Migraine headaches are characterised by severe and often pulsating or throbbing pain.  They are often limited to a localised area and accompanied by photophobia, phonophobia, osmophobia, and nausea/vomiting.  They may be preceded by an "aura" or prodrome (classical migraine) of mood and appetite changes and visual disturbances OR they may appear without warning (common migraine).  Some clinicians classify the prodrome as behavioural or central changes that may precede the attack by as much as 48 hours and limit the term aura to describe the 30 to 60 minute period of visual, sensory, or motor changes immediately preceding the attack.  The trigeminal neurones of the dura mater have been implicated in the pathology of migraine.
Theories of migraine etiology:
Vascular Theory -- The oldest of the theories states that vascular constriction occurs during the prodrome.  This may be mediated by a release of serotonin, thus serotonin induced vasoconstriction.  Following this vasoconstriction, vasodilatation occurs during the actual headache.  It has been theorised that this could be due to a depletion of serotonin.  More current theories associate the vasodilatation with either  the action of serotonin at 5-HT_2B receptors or the release of vasodilatatory substances (neuropeptides and/or  neurokinins such as calcitonin gene-related peptide, substance P, and neurokinin A) that cause dilatation.  The vasodilatation may be related to or actually be responsible for the opening of anastomoses or shunts that divert blood flow from cerebral capillaries.  This decrease in blood flow results in local areas of cerebral ischaemia and pain.  Conversely, some clinicians believe that the pain may be associated with the vasodilatation directly or vascular extravasation of plasma which then stimulates sensory pain fibres.   While this theory works well for classical migraine, it obviously does not completely explain common migraine, where the prodrome (and presumably the initial vasoconstriction) does not occur.

Spreading Depression Theory -- The theory supports the idea that some impetus causes a small local area of the brain to reduce its electrical activity.  The theory is based upon reduced activity that has been mapped, originating in the occipital lobe and spreading anteriorly.  This depression of cortical electrical activity has been correlated with a secondary reduction in blood flow.  (In simpler terms -- decreased activity leads to decreased blood flow leads to ischaemia.)

Serotonin Theory -- This theory is actually a broad statement that supports the role serotonin plays in the pathogenesis of migraine.  It is supported by increases in both serotonin and 5-HIAA during a migraine attack.

Other Hypotheses support the role that neurotransmitters or hormones (glutamate, nitric oxide, opioids, oestrogens) and changes in anatomy (raphe nucleus, vasculature) play in migraine development.  These may be either primary or secondary factors in the pathogenesis.  In all likelihood, migraines are the result of activities from each of these theories.
 

Triggering Factors -- Migraine attacks may be precipitated by a number of factors, including tyramine containing (red wine, aged cheeses) and other (chocolate, alcohol, cold cuts) foods, irregular sleep patterns, acute changes in stress (the attacks often occur AFTER the stressful situation has passed), sudden shifts in time zones, altitude, or barometric pressure, and the menstrual cycle (implying a role for oestrogen, which may influence serotonin activity).
 
Treatment of Migraine
Serotonin Agonists -- Sumatriptin, Zolmitriptan, Naratriptan, Rizatriptan (almotriptan, eletriptan, frovatriptan)
These agents are relatively selective agonists for the 5-HT_1B/1D serotonin subreceptor.  It is believed that these selective serotonin agonists may be working through two and possibly three distinct mechanisms to benefit the patient.
Firstly, these drugs may either directly cause vasoconstriction, thus reducing the vessel size to its' pre-headache diametre (a 5-HT_1B  effect) or, as is generally believed, prevent the release of the vasodilatatory substances from trigeminal neurones (a 5-HT_1D effect).

Secondly, these drugs may be preventing the dural plasma protein extravasation from the vessels, either by preventing vasodilatation or by inhibiting the release of substances that permit protein release.

Lastly, these drugs have demonstrated an ability to prevent pain transmission and to have anti-nociceptive properties in several models of pain.  Trigeminal action potentials are suppressed in response to administration of sumatriptan and similar drugs.  This has been associated with a decrease in the release of CGRP, substance P, and other neuropeptides that are known to mediate pain.  Other evidences suggests that this action may be mediated by cholinergic pathways and/or that this pathway may mediate opiate anti-nociception.


These agents will have an onset of action of approximately 12 min if injected or 1 to 2 hours if taken orally.  (NOTE that the duration of action, especially of injectable sumatriptan, may be shorter than the duration of migraine attack, necessitating additional treatment.)  Approximately 71% of patients report total alleviation of a migraine attack with this class of drugs.  Almost 100% have at least partial relief.   In addition to analgesia, patients report that photophobia and phonophobia are also attenuated.  Rizatriptan appears to have a faster onset of action than sumatriptan.  Naratriptin has a slightly greater bioavailabilty and longer half-life than others of the class.  Otherwise, the four drugs are very similar in action and efficacy.

Side Effects -- These agents may produce feelings of warmth, paraesthesias, dizziness, and tightness (3%) or heaviness (2%) in the chest.  Rarely will patients experience chest pain.  However, there are clinical reports of sumatriptan-induced angina (presumably by coronary vasoconstriction).  Therefore, these agents are contraindicated in any patients with coronary artery disease or Prinzmetal's angina.  Additionally, they should be used cautiously and only if necessary in patients with hypertension or other risk factors for ischaemic heart disease.
 

ERGOT ALKALOIDS -- This family of natural and semi-synthetic drugs arise from the fungus Claviceps purpurea, which often infects grains (particularly rye).  They have numerous sites of action with an equally complex pharmacologic profile.
 

	alpha-Adrenergic	Dopaminergic	Serotonergic	Smooth Muscle
Bromocriptine	Antagonist -	Agonist +++	Antagonist -	None
Ergonovine	Agonist +	Agonist +	Antagonist -/PA	Contraction +++
Ergotamine	Antagonist --/PA	None	Agonist +/PA	Contraction +++
Dihydroergotamine	Antagonist -/PA	Antagonist -	Antagonist -/PA	Contraction +
Methysergide	Agonist +/None	Agonist +/None	Antagonist ---/PA	Contraction +/0
LSD	None	Agonist +++	Antagonist --	Contraction +

Effects of ergot alkaloids
CNS -- Hallucination (5-HT₂ Agonist) and Decreased prolactin secretion (Dopamine Agonist)

Vascular Smooth Muscle -- Effects are drug/species/vessel specific.  In general, they produce intense and prolonged vasoconstriction (alpha adrenergic and serotonergic effects)

Uterine Smooth Muscle -- Intense contraction (greater at term) with potential for spontaneous abortion.

Bronchial Smooth Muscle -- Little Effect.

Gastrointestinal Smooth Muscle -- Varies greatly with individual, but produces contraction with concomitant nausea/vomiting and diarrhoea.
 

Ergotism -- Ergot Toxicity (St. Anthony's Fire) is characterised by hallucinations and delusions, severe nausea/vomiting/diarrhea, and vasospasm that first manifests as cold extremities and progresses to necrosis of ischaemic tissues, gangrene and death (including intestinal necrosis).

Uses of ergot derivatives:

Migraine -- Ergotamine and dihydroergotamine are used most effectively.  They are more effective if given during the prodrome and are less likely to alleviate the attack once started than newer, more selective drugs.  They may be given orally, rectally (if vomiting prohibits per os dosing) or nasally (for quicker onset of action).

Hyperprolactinaemia and post-partum lactation suppression -- Bromocriptine is used for the former and formerly used for the latter for its strong dopaminergic activity.

Post-partum haemorrhage -- Ergot alkaloids via vasoconstriction and uterine contraction, will decrease haemorrhage following delivery.  However, the patient must be monitored closely to prevent adverse reactions.

SEROTONIN ANTAGONISTS
Only one class of drugs is marketed that acts as selective serotonin antagonists
These agent competitively inhibit the action of serotonin at the 5-HT₃ receptor (peripherally at the enteric and somatic nerves on the gut and possibly centrally in the area postrema)

Ondansetron and Granisetron. -- These drugs exert the above action, thereby decreasing serotonin-mediated emesis.  They are approved for prophylaxis of chemotherapy-induced and post-surgical nausea and vomiting.  Side effects for both include headache, constipation, dizziness, musculoskeletal pain,  and for granisetron, somnolence and diarrhoea.  Overdoses have produced the following toxic effects:  transient blindness, constipation, and vasovagal responses resulting in second degree heart block.  These have occurred in only one patient each.

Alosetron -- This drug acts by the same mechanism, however it was approved for the treatment of irritable bowel syndrome (IBS) in women that presents primarily as diarrhoea.  It had no beneficial effects in male patients.  It was removed from the market voluntarily by the manufacturer due to incidences of ischaemic colitis and severe constipation that resulted in bowel obstruction and, in some cases, bowel rupture.  Numerous, post-marketing cases of this nature required hospitalisation.

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