Prolactin in headache and migraine: A systematic review of clinical studies.

OBJECTIVE: To systemically review clinical studies investigating the role of prolactin and its receptors in headache and migraine. BACKGROUND: Migraine prevalence is more common in women compared to men. As prolactin is a crucial regulator of the hypothalamus-pituitary-gonadal axis, prolactin and its receptors might contribute to signaling mechanisms underlying migraine. METHODS: In this systematic review, we searched PubMed and EMBASE with the terms: prolactin, hyperprolactinemia, macroprolactinemia, hypoprolactinemia, migraine, headache, head pain and trigeminal pain pathway for clinical studies investigating prolactin signaling in headache and migraine. Two reviewers independently screened 841 articles for population, intervention, comparison, outcome, and study design. Studies were restricted to the English language and were excluded if they had a nonexperimental methodology. RESULTS: Nineteen clinical studies met the inclusion criteria and were included in the qualitative and quantitative analysis. The main findings were that serum prolactin levels were found to be higher in individuals with migraine compared to healthy controls, and prolactinomas (prolactin-secreting pituitary adenomas) were correlated with higher incidence of headache in otherwise healthy individuals and migraine attacks in individuals with migraine. CONCLUSION: Considerable evidence suggests a key role of prolactin and its receptors in migraine pathophysiology. Further randomized and placebo-controlled clinical studies targeting prolactin signaling are needed to further clarify influences of prolactin in migraine attack initiation.

Prolactin in headache and migraine: A systematic review of preclinical studies.

OBJECTIVE: To systemically review preclinical studies investigating the implication of prolactin signaling in headache and migraine pathophysiology. BACKGROUND: The features of migraine attacks, including characteristics, duration, frequency, and prevalence, are sex-dependent with variability across a lifetime, indicating the involvement of the hypothalamus-pituitary-gonadal axis. Prolactin is a key regulator of this axis, and a new line of evidence implicates prolactin signaling in sex-related differences in pain perception. METHODS: In this systematic review, we searched PubMed and EMBASE for the terms prolactin, hyperprolactinemia, macroprolactinemia, hypoprolactinemia, migraine, headache, head pain, and trigeminal pain pathway to find preclinical studies investigating prolactin signaling in headache and migraine. Two reviewers independently screened 841 articles for population, intervention, comparison, outcome, and study design. Studies were restricted to the English language and were excluded if they had a nonexperimental methodology. RESULTS: Of a total of 15 preclinical articles selected, 11 were both ex vivo and in vivo, 3 were ex vivo, and 1 was an in vivo study. The main findings were that prolactin receptors are distributed in the trigeminal pain pathway, and prolactin induced migraine-like behavior in rodents. Moreover, prolactin signaling has a crucial role in calcitonin gene-related peptide (CGRP) release, a key molecule in migraine pathogenesis, and prolactin gene deletion attenuated CGRP-induced migraine-like behavior. CONCLUSION: Preclinical data indicate a key role of prolactin and its receptors in mechanisms causing migraine. Further randomized and placebo-controlled clinical studies targeting prolactin signaling are needed to further clarify the influences of prolactin in migraine-attack initiation.

Human Cerebral Perfusion, Oxygen Consumption, and Lactate Production in Response to Hypoxic Exposure.

Exposure to moderate hypoxia in humans leads to cerebral lactate production, which occurs even when the cerebral metabolic rate of oxygen (CMRO2) is unaffected. We searched for the mechanism of this lactate production by testing the hypothesis of upregulation of cerebral glycolysis mediated by hypoxic sensing. Describing the pathways counteracting brain hypoxia could help us understand brain diseases associated with hypoxia. A total of 65 subjects participated in this study: 30 subjects were exposed to poikilocapnic hypoxia, 14 were exposed to isocapnic hypoxia, and 21 were exposed to carbon monoxide (CO). Using this setup, we examined whether lactate production reacts to an overall reduction in arterial oxygen concentration or solely to reduced arterial oxygen partial pressure. We measured cerebral blood flow (CBF), CMRO2, and lactate concentrations by magnetic resonance imaging and spectroscopy. CBF increased (P < 10-4), whereas the CMRO2 remained unaffected (P > 0.076) in all groups, as expected. Lactate increased in groups inhaling hypoxic air (poikilocapnic hypoxia: $0.0136\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P < 10-6; isocapnic hypoxia: $0.0142\ \frac{\mathrm{mmol}/\mathrm{L}}{\Delta{\mathrm{S}}_{\mathrm{a}}{\mathrm{O}}_2}$, P = 0.003) but was unaffected by CO (P = 0.36). Lactate production was not associated with reduced CMRO2. These results point toward a mechanism of lactate production by upregulation of glycolysis mediated by sensing a reduced arterial oxygen pressure. The released lactate may act as a signaling molecule engaged in vasodilation.

Amylin Analog Pramlintide Induces Migraine-like Attacks in Patients.

OBJECTIVE: Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood, and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene-related peptide (CGRP). METHODS: Thirty-six migraine without aura patients were enrolled in a randomized, double-blind, 2-way, crossover, positive-controlled clinical trial study to receive infusion of an amylin analogue pramlintide or human αCGRP on 2 different experimental days. Furthermore, translational studies in cells and mouse models, and rat, mouse and human tissue samples were conducted. RESULTS: Thirty patients (88%) developed headache after pramlintide infusion, compared to 33 (97%) after CGRP (p = 0.375). Fourteen patients (41%) developed migraine-like attacks after pramlintide infusion, compared to 19 patients (56%) after CGRP (p = 0.180). The pramlintide-induced migraine-like attacks had similar clinical characteristics to those induced by CGRP. There were differences between treatments in vascular parameters. Human receptor pharmacology studies showed that an amylin receptor likely mediates these pramlintide-provoked effects, rather than the canonical CGRP receptor. Supporting this, preclinical experiments investigating symptoms associated with migraine showed that amylin treatment, like CGRP, caused cutaneous hypersensitivity and light aversion in mice. INTERPRETATION: Our findings propose amylin receptor agonism as a novel contributor to migraine pathogenesis. Greater therapeutic gains could therefore be made for migraine patients through dual amylin and CGRP receptor antagonism, rather than selectively targeting the canonical CGRP receptor. ANN NEUROL 2021;89:1157-1171.

Effect of KATP channel blocker glibenclamide on PACAP38-induced headache and hemodynamic.

OBJECTIVE: To determine whether glibenclamide, a non-selective adenosine 5'-triphosphate-sensitive K+ (KATP) channel blocker, attenuates pituitary adenylate cyclase-activating polypeptide-38 (PACAP38)-induced headache and vascular changes in healthy volunteers. METHODS: In a double-blind, randomized, placebo controlled and crossover design, 22 healthy volunteers were assigned to receive an intravenous infusion of 10 picomole/kg/min pituitary adenylate cyclase-activating polypeptide-38 over 20 minutes followed by oral administration of 10 mg glibenclamide or placebo. The primary endpoint was the difference in incidence of headache (0-12 hours) between glibenclamide and placebo. The secondary endpoints were a difference in area under the curve for headache intensity scores, middle cerebral artery velocity (VmeanMCA), superficial temporal artery diameter, radial artery diameter, heart rate, mean arterial blood pressure and facial skin blood flow between the two study days. RESULTS: Twenty participants completed the study. We found no difference in the incidence of pituitary adenylate cyclase-activating polypeptide-38-induced headache after glibenclamide (19/20, 95%) compared to placebo (18/20, 90%) (P = 0.698). The area under the curve for headache intensity, middle cerebral artery velocity, superficial temporal artery diameter, radial artery diameter, facial skin blood flow, heart rate and mean arterial blood pressure did not differ between pituitary adenylate cyclase-activating polypeptide-38-glibenclamide day compared to pituitary adenylate cyclase-activating polypeptide-38-placebo day (P > 0.05). CONCLUSIONS: Posttreatment with 5'-triphosphate-sensitive K+ channel inhibitor glibenclamide did not attenuate pituitary adenylate cyclase-activating polypeptide-38-induced headache and hemodynamic changes in healthy volunteers. We suggest that pituitary adenylate cyclase-activating polypeptide-38-triggered signaling pathway could be mediated by specific isoforms of sulfonylurea receptor subunits of 5'-triphosphate-sensitive K+ channels and other types of potassium channels.

Opening of ATP sensitive potassium channels causes migraine attacks with aura.

Migraine afflicts more than one billion individuals worldwide and is a leading cause of years lived with disability. In about a third of individuals with migraine aura occur in relation to migraine headache. The common pathophysiological mechanisms underlying migraine headache and migraine aura are yet to be identified. Based on recent data, we hypothesized that levcromakalim, an ATP-sensitive potassium channel opener, would trigger migraine attacks with aura in patients. In a randomized, double-blind, placebo-controlled, crossover study, 17 patients aged 21-59 years and diagnosed with migraine with aura exclusively were randomly allocated to receive an infusion of 0.05 mg/min levcromakalim or placebo (isotonic saline) on two different days (ClinicalTrials.gov, ID: NCT04012047). The primary end points were the difference in incidence of migraine attacks with or without aura, headache and the difference in the area under the curve for headache intensity scores (0-12 h). Seventeen patients completed the study. Fourteen of 17 (82%) patients developed migraine attacks with and without aura after levcromakalim compared with 1 of 17 (6%) after placebo (P < 0.001). Ten patients (59%) developed migraine with aura after levcromakalim compared with none after placebo (P = 0.002). One additional patient reported 'possible' aura, only partially fulfilling the criteria. Levcromakalim is likely a novel migraine aura-inducing substance in humans. These findings highlight the ATP-sensitive potassium channel as a shared target in migraine aura and migraine headache. Likely, ATP-sensitive potassium channel opening leads to triggering of aura and headache, respectively, via distinct mechanisms.

Nocebo response in human models of migraine: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled, two-way crossover trials in migraine without aura and healthy volunteers.

BACKGROUND: Human models of migraine have been used for the past 30 years to test putative 'trigger' molecules and ascertain whether they induce migraine attacks in humans. However, nocebo effects using this model have never been systematically explored. OBJECTIVE: To assess the nocebo response rate in randomised clinical trials conducted at the Danish Headache Center, and in which human models of migraine were used. METHODS: In this systematic review and meta-analysis, we searched PubMed for studies of human models of migraine with a randomised, double-blind, placebo-controlled, two-way crossover design that included data on the incidence of migraine attacks or headache after infusion of placebo. A total of 943 articles were screened by title and abstract. Of these, 27 studies met the inclusion criteria (published between 1994 and 2020) and were included in the qualitative and quantitative analysis. We performed a random effects meta-analysis for the incidence of migraine attacks or delayed headache after placebo infusion. RESULTS: Twenty-seven studies were eligible for inclusion: 12 studies reported data for adults with migraine (n = 182), whereas 16 studies reported data on healthy volunteers (n = 210). For adults with migraine, the incidence of migraine attacks after placebo was 8.1% (95% CI = 2.5-15.5%, I2 = 50.8%). The incidence of delayed headache was 25.9% (95% CI = 18.5-34.1%, I2 = 18.9%). For healthy volunteers, the incidence of migraine attacks after placebo was 0.5% (95% CI = 0.0-3.6%, I2 = 0.0%) while the incidence of delayed headache was 10.5% (95% CI = 4.8-17.6%, I2 = 45.2%). CONCLUSION: The nocebo response in randomised, placebo-controlled two-way crossover trials with intravenous infusions of placebo in migraine is negligible. Future studies using human models of migraine can be conducted by assuming a nocebo response rate of 15.5%.

Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.

OBJECTIVE: To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks. METHODS: A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study. RESULTS: Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo (p = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) (p = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of placebo (p < 0.001).Conclusions and relevance: Early treatment with intravenously administered sumatriptan prevented PACAP38-induced migraine. Prevention of migraine attacks was associated with vasoconstriction by sumatriptan in the earliest phases of PACAP provocation. These results suggest that sumatriptan prevents PACAP38-induced migraine by modulation of nociceptive transmission within the trigeminovascular system.Trial Registration: ClinicalTrials.gov (NCT03881644).

PACAP27 induces migraine-like attacks in migraine patients.

INTRODUCTION: Pituitary adenylate cyclase-activating polypeptide (PACAP) is found in two functional isoforms, namely PACAP38 and PACAP27. The migraine-inducing properties of PACAP38 are well studied. However, it is not known whether the lesser-known and under-studied protein isoform, PACAP27, can also induce migraine attacks. Here, we studied the effect of human PACAP27 infusion on induction of migraine in a provocation model. METHODS: In a crossover study, 20 migraine without aura patients were randomly assigned to receive human PACAP27 (10 picomol/kg/min) or saline (placebo) infusion over 20 min. We recorded the migraine and associated symptoms. RESULTS: All patients completed the study. PACAP27 provoked migraine-like attacks in 11 patients (55%) and two developed attacks after placebo (10%) (p = 0.022). The headache intensity and duration after PACAP27 was significantly greater compared to placebo (p = 0.003). CONCLUSION: PACAP27 triggers migraine attacks without aura. These novel data strengthen the role of PACAP and its receptors in migraine pathogenesis.

Effect of KATP channel blocker glibenclamide on levcromakalim-induced headache.

INTRODUCTION: Administration of ATP-sensitive potassium channel opener levcromakalim triggers headache in healthy volunteers and migraine attacks in migraine patients. Here, we investigated the effect of ATP-sensitive potassium channel blocker glibenclamide on levcromakalim-induced headache in healthy volunteers. METHODS: In a randomized, double-blind, placebo-controlled, three-way cross-over study, 15 healthy volunteers aged 18-40 years were randomly allocated to receive glibenclamide and levcromakalim (day 1), glibenclamide and placebo (day 2), and placebo and placebo (day 3) on three different days separated by at least 1 week. The primary endpoints were the difference in incidence of headache and the difference in area under the curve for headache intensity scores (0-12 hours) between the days. RESULTS: Fifteen healthy volunteers completed the 3 days of the study. More participants (12/15, 80%) developed headache on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day (5/15, 33%) (p = 0.01; mean difference 47%; 95% confidence interval 18-75%) and compared to the placebo-placebo day (1/15, 7%) (p = 0.001; mean difference 73%; 95% confidence interval 48-99%). We found no difference in headache incidence between glibenclamide-placebo day and placebo-placebo day (p = 0.12; mean difference 27%; 95% confidence interval 1.3-52%). The area under the curve for headache intensity was significantly larger on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day (p = 0.003); and compared to the placebo-placebo day (p = 0.001). We found no difference in the area under the curve between the glibenclamide-placebo day compared to the placebo-placebo day (p = 0.07). The median time to onset for headache after levcromakalim infusion with glibenclamide pretreatment was delayed (180 min) compared to levcromakalim without pretreatment (30 min) from a previously published study. CONCLUSION: Glibenclamide administration did not cause headache, and glibenclamide pretreatment did not prevent levcromakalim-induced headache. However, glibenclamide delayed the onset of levcromakalim-induced headache. More selective blockers are needed to further elucidate the role of the ATP-sensitive potassium channel in headache initiation.Trial Registration: ClinicalTrials.gov NCT03886922.

Opening of BKCa channels alters cerebral hemodynamic and causes headache in healthy volunteers.

INTRODUCTION: Preclinical data implicate large conductance calcium-activated potassium (BKCa) channels in the pathogenesis of headache and migraine, but the exact role of these channels is still unknown. Here, we investigated whether opening of BKCa channels would cause headache and vascular effects in healthy volunteers. METHODS: In a randomized, double-blind, placebo-controlled, cross-over study, 21 healthy volunteers aged 18-39 years were randomly allocated to receive an intravenous infusion of 0.05 mg/min BKCa channel opener MaxiPost and placebo on two different days. The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0-12 hours) and for middle cerebral artery blood flow velocity (VMCA) (0-2 hours) between MaxiPost and placebo. The secondary endpoints were the differences in area under the curve for superficial temporal artery and radial artery diameter (0-2 hours) between MaxiPost and placebo. RESULTS: Twenty participants completed the study. Eighteen participants (90%) developed headache after MaxiPost compared with six (30%) after placebo (p = 0.0005); the difference of incidence is 60% (95% confidence interval 36-84%). The area under the curve for headache intensity (AUC0-12 hours, p = 0.0003), for mean VMCA (AUC0-2 hours, p = 0.0001), for superficial temporal artery diameter (AUC0-2 hours, p = 0.003), and for radial artery diameter (AUC0-2 hours, p = 0.03) were significantly larger after MaxiPost compared to placebo. CONCLUSION: MaxiPost caused headache and dilation in extra- and intracerebral arteries. Our findings suggest a possible role of BKCa channels in headache pathophysiology in humans. ClinicalTrials.gov, ID: NCT03887325.

Meningeal contribution to migraine pain: a magnetic resonance angiography study.

The origin of migraine pain is unknown but possibly implicates the dura mater, which is pain sensitive in proximity to the meningeal arteries. Therefore, subtle changes in vessel calibre on the head pain side could reflect activation of dural perivascular nociceptors that leads to migraine headache. To test this hypothesis, we measured circumference changes of cranial arteries in patients with cilostazol-induced unilateral migraine without aura using 3 T high resolution magnetic resonance angiography. The middle meningeal artery was of key interest, as it is the main supply of the dura mater. We also measured the superficial temporal and external carotid arteries as additional extracranial segments, and the middle cerebral, the cerebral and cavernous parts of the internal carotid (ICAcerebral and ICAcavernous), and the basilar arteries as intracranial arterial segments. Magnetic resonance angiography scans were performed at baseline, migraine onset, after sumatriptan, and ≥27 h after migraine onset. Thirty patients underwent magnetic resonance angiography scans, of which 26 patients developed unilateral attacks of migraine without aura and were included in the final analysis. Eleven patients treated their migraine with sumatriptan while the remaining 15 patients did not treat their attacks with analgesics or triptans. At migraine onset, only the middle meningeal artery exhibited greater circumference increase on the pain side (0.24 ± 0.37 mm) compared to the non-pain side (0.06 ± 0.38 mm) (P = 0.002). None of the remaining arteries revealed any pain-side specific changes in circumference (P > 0.05), but exhibited bilateral dilation. Sumatriptan constricted all extracerebral arteries (P < 0.05). In the late phase of migraine, we found sustained bilateral dilation of the middle meningeal artery. In conclusion, onset of migraine is associated with increase in middle meningeal artery circumference specific to the head pain side. Our findings suggest that vasodilation of the middle meningeal artery may be a surrogate marker for activation of dural perivascular nociceptors, indicating a meningeal site of migraine headache.10.1093/brain/awy300_video1awy300media15983750185001.

Investigation of sumatriptan and ketorolac trometamol in the human experimental model of headache.

BACKGROUND: Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache in healthy volunteers but the precise mechanisms by which PACAP38 leads to headache are unclear. We investigated the headache preventive effect of sumatriptan and ketorolac on PACAP38-induced headache in healthy volunteers. In addition, we explored contribution of vascular mechanisms to PACAP38-induced headache using high resolution magnetic resonance angiography. METHODS: Thirty-four healthy volunteers were divided in two groups (A and B) and received infusion of PACAP38 (10 picomol/kg/min) over 20 min. Group A was pretreated with intravenous sumatriptan (4 mg) or ketorolac (30 mg) 20 min before infusion of PACAP38. Group B received infusion of sumatriptan or ketorolac as post-treatment 90 min after infusion of PACAP38. In both experiments, we used a randomized, double-blind, cross-over design. We recorded headache characteristics and circumference of extra-intracerebral arteries. RESULTS: We found no difference in AUC (0-6 h) of PACAP38-induced headache in group A, pretreated with sumatriptan or ketorolac (p = 0.297). There was no difference between sumatriptan and ketorolac in PACAP38-induced circumference change (AUCBaseline-110 min) of MMA (p = 0.227), STA (p = 0.795) and MCA (p = 0.356). In group B, post-treatment with ketorolac reduced PACAP38-headache compared to sumatriptan (p < 0.001). Post-treatment with sumatriptan significantly reduced the circumference of STA (p = 0.039) and MMA (p = 0.015) but not of MCA (p = 0.981) compared to ketorolac. In an explorative analysis, we found that pre-treatment with sumatriptan reduced PACAP38-induced headache compared to no treatment (AUC0-90min). CONCLUSIONS: Post-treatment with ketorolac was more effective in attenuating PACAP38-induced headache compared to sumatriptan. Ketorolac exerted its effect without affecting PACAP38-induced arterial dilation, whereas sumatriptan post-treatment attenuated PACAP38-induced dilation of MMA and STA. Pre-treatment with sumatriptan attenuated PACAP38-induced headache without affecting PACAP38-induced arterial dilation. Our findings suggest that ketorolac and sumatriptan attenuated PACAP38-induced headache in healthy volunteers without vascular effects. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03585894). Registered 13 July 2018.

Extracranial activation of ATP-sensitive potassium channels induces vasodilation without nociceptive effects.

INTRODUCTION: Levcromakalim opens ATP-sensitive potassium channels (KATP channel) and induces head pain in healthy volunteers and migraine headache in migraine patients, but no pain in other parts of the body. KATP channels are expressed in C- and Aδ-fibers, and these channels might directly activate nociceptors and thereby evoke pain in humans. METHODS: To assess the local effect of KATP channel opening in trigeminal and extra-trigeminal regions, we performed a crossover, double-blind, placebo-controlled study in healthy volunteers. Participants received intradermal and intramuscular injections of levcromakalim and placebo in the forehead and the forearms. RESULTS: Intradermal and intramuscular injections of levcromakalim did not evoke more pain compared to placebo in the forehead (p > 0.05) and the forearms (p > 0.05). Intradermal injection of levcromakalim caused more flare (p < 0.001), skin temperature increase (p < 0.001), and skin blood flow increase (p < 0.001) compared to placebo in the forehead and the forearms. CONCLUSION: These findings suggest that it is unlikely that levcromakalim induces head pain by direct activation of peripheral neurons.

Levcromakalim, an Adenosine Triphosphate-Sensitive Potassium Channel Opener, Dilates Extracerebral but not Cerebral Arteries.

BACKGROUND: ATP-sensitive potassium (KATP ) channel opener levcromakalim induces migraine attacks in migraine patients. Underlying mechanisms responsible for headache and migraine induction after levcromakalim infusion are unknown. OBJECTIVE: To investigate the effect of levcromakalim on the cranial arteries and to explore the possible relationship between the middle meningeal artery (MMA) dilation and headache. METHODS: In a double-blind, randomized, placebo-controlled study, 20 healthy volunteers were scanned at the baseline and repeatedly after infusion of levcromakalim (n = 14) and placebo (n = 6). All participants received a subcutaneous injection of sumatriptan 6 mg before the last scanning. RESULTS: The MMA circumference was significantly larger after levcromakalim compared with placebo (P < .0001). The MMA dilation lasted over 5 hours during observational period. We found a significant association between headache and MMA dilation (P < .0001). The superficial temporal artery (STA) circumference was significantly larger after levcromakalim compared with placebo (P = .03) over the initial period (110 minutes). Over the entire observational period, there was no difference in circumference of the STA and the middle cerebral artery (MCA) between levcromakalim and placebo. CONCLUSION: Levcromakalim dilated the MMA but not MCA. The MMA dilation was associated with headache. Future studies should investigate whether opening of KATP channels can activate and sensitize the perivascular nociceptors.

Carbon monoxide inhalation induces headache but no migraine in patients with migraine without aura.

INTRODUCTION: Carbon monoxide is an endogenously produced signaling gasotransmitter known to cause headache and vasodilation. We hypothesized that inhalation of carbon monoxide would induce migraine-like attacks in migraine without aura patients. METHODS: In a randomized, double-blind, placebo-controlled crossover design, 12 migraine patients were allocated to inhalation of carbon monoxide (carboxyhemoglobin 22%) or placebo on two separate days. Headache and migraine characteristics were recorded during hospital (0-2 hours) and post-hospital (2-13 hours) phases. RESULTS: Six patients (50%) developed migraine-like attacks after carbon monoxide compared to two after placebo (16.7%) ( p = 0.289). The median time to onset of migraine-like attacks after carbon monoxide inhalation was 7.5 h (range 3-12) compared to 11.5 h (range 11-12) after placebo. Nine out of 12 patients (75%) developed prolonged headache after carbon monoxide. The area under the curve for headache score (0-13 hours) was increased after carbon monoxide compared with placebo ( p = 0.033). CONCLUSION: Carbon monoxide inhalation did not provoke more migraine-like attacks in migraine patients compared to placebo, but induced more headache in patients compared to placebo. These data suggest that non-toxic concentrations of carbon monoxide had low potency in migraine induction and that the carbon monoxide inhalation model is not suitable to study migraine.

Migraine induction with calcitonin gene-related peptide in patients from erenumab trials.

BACKGROUND: Migraine prevention with erenumab and migraine induction by calcitonin gene-related peptide (CGRP) both carry notable individual variance. We wanted to explore a possible association between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP. METHODS: Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized cross-over design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess the efficacy of previous antibody treatment. The patients were stratified into groups of high responders and poor responders. Primary outcomes were incidence of migraine-like attacks and area under the curve of headache intensity after infusion of CGRP and placebo. All interviews and experiments were performed in laboratories at the Danish Headache Center, Copenhagen, Denmark. RESULTS: Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p = 0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0-90 min (p = 0.009), and 2-12 h (p = 0.014). The median peak headache intensity score was 5 (5-9) after CGRP, compared to 2 (0-4) after placebo (p = 0.004). CONCLUSIONS: Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. If an association is evident, CGRP provocation could prove a biomarker for predicting antibody treatment efficacy. TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov with identifier: NCT03481400 .

Endovascular thrombectomy and post-procedural headache.

BACKGROUND: We investigated the prevalence of post-procedural headache in patients who have undergone thrombectomy for ischemic stroke, and correlated history of migraine with risk of peri-procedural complications. A total of 314 patients underwent thrombectomy at the Danish National Hospital from January 2012 to December 2014. Eligible subjects were phone-interviewed using a purpose-developed semi-structured questionnaire according to the International Classification of Headache Disorders 3, beta version criteria. FINDINGS: Among 96 eligible subjects, there was a significant decrease in migraine (p = 0.022) within the first 3 months after EVT compared to 1 year before treatment, which was further evident at interview time (on average 1.6 years after EVT, p = 0.013). A minority of patients experienced headaches for the first time within 3 months of their EVT (migraine 2, TTH 9), which persisted at interview time for subjects with migraine. Out of 12 subjects with peri-procedural complications, 2 had a history of migraine with aura. CONCLUSION: Thrombectomy leads to a significant decrease in previously known migraine, and new onset of headache in a small subset of patients. A history of migraine does not appear to predispose to peri-procedural complications.

Arterial responses to infusion of glucagon-like peptide-1 in humans: A randomized trial study.

Glucagon-like-peptide-1 (GLP-1) is an incretin hormone implicated in several metabolic and neurological disorders. GLP-1 induces vasodilation and increases blood flow in the peripheral circulation. Whether GLP-1 alters cerebral hemodynamics in humans is yet to be elucidated. In a crossover, double-blind, placebo-controlled, and randomized design, 21 healthy volunteers were assigned to receive intravenous GLP-1 infusion (2.5 pmol/kg/min) or placebo over 20 min on two different days separated by at least one week. We used a noninvasive, well-validated transcranial doppler (TCD) and ultrasound dermascan to reveal the effect of GLP-1 on intra- and extracerebral arteries. The mean blood flow velocity in the middle cerebral artery (VMCA), the diameter of the superficial temporal artery (STA) and radial artery (RA), and facial skin blood flow were measured. In addition, we documented headache and its associated symptoms during and after infusion. Twenty participants were included in the final analysis. We found no difference in the VMCA (P = 0.227), diameter of the STA (P = 0.096) and the RA (P = 0.221) and facial blood flow (P = 0.814) after GLP-1 compared to placebo. There were no differences in HR, SAT, EtCO2, or RF (P > 0.05) on the GLP-1 day compared to the placebo day. We found no differences in the incidence of headache after GLP-1 (n = 10) compared to placebo (n = 7) (P = 0.250). GLP-1 infusion did not affect cerebral hemodynamics and induce headache in humans. Further preclinical studies with validated methods are required to determine if intra - and extracerebral vasculature express GLP-1Rs in humans.

Effect of Adrenomedullin on Migraine-Like Attacks in Patients With Migraine: A Randomized Crossover Study.

OBJECTIVE: To determine whether the IV infusion of adrenomedullin, a potent vasodilator belonging to calcitonin family of peptides, provokes attacks of migraine in patients. METHODS: Twenty patients with migraine without aura participated in a placebo-controlled and double-blind clinical study. In a randomized crossover design, the patients received an IV infusion of human adrenomedullin (19.9 pmol/kg/min) or placebo (saline) administrated via an automated IV pump (20 minutes). The patients participated in 2 study days with a washout period of minimum of 7 days. The primary outcome of the study was predefined as a difference in migraine incidence (0-12 hours), and the secondary outcomes were the area under curve (AUC0-12 hours) for the headache intensity score and AUC0-90 minutes for mean arterial blood pressure (MAP), flushing, and heart rate (HR). RESULTS: Eleven patients with migraine without aura (55%) fulfilled migraine attacks criteria after adrenomedullin infusion compared to only 3 patients who reported attack (15%) after placebo (p = 0.039). We found that patients reported in a period of 0 to 12 hours stronger headache intensity after adrenomedullin compared to placebo infusion (p = 0.035). AUC0-90 minutes value for HR and flushing (p < 0.05) was significant and for MAP (p = 0.502) remained unchanged. Common reported adverse events were facial flushing, heat sensation, and palpitation (p < 0.001). CONCLUSION: Our data implicate adrenomedullin in migraine pathogenesis. This suggests that adrenomedullin or its receptors are novel therapeutic targets for the treatment of migraine. However, we cannot discount the possibility that adrenomedullin may be acting through the canonical calcitonin gene-related peptide receptor. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT04111484.