The Premonitory Symptoms (Prodrome): A Tertiary Care Study of 893 Migraineurs

Leslie Kelman, MD

Disclosures

Headache. 2004;44(9) 

In This Article

Comment

Premonitory symptoms provide a potential early warning signal for the migraine attack and highlight the neuronal mechanisms of migraine. It has been shown that patients are able to correctly predict subsequent headaches based on premonitory symptoms 72% of the time.[10] The improvement in the migraine attack using dopamine antagonists[11,12] preemptively raises the issue of dopamine mechanisms[13] in prodrome. In addition, similar success with ergots[14] and triptans[5,6] given in prodrome to prevent the full-blown migraine attack expand the range of mechanisms to serotonin receptor dysfunction.

The triptan treatment paradigm is shifting.[15,16,17,18] Earlier treatment of the headache phase of the migraine attack itself improves the percentage of patients responding to triptans, reduces the need both for a second dose of triptan and for rescue medication, and reduces recurrence. However, treatment during the aura phase has not been documented to prevent or reduce the headache attack.[19] Prodrome, conversely, appears to offer a unique opportunity for early treatment. As early as 1983[11] it was shown that a dopamine antagonist, domperidone 30 mg given in the prodrome, had a therapeutic gain of 61% compared to placebo in the prevention of a migraine attack. Prevention failed if treatment was delayed to within 6 hours of the headache phase. More recently, naratriptan in an open label study[5] was shown to be effective in preventing the headache attack in 60% of patients and reducing the severity in some of the remaining patients. Associated symptoms and other headache variables were not addressed. In the latter study, the poor response in patients with headache onset within 2 hours of taking naratriptan (taken when patients felt certain a migraine headache was inevitable) may reflect the relatively slowness of the onset of naraptriptan or may indicate that the seeds for the headache had already been set in motion at the time of triptan administration (eg irreversible transcription may already have occurred).

The current study documented that in up to 65% of patients with prodrome, the premonitory symptoms lasted for 2 hours or less. Therapeutically, a rapidly acting triptan may be beneficial in preventing the headache phase in these cases. In patients with longer duration of prodrome other triptans may suffice. Triptans with a longer half life may be optimal in this situation. This needs to be tested.

There is little justification in clinically treating IHS 1.7 migraine differently from IHS 1.1-1.6 migraine.[20] Therefore the prodrome treatment paradigm should be applied to this large group of patients as well.

The current study documented that about one third of patients, irrespective of the type of migraine, experienced prodrome or premonitory symptoms. This contrasts with reports of 56%,[4] 65%,[21] 88%, and 98%,[22] in pre-IHS classification series, and more recently population studies reported frequencies of 6.5% to 9.8% with no significant difference in gender or the presence of aura.[1] In a recent study, a frequency of 33% was described in patients without aura in at least 50% of attacks.[3]

The commonest symptoms in the current study were fatigue, mood changes, and gastrointestinal symptoms with other symptoms being much less frequent. Other series have divided symptoms into positive and negative symptoms,[24] nonevolutive (preceding the headache by up to 48 hours) and evolutive (starting 6 hours before the headache and building to a peak at the onset of the attack),[22] and psychologic, neurologic, and general.[25] Another subdivision included the categories of general complaints, symptoms related to the head, abnormalities of eyes or sight, sensory intolerance, mood and behavior variations, and abdominal symptoms.[22] Of interest is the very low percentage of patients reporting neck symptoms in the prodrome in the current study. Other smaller studies specifically studying neck symptoms in the prodrome documented frequencies of 31%[26] (patients specifically asked about neck stiffness) and 61%[27,28] (method of data collection and percentage of patients having prodrome not given). This difference may lie to some degree in the method of data collection. In the current study, patients were not specifically asked if they had neck symptoms. In a migraine population selected by their perceived ability to predict prodrome, 49.7% of patients with prodrome listed neck stiffness.[10] In this latter study, responses were elicited by patients initially choosing from a list of symptoms including neck stiffness.

Unlike aura, there was no gender difference in prodrome frequency and this was also not seen in prodrome duration. Prodrome frequency was greater in migraine 1.1-1.6 than in migraine 1.7 but there was no difference in prodrome duration. Prodrome duration was longer in migraine 1.1-1.6 with headache frequency less than 15 days per month than in migraine 1.1-1.6 with headache frequency greater than 14 days per month.

This study expands a previous small study[3] showing an increased frequency of triggers in patients experiencing prodrome. An alternative possibility is that the heightened sensitivity of the brain in the prodrome causes an increased awareness and lesser tolerance of "triggers." Indeed, the triggers may not really be triggers in these circumstances but reflect accompaniments of a migraine attack.

The current study also suggests that prodrome reflects patients with more full-blown migraine attacks (aura, some headache features, and postdrome). The converse, that prodrome may in some way stimulate a cascade of events by activating specific brain pathways, such as in the modular theory of migraine,[29] is an intriguing possibility.

This study suffers from some imperfections. This is a study of tertiary care patients and not a population cross-sectional study. No diary documentation was available, although some patients had documented headache profiles for prior provider evaluations. Also lacking in this study is the temporal evolution of the prodrome profile. It remains an unresolved issue whether data are better collected by direct questioning ("do you have neck stiffness?") or by eliciting responses without any hint of suggestion.

To date, treating in the prodrome phase appears to impact the headache phase. Therefore patients should be encouraged to treat as early as possible in a migraine attack, namely in the prodrome. Some interesting issues arise. Can prodrome be aborted without affecting the rest of the headache? If possible, this would certainly shed some light on the migraine process. Can all the triptans used in the premonitory phase abort the subsequent headache or is this determined by respective triptan characteristics? These issues remain to be tested.

This study provides a portrait of prodrome in a large cohort of patients. It emphasizes the potential for preventing the acute headache phase by treating in the prodrome and highlights differences between patients with and without prodrome.


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