saliva. Higher expression of hsa-miR-34a-5p and hsa-miR-375 was detected in saliva of untreated MWAs compared to healthy subjects (hsa-miR-34a-5p: p < 0.05; hsa-miR-375 p < 0.01). Furthermore, in MWA treated subjects, a significant decrease of hsa-miR-34a-5p and of hsa-miR-375 was documented in saliva and blood compared to MWA untreated ones. Altogether, these findings suggested thathsa-miR-34a-5p and hsa-miR-375 are expressed equally in blood and saliva and that they could be a useful biomarker of disease and of drug efficacy in patients with MWA.

Anxiety Sensitivity as a Risk Indicator for Anxiety, Depression, and Headache Severity in Women With Migraine.

The primary aim of this exploratory study was to assess the relationship between anxiety sensitivity and emotional disorders, migraine characteristics, and migraine-related fear and avoidance behaviors in women with probable migraine. Anxiety and depressive disorders are the most frequent comorbid psychiatric conditions in migraine, particularly in women; however, the underlying reasons for these comorbidities are uncertain. Anxiety sensitivity, the tendency to catastrophically appraise anxiety and bodily sensations in terms of their physical, social, or cognitive consequences, is a psychological factor that may contribute to the comorbidity of anxiety and depressive disorders and migraine. It was hypothesized that anxiety sensitivity would be associated with greater migraine severity and psychiatric symptoms. Participants were women (n=100) who screened positive for migraine on the validated IDMigraine Screener participated in an anonymous single-session online survey-based study on migraine. The Anxiety Sensitivity Index-3 total and subscales scores were used to assess anxiety sensitivity. Anxiety and depression symptoms were assessed with the brief Patient Health Questionnaire. On average, anxiety sensitivity was clinically elevated (mean±SD: 24.0±15.2). Anxiety sensitivity cognitive and social concerns were most strongly correlated with severity of anxiety (r's=.38-.46) and depressive symptoms (r=.35-.39, P's<.001), and all anxiety sensitivity facets were related to fear of head pain (r's=.35-.38, P's<.001). Anxiety sensitivity cognitive concern facet was uniquely related to headache patterns, including longer migraine attack duration (r=.22, P=.029) and pain intensity (r=.24, P=.029), pain-related avoidance, including avoiding movement and more frequent misuse of prescribed or non-prescribed pain medication (r's=.20-.21, P's<.01). These novel findings indicate that anxiety sensitivity, specifically fearful appraisal of bodily sensations, are linked to both psychiatric symptoms and migraine severity in women. In this cross-sectional study, causal sequence cannot be determined. If anxiety sensitivity leads to more severe pain and psychiatric distress, targeting anxiety sensitivity could lead to better headache outcomes.

Defined concatenated α6α1β3γ2 GABAA receptor constructs reveal dual action of pyrazoloquinolinone allosteric modulators.

Pyrazoloquinolinones (PQs) have been extensively studied as modulators of GABAA receptors with different subunit composition, exerting modulatory effects by binding at α+/β- interfaces of GABAA receptors. PQs with a substituent in position R7 have been reported to preferentially modulate α6- subunit containing GABAA receptors which are mostly expressed in the cerebellum but were also found in the olfactory bulb, in the cochlear nucleus, in the hippocampus and in the trigeminal sensory pathway. They are considered potentially interesting in the context of sensori-motor gating deficits, depressive-like behavior, migraine and orofacial pain. Here we explored the option to modify the lead ligands' R7 position. In the compound series we observed two different patterns of allosteric modulation in recombinantly expressed α6β3γ2 receptors, namely monophasic and biphasic positive modulation. In the latter case the additional phase occurred in the nanomolar range, while all compounds displayed robust modulation in the micromolar range. Nanomolar, near silent binding has been reported to occur at benzodiazepine binding sites, but was not investigated at the diazepam insensitive α6+/γ2- interface. To clarify the mechanism underlying the biphasic effect we tested one of the compounds in concatenated receptors. In these constructs the subunits are covalently linked, allowing to form either the α6+/γ2- interface, or the α6+/β3- interface, to study the resulting modulation. With this approach we were able to ascribe the nanomolar modulation to the α6+/γ2- interface. While not all compounds display the nanomolar phase, the strong modulation at the α6+/β3 interface proved to be tolerant for all tested R7 groups. This provides the future option to introduce e.g. isotope labelled or fluorescent moieties or substituents that enhance solubility and bioavailability.

Investigation of the educational effectiveness of cognitive-behavioral approach (CBT) coupled with relaxation on migraine pain

Investigation of the educational effectiveness of cognitive-behavioral approach (CBT) coupled with relaxation on migraine pain

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors.

CGRP, adrenomedullin (ADM), and adrenomedullin 2 (ADM2) family peptides are important neuropeptides and hormones for the regulation of neurotransmission, vasotone, cardiovascular morphogenesis, vascular integrity, and feto‒placental development. These peptides signal through CLR/RAMP1, 2 and 3 receptor complexes. CLR/RAMP1, or CGRP receptor, antagonists have been developed for the treatment of migraine headache and osteoarthritis pain; whereas CLR/RAMP2, or ADM receptor, antagonists are being developed for the treatment of tumor growth/metastasis. Based on the finding that an acylated chimeric ADM/ADM2 analog potently stimulates CLR/RAMP1 and 2 signaling, we hypothesized that the binding domain of this analog could have potent inhibitory activity on CLR/RAMP receptors. Consistent with this hypothesis, we showed that acylated truncated ADM/ADM2 analogs of 27–31 residues exhibit potent antagonistic activity toward CLR/RAMP1 and 2. On the other hand, nonacylated analogs have minimal activity. Further truncation at the junctional region of these chimeric analogs led to the generation of CLR/RAMP1-selective antagonists. A 17-amino-acid analog (Antagonist 2–4) showed 100-fold selectivity for CLR/RAMP1 and was >100-fold more potent than the classic CGRP receptor antagonist CGRP8-37. In addition, we showed (1) a lysine residue in the Antagonist 2–4 is important for enhancing the antagonistic activity, (2) an analog consisted of an ADM sequence motif and a 12-amino-acid binding domain of CGRP exhibits potent CLR/RAMP1-inhibitory activity, and (3) a chimeric analog consisted of a somatostatin analog and an ADM antagonist exhibits dual activities on somatostatin and CLR/RAMP receptors. Because the blockage of CLR/RAMP signaling prevents migraine pain and suppresses tumor growth/metastasis, further studies of these analogs, which presumably have better access to the tumor microenvironment and nerve endings at the trigeminal ganglion and synovial joints as compared to antibody-based therapies, may lead to the development of better anti-CGRP therapy and alternative antiangiogenesis therapy. Likewise, the use of bifunctional somatostatin-ADM antagonist analogs could be a promising strategy for the treatment of high-grade neuroendocrine tumors by targeting an antiangiogenesis agent to the neuroendocrine tumor microenvironment.

Exploration of purinergic receptors as potential anti-migraine targets using established pre-clinical migraine models.

The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine. We aimed to explore purinergic receptors as potential anti-migraine targets. We used the human middle meningeal artery as a proxy for the trigeminal system to screen for possible anti-migraine candidates. The human findings were followed by intravital microscopy and calcitonin gene-related peptide release measurements in rodents. We show that the purinergic P2Y13 receptor fulfills all the features of a potential anti-migraine target. The P2Y13 receptor is expressed in both the human trigeminal ganglion and middle meningeal artery and activation of this receptor causes: a) middle meningeal artery contraction in vitro; b) reduced dural artery dilation following periarterial electrical stimulation in vivo and c) a reduction of CGRP release from both the dura and the trigeminal ganglion in situ. Furthermore, we show that P2X3 receptor activation of the trigeminal ganglion causes calcitonin gene-related peptide release and middle meningeal artery dilation. Both an agonist directed at the P2Y13 receptor and an antagonist of the P2X3 receptor seem to be viable potential anti-migraine therapies.

Scale-free amplitude modulation of low-frequency fluctuations in episodic migraine.

Arrhythmic fluctuations in neural activity occur at many levels of the nervous system. Such activity does not have a characteristic temporal periodicity but can exhibit statistical similarities, most commonly power-law scaling behavior, which is indicative of scale-free dynamics. The recurrence of scaling laws across many different systems and its manifestation in behavior has prompted a search for unifying principles in human brain function. With this in mind, a focused search for abnormities in scale-free dynamics is of considerable clinical relevance to migraine and other clinical pain disorders. Here, we examined the scale-free properties of the resting-state functional magnetic resonance imaging (fMRI) signal in the broadband frequency range known to be related to spontaneous neural activity (0.01-0.1 Hz). In a large cohort of episodic migraine patients (N = 40), we observed that the strength of long-range temporal correlations in the fMRI signal (captured by the scaling exponent α) was significantly higher in the sensorimotor network compared with healthy controls. Increases in the scaling exponent were positively correlated with fMRI signal variance and negatively correlated with the patient's self-reported headache intensity. These changes in the fMRI signal suggest that the temporal structure of amplitude fluctuations carries valuable information about the dynamic state of the underlying neuronal networks and ensuing sensory impairments in migraine. The demonstrated scaling laws pose a novel quantitative approach for examining clinically relevant interindividual variability in migraine and other pain disorders.

Meningeal Mast Cells Contribute to ATP-Induced Nociceptive Firing in Trigeminal Nerve Terminals: Direct and Indirect Purinergic Mechanisms Triggering Migraine Pain.

Peripheral mechanisms of primary headaches such as a migraine remain unclear. Meningeal afferents surrounded by multiple mast cells have been suggested as a major source of migraine pain. Extracellular ATP released during migraine attacks is a likely candidate for activating meningeal afferents via neuronal P2X receptors. Recently, we showed that ATP also increased degranulation of resident meningeal mast cells (Nurkhametova et al., 2019). However, the contribution of ATP-induced mast cell degranulation in aggravating the migraine pain remains unknown. Here we explored the role of meningeal mast cells in the pro-nociceptive effects of extracellular ATP. The impact of mast cells on ATP mediated activation of peripheral branches of trigeminal nerves was measured electrophysiologically in the dura mater of adult wild type (WT) or mast cell deficient mice. We found that a spontaneous spiking activity in the meningeal afferents, at baseline level, did not differ in two groups. However, in WT mice, meningeal application of ATP dramatically (24.6-fold) increased nociceptive firing, peaking at frequencies around 10 Hz. In contrast, in mast cell deficient animals, ATP-induced excitation was significantly weaker (3.5-fold). Application of serotonin to meninges in WT induced strong spiking. Moreover, in WT mice, the 5-HT3 antagonist MDL-7222 inhibited not only serotonin but also the ATP induced nociceptive firing. Our data suggest that extracellular ATP activates nociceptive firing in meningeal trigeminal afferents via amplified degranulation of resident mast cells in addition to direct excitatory action on the nerve terminals. This highlights the importance of mast cell degranulation via extracellular ATP, in aggravating the migraine pain.

Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.

ObjectiveTo assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine.BackgroundThere is a significant unmet need for novel effective well‐tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation – an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. A recent pilot study showed that REN can significantly reduce headache. We have conducted a randomized, double‐blind, sham‐controlled study to further evaluate the efficacy and safety of REN for the acute treatment of migraine.MethodsThis was a randomized, double‐blind, sham‐controlled, multicenter study conducted at 7 sites in the United States and 5 sites in Israel. Two hundred and fifty‐two adults meeting the International Classification of Headache Disorders criteria for migraine with 2‐8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation. A smartphone‐controlled wireless device was applied for 30‐45 minutes on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non‐painful intensity level. Migraine pain levels were recorded at baseline, 2, and 48 hours post‐treatment. Most bothersome symptoms (MBS) were also recorded. The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post‐treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Relief of MBS and pain‐free at 2 hours were key secondary endpoints.ResultsActive stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI95%, 15.6‐40.2]; P < .0001), pain‐free (37.4% vs 18.4%, P = .003), and MBS relief (46.3% vs 22.2%, P = .0008) at 2 hours post‐treatment. The pain relief and pain‐free superiority of the active treatment was sustained 48 hours post‐treatment. The incidence of device‐related adverse events was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], P = .499).ConclusionsREN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non‐pharmacological alternative for acute migraine treatment.

Calcitonin Gene-Related Peptide Modulators - The History and Renaissance of a New Migraine Drug Class.

Several lines of evidence pointed to an important role for CGRP in migraine. These included the anatomic colocalization of CGRP and its receptor in sensory fibers innervating pain-producing meningeal blood vessels, its release by trigeminal stimulation, the observation of elevated CGRP in the cranial circulation during migraine with normalization concomitant with headache relief by sumatriptan, and translational studies with intravenous (IV) CGRP that evoked migraine only in migraineurs. The development of small molecule CGRP receptor antagonists (CGRP-RAs) that showed clinical antimigraine efficacy acutely and prophylactically in randomized placebo-controlled clinical trials subsequently gave definitive pharmacological proof of the importance of CGRP in migraine. More recently, CGRP target engagement imaging studies using a CGRP receptor PET ligand[11 C]MK-4232 demonstrated that there was no brain CGRP receptor occupancy at clinically effective antimigraine doses of telcagepant, a prototypic CGRP-RA. Taken together, these data indicated that (1) the therapeutic site of action of the CGRP-RAs was peripheral not central; (2) that IV CGRP had most likely evoked migraine through an action at sites outside the blood-brain barrier; and (3) that migraine pain was therefore, at least in part, peripheral in origin. The evolution of CGRP migraine science gave impetus to the development of peripherally acting drugs that could modulate CGRP chronically to prevent frequent episodic and chronic migraine. Large molecule biologic antibody (mAb) approaches that are given subcutaneously to neutralize circulating CGRP peptide (fremanezumab, galcanezumab) or block CGRP receptors (erenumab) have shown consistent efficacy and tolerability in multicenter migraine prevention trials and are now approved for clinical use. Eptinezumab, a CGRP neutralizing antibody given IV, shows promise in late stage clinical development. Recently, orally administered next-generation small molecule CGRP-RAs have been shown to have safety and efficacy in acute treatment (ubrogepant and rimegepant) and prevention (atogepant) of migraine, giving additional CGRP-based therapeutic options for migraine patients.

New Medications in the Treatment of Acute Migraine.

Migraine is a common disorder affecting 12% of the US population. Use of triptans results in migraine pain relief within 2 hours in 16% to 51% of patients. However, due to their vasoconstrictive properties, triptans are contraindicated in patients with cardiovascular disease, peripheral vascular disease, cerebrovascular disease, and uncontrolled hypertension because of the potential for ischemia. This article will review 2 new classes of drugs being developed for the treatment of acute migraine without vasoconstrictive effects.