Premonitory symptoms in glyceryl trinitrate triggered migraine attacks: a case-control study

Abstract

Spontaneous and pharmacologically provoked migraine attacks are frequently preceded by nonheadache symptoms called premonitory symptoms. Here, we systematically evaluated premonitory symptoms in migraine patients and healthy controls after glyceryl trinitrate (GTN) infusion. In women with migraine without aura (n = 34) and age-matched female controls (n = 24), we conducted systematically a semistructured interview assessing 21 possible premonitory symptoms every 15 minutes in the 5 hours after GTN infusion (0.5 µg/kg/min over 20 minutes). Migraine-like headaches occurred in 28/34 (82.4%) migraineurs (GTN responders). After GTN, 26/28 (92.9%) responders, 6/6 (100%) nonresponders, and 13/24 (54.2%) controls reported at least one possible premonitory symptom. Concentration difficulties (P = 0.011), yawning (P = 0.009), nausea (P = 0.028), and photophobia (P = 0.001) were more frequently reported by those migraineurs who developed a migraine-like attack vs healthy controls. Importantly, concentration difficulties were exclusively reported by those who developed a migraine-like attack. Thus, our findings support the view that GTN is able to provoke the naturally occurring premonitory symptoms and show that yawning, nausea, photophobia, and concentration difficulties are most specific for an impending GTN-induced migraine-like headache. We suggest that these symptoms may also be helpful as early warning signals in clinical practice with concentration difficulties exclusively reported by those who develop a migraine-like attack.

Cortical glutamate and gamma-aminobutyric acid over the course of a provoked migraine attack, a 7 Tesla magnetic resonance spectroscopy study

“…Despite their similarity with spontaneous attacks, induced attacks need to be referred to as ‘migraine-like headaches’, because by nature they cannot fulfill the criteria for migraine without aura, which require the attack to be spontaneous and last (untreated) at least 4 h ( Headache Classification Committee of the International Headache Society (IHS), 2018 ). Therefore, similarly to previously published provocation studies, we used the following criteria for defining migraine-like attacks, fulfilling either: 1) moderate to severe headache (VRS ≥ 4) fulfilling ICHD-3 criteria C and D for migraine without aura; or 2) headache described as mimicking the patients' usual migraine attack and treated with acute migraine medication ( Arngrim et al, 2016 , Onderwater et al, 2020 ).…”

“…Glyceryl trinitrate provocation studies have only rarely been able to provoke aura symptoms and generally provokes migraine-like attacks in over eighty percent of migraine without patients ( Ashina et al, 2013 ). In both GTN provoked and spontaneous attacks patients may experience premonitory symptoms in the preictal phase, and using neuroimaging techniques activation of hypothalamus, occipital cortex and brainstem has been demonstrated ( Ferrari et al, 2015 , Maniyar et al, 2014a , Maniyar et al, 2014b , Onderwater et al, 2020 , Schulte and May, 2016 ; van Oosterhout et al, 2021 , Weiller et al, 1995 ).…”

Migraine Is More Than Just Headache: Is the Link to Chronic Fatigue and Mood Disorders Simply Due to Shared Biological Systems?

“…The premonitory phase has been studied in some detail in the literature over the years, in both adults and children, with a variety of study designs and patient populations ( Blau, 1980 ; Drummond and Lance, 1984 ; Waelkens, 1985 ; Rasmussen and Olesen, 1992 ; Russell et al, 1996 ; Giffin et al, 2003 ; Kelman, 2004 ; Quintela et al, 2006 ; Schoonman et al, 2006 ; Cuvellier et al, 2009 ; Guo et al, 2016 ; Karsan et al, 2016 , 2020b ; Laurell et al, 2016 ; Jacobs and Pakalnis, 2019 ; Onderwater et al, 2020 ; Wang et al, 2021 ). While some studies have looked at prevalence and the ability of these symptoms to predict impending headache, others have focused on phenotype.…”

Provoked versus spontaneous migraine attacks: pathophysiological similarities and differences

“…Provocation studies have found that glyceryl trinitrate induces migraine attacks that are preceded by premonitory symptoms, i.e. non-headache symptoms that occur within minutes to hours before the onset of headache in attacks with migraine without aura [ 22 , 23 ]. Premonitory symptoms are regarded as surrogate markers of activation within central nervous system structures, such as the hypothalamus [ 19 ].…”