The Migraine Timing Cycle

an J Neurol Sci. 1999 Nov;26 Suppl 3:S12-9.

Pathophysiology of migraine--new insights.

Hargreaves RJ1, Shepheard SL.

Author information


Current theories propose that the primary dysfunction in migraine occurs within the CNS and that this evokes changes in blood vessels within pain-producing intracranial meningeal structures that give rise to headache pain. Migraine is now thought of as a neurovascular disorder. It has been proposed that genetic abnormalities may be responsible for altering the response threshold to migraine specific trigger factors in the brain of a migraineur compared to a normal individual. The exact nature of the central dysfunction that is produced in migraineurs is still not clear and may involve spreading depression-like phenomena and activation of brain stem monoaminergic nuclei that are part of the central autonomic, vascular and pain control centers. It is generally thought that local vasodilatation of intracranial extracerebral blood vessels and a consequent stimulation of surrounding trigeminal sensory nervous pain pathways is a key mechanism underlying the generation of headache pain associated with migraine. This activation of the 'trigeminovascular system' is thought to cause the release of vasoactive sensory neuropeptides, especially CGRP, that increase the pain response. The activated trigeminal nerves convey nociceptive information to central neurons in the brain stem trigeminal sensory nuclei that in turn relay the pain signals to higher centers where headache pain is perceived. It has been hypothesized that these central neurons may become sensitized as a migraine attack progresses. The 'triptan' anti-migraine agents (e.g. sumatriptan, rizatriptan, zolmitriptan naratriptan) are serotonergic agonists that have been shown to act selectively by causing vasoconstriction through 5-HT1B receptors that are expressed in human intracranial arteries and by inhibiting nociceptive transmission through an action at 5-HT1D receptors on peripheral trigeminal sensory nerve terminals in the meninges and central terminals in brain stem sensory nuclei. These three complementary sites of action underlie the clinical effectiveness of the 5-HT1B/1D agonists against migraine headache pain and its associated symptoms.

Migraine timing cycle

1 Trigeminal activation and cerebral arterial vasodilation.

2 20-40 minutes later the neurochemicals CGRP, Neurokinin A, and Substance P are released by the migraine process from ganglia to inflame the trigeminal nerve, the arteries, and later the thalamus. 

3 At 2 hours the arteries vasodilate and are inflamed.  Blood pulsing through dilated, inflamed arteries causes pulsatile, pounding headache.

4 Past 3 hours the thalamus, also known as the pain center of the brain is turned on by the migraine process.

If I drop a brick on my foot the tissue of the foot is damaged and the pain is carried by pain nerves in the foot to the leg, to the spinal cord, and up to the thalamus in the brain where pain is registered.  Migraine is a chemical inflammatory condition affecting the 5th nerve, the arteries, and thalamus.  Phase 4 is also called central sensitization and this is the worst and most painful part of a migraine.  During central sensitization touch may be perceived as painful, so the head is sensitive to touch or wear glasses, or lie on one side in the bed.  This is called allodynia, a sure clinical sign of central sensitization.  Central sensitization is like sunburn.  Normally it doesn’t hurt to touch my arm, but if it does if it is sunburned.  Sunburn is like allodynia.

Migraine is an episodic disorder of headache lasting 4-72 hours.  After a migraine within a day or so the neuropeptides in the brain are metabolized and leave the body in a few days through the liver and then the toilet.  However, if one over treats with certain drugs (caffeine, NSAIDS, Tylenol, pseudoephedrine, triptans, hydrocodone, or butalbital drugs) then the drugs drive the cylic production of the inflammatory neurochemicals and the headache keeps on going.  At that point episodic migraine may be transformed to Chronic migraine which is defined as >15 headache days a month, eight of which meet the criteria for migraine.  This occurs because the body doesn’t have enough time to eliminate the drugs or the released neuropeptides and they stay in the brain and active this system so that 1-2-3-4 occur continuously, resulting in frequent, oftentimes daily headache.  In the 1988 International Classification of headache this syndrome was named “Rebound headache,” but now this term has been replaced by “Medication Overuse Headache.”  This is a common headache diagnosis and problem, comprising about 80-90 % of visits to a headache specialist.

The international classification of headache states that in general all migraine patients should limit caffeine, painkillers, and triptans to only 2 days a week.  This is the most that the body can tolerate and get rid of the drug and the neurochemicals without transforming into more frequent headaches.