PACAP27 induces migraine-like attacks in migraine patients

Al‐Karagholi, Mohammad Al‐Mahdi; Arngrim, Nanna; Olesen, Jes; Ashina, Messoud

doi:10.1177/0333102419864507

Cited by 69 publications

(69 citation statements)

References 46 publications

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“…Of these, 27 studies met the inclusion criteria (1994 and 2020) and were included in the qualitative and quantitative analysis (9–35) (Figure 1). Twelve studies (10 published and two studies under review) reported data on the incidence of migraine attacks after placebo in individuals with migraine without aura (9–17,31,33), whereas 10 studies did so in healthy volunteers (18,19,22,23,25,27,29,30,32,34). Furthermore, 16 studies reported data on the incidence of delayed headache after placebo in healthy volunteers (13,18–30,32,34).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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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 with intravenous infusion 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%.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2020

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“…• To utilize anti-PACAP drugs in migraine prophylaxis, their longterm safety must be examined and clarified. Moreover, their advantages should be compared with those of the anti-CGRP monoclonal antibodies that are available patients provoked in a crossover study significantly more migraine-like attacks than placebo, further strengthening the role of PACAP in the pathogenesis of migraine [39].…”

Section: Article Highlightsmentioning

confidence: 99%

Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) with monoclonal antibodies in migraine prevention: a brief review

Rustichelli

Castro

Baraldi

et al. 2020

Expert Opinion on Investigational Drugs

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Introduction: Interest is growing in the role of pituitary adenylate cyclase-activating polypeptide (PACAP) and its specific PAC1 receptor in migraine and in their antagonism as a strategy for migraine prevention. Areas covered: We discuss and critically evaluate (i) the evidence of the role of PACAP in migraine pathophysiology and (ii) the first clinical trials in migraine prophylaxis with monoclonal antibodies AMG 301 and ALD1910 which act against PAC1 and PACAP38 respectively. We examined PubMed, Scopus, and ClinicalTrials.gov electronic databases to examine the relevant material. Expert opinion: There is much proof of the ability of PACAP to cause migraine, but there is limited evidence that blocking PACAP or PAC1 receptor can prevent migraine. However, the potential of anti-PACAP antibodies in migraine prophylaxis is high. Theoretically, if these antibodies block the activation of the trigeminovascular system, they will prevent the onset of migraine attacks. There are still knowledge gaps in the role of PACAP in migraine and the risk/benefit ratio of anti-PACAP antibodies must be carefully studied.

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“…Most participants reported facial flushing and puffiness persisting over 24 h post PACAP38 infusion. PACAP is found in human skin [53] and PACAP infusion causes intense facial flushing [21].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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 PACAP38induced circumference change (AUC Baseline-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). Posttreatment 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 (AUC 0-90min). 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

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PACAP27 induces migraine-like attacks in migraine patients

Cited by 69 publications

References 46 publications

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

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

Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) with monoclonal antibodies in migraine prevention: a brief review

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

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