Objective.-The monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor are new antimigraine drugs from which many patients already benefit. Very few side effects have been reported from the antibody trials, including very few gastrointestinal (GI) side effects. The current data derive from a double-blind cross-over study of CGRP infusion for 2 hours. We present the GI side effects of the infusion and raise the question if underreporting of GI symptoms in CGRP antibody trials has occurred. We also discuss why constipation may be more likely with CGRP receptor blockade than with CGRP neutralizing antibodies.Methods.-Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP 1.5 µg/minutes on 2 different days. The participants were pretreated with sumatriptan tablets (2 × 50 mg) 1 day and with placebo the other day. During the infusion, the participants were asked about side effects including a detailed description about their GI symptoms. Clinical observations like flatulence, rumbling, and use of bedpan were also noted. After the infusion, the participants filled out a questionnaire about side effects at home until 12-hour after the infusion start. The study was conducted at the Danish Headache Center at Rigshospitalet Glostrup in the period February 2018 to July 2018.Results.-On both study days 93% (27/29 participants) experienced symptoms from the GI system during the infusion. Rumbling, stomach pain, nausea, diarrhea, and an urge to defecate were the most commonly experienced GI side effects. There was no difference in symptoms between placebo and sumatriptan pretreatment.Conclusion.-We conclude that a 2-hour infusion of CGRP causes frequent and sometimes severe symptoms from the GI system. The symptoms are not antagonized by sumatriptan. More attention should be paid to constipation as a possible side effect of CGRP receptor antagonists.

ObjectiveTo review the existing literature on histamine and migraine with a focus on the molecule, its receptors, its use in inducing migraine, and antihistamines in the treatment of migraine.BackgroundHistamine has been known to cause a vascular type headache for almost a hundred years. Research has focused on antihistamines as a possible treatment and histamine as a migraine provoking agent but there has been little interest in this field for the last 25 years. In recent years two additional histamine (H3 and H4) receptors have been discovered and a series of non-sedating antihistamines have been developed. It is therefore timely to review the field again.MethodsFor this review the PubMed/MEDLINE database was searched for eligible studies. We searched carefully for all articles on histamine, antihistamines and histamine receptors in relation to migraine and the nervous system. The following search terms were used: histamine, migraine disorders, migraine, headache, antihistamines, histamine antagonists, clinical trials, induced headache, histamine H3 receptor, histamine H4 receptor and pharmacology. Four hundred thirty-six titles were read, 135 abstracts were read, 112 articles were read in full and 53 articles were used in this review. Review process resulted in 12 articles added to a total of 65.FindingsEarly studies of H1 and H2 antihistamines lack scientific strength and show conflicting results. Most of the antihistaminic drugs used in these trials bind also to other receptors which makes it difficult to conclude on the antihistaminic effect. Histamine is an efficient inducer of migraine attacks in migraine patients by an H1 mechanism most likely extracerebrally. These findings merit further investigation of antihistamines in clinical drug trials. The H3 and H4 receptors are found in primarily in CNS and immune tissues, respectively. H3 is likely to be involved in antinociception and has been linked with cognitive, neurodegenerative and sleep disorders. The only marketed H3 agent, pitolisant, is a brain penetrant H3 antagonist/inverse agonist which increases central histamine and causes headache. The experimental H3 agonist Nα-methylhistamine has shown promising results as a migraine preventative in studies of uncertain quality. With the current limited knowledge of the H4 receptor it is questionable whether or not the receptor is involved in migraine.ConclusionThere is insufficient support for first generation antihistamines (both H1 and H2) as preventive migraine medications and sedation and weight gain are unacceptable side effects. Non-sedating H1 antihistamines need to be appropriately tested. Central H3 receptors seem to have a role in migraine that merit further investigation. The histaminergic system may be a goal for novel migraine drugs.

BackgroundCilostazol is an inhibitor of phosphodiesterase 3 and thus causes accumulation of cAMP. It induces migraine-like attacks in migraine patients. Whether the cilostazol model responds to sumatriptan in migraine patients and therefore is valid for testing of future anti-migraine medications has never been investigated.MethodsIn a cross-over study, 30 patients received cilostazol (200 mg p.o.) on two separate days each day followed by oral self-administered placebo or sumatriptan 50 mg. We recorded headache characteristics and associated symptoms using a questionnaire. The 30 participants were asked to subsequently treat their spontaneous attacks with sumatriptan (50 mg) or placebo in a double-blind cross-over design and 15 participants did so.ResultsCilostazol induced headache with some migraine characteristics in all participants; 18 patients on the sumatriptan day and 19 patients on the placebo day fulfilled criteria for a migraine-like attack. The difference in median headache intensity between sumatriptan and placebo at 2 h was not significant (p = 0.09), but it was at 4 h (p = 0.017). During spontaneous attacks, the difference between placebo and sumatriptan was not significant at 2 h (p = 0.26), but it was highly significant at 4 h (p = 0.006).ConclusionThe cilostazol model in migraine patients could not be validated by a sufficient sumatriptan response. The model may perhaps respond to new drugs that act intracellularly or directly on ion channels.Trial registrationThe study is registered on clinicaltrials.gov (NCT02486276)Electronic supplementary materialThe online version of this article (10.1186/s10194-018-0841-7) contains supplementary material, which is available to authorized users.