• Migraine
  • Clinical Presentations:
    • Often accompanied by brief aura (visual scotomas, hemianopia, beach abnormalities
    • Severe, throbbing, usually unilateral headache (few hours to a few days in duration)
    • Familial disease:
      1. more common in women
      2. onset: early adolescence; less common in older patients
      3. Migraine associated with stress
      4. Headache frequency: Range -- to or more per week to once a year
  • Migraine Pathophysiology:
    •  Vasomotor mechanism -- inferred from:
      1. increased temporal artery pulsation magnitude
      2. pain relief (by ergotamine) occurs with decreased artery pulsations
    • Migraine attack associated with (based on histological studies):
      • sterile neurogenic perivascular edema
      • inflammation (clinically effective antimigraine medication reduce perivascular inflammation)

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    • Serotonin involvement (evidence for):
      • Throbbing headache: associated with decreased serum and platelet serotonin
      • Presence of serotonergic nerve terminals at meningeal blood vessels
      • Antimigraine drugs influence serotonergic neurotransmitter
      • Some migraine chemical triggers may work through serotonin pathways, i.e. decreasing estrogen (associated with the menstrual cycle) and increased prostaglandin E₁.

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  • Drug Treatment (migraine):
    • Ergotamine: best results when drug administered prior to the attack (prodromal phase) -- less effective as attack progresses
      • Ergotamine may be combined with caffeine; caffeine promotes ergot alkaloid absorption
      • Vasoconstriction associated with excessive ergotamine use may be long-lasting and potentially severe.
      • Ergotamine: availableby oral, IV,or intramuscular routes of administration
    • Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine (nasal or oral formulations dihydroergotamine are being assessed)
    • Sumatriptan (Imitrex): alternative to ergotamine for acute migraine treatment; not recommended for patients with coronary vascular disease risk.
      • formulations: subcutaneous injection, oral, nasal spray
      • selective serotonin-receptor agonist (short duration of action)
      • probably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasal spray)
      • subcutaneous injection: relief within two hours for 70% -- 80% of patients
    • New Triptans:
      •  Zolmitriptan--more rapid onset than oral sumatriptan (Imitrex)
      •  Naratriptan--
        • slower onset; longer half-life
      •  Rizatriptan-- more rapid onset than oral sumatriptan
    • Analgesics:-- may be sufficient for model/moderate migraine
      • Aspirin
      • Aspirin combination (Fiorinal --aspirin + caffeine + butalbital)
      • Acetaminophen
      • Acetaminophen combinations (Midrin-- acetaminophen + isometheptene + dichloralphenazone)
      • Excedrin Migraine: acetaminophen + aspirin +caffeine
      • Oral opioids: usual systemic opioid adverse effects
      • Butorphanol nasal spray --opioid agonist-antagonist
        • effective for moderate/severe migraine; psychiatric reactions/drug abuse have been reported
    •  Drug-Drug interactions:
      •  A triptan should not be used within one-day following another triptan or any ergotamine-containing drug (vasoconstriction may be additive)
      •  Ergot derivatives should not be taken or until 24 hours or more following a triptan
      •  "Serotonin Syndrome": weakness, hyperreflexia, incoordination following use of a selective serotonin reuptake inhibitor (SSRIs) with a triptan
      •  All triptans except naratriptan are contraindicated in patients taking MAO inhibitors (or within two weeks of discontinuation of MAO inhibitors)

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  • Migraine Prophylaxis:
    •  Ergonovine
    •  Methysergide (Sansert)
      • effective in about 60% of patients
      •  40%: frequency of toxicity
      • NOT effective in treating an active migraine attack or even preventing an impending attack.
      • Methysergide toxicity:
        • retroperitoneal fibroplasia
        •  subendocardial fibrosis
        • The side effects are the basis of recommending a 3-4 week drug holiday every six months
    •  Propranolol (Inderal) -- prophylaxis- Most common for continuous prophylaxis
      •  propranolol (Inderal) and  timolol (Blocadren) FDA approval for this indication
      • note all beta-blockers: contraindicated in asthmatics
      • best established drug for migraine attack prevention.
    •  Amitriptyline (Elavil, Endep) -- prophylaxis-- most frequently used among the tricyclic antidepressants
    •  Valproic acid (Depakene, Depakote) --effective in decreasing migraine frequency; FDA approval for this indication;
    •  Nonsteroidal antiinflammatory drugs (NSAIDs) -- naproxen sodium; flurbiprofen -- used for attack prevention and aborting acute attack
• Hyperprolactinemia:(amenorrhea, infertility inwomen, galactorrhea)
  • may be caused by:
    • prolactin-secreting anterior pituitary tumors
    • centrally-acting anti-dopaminergic drugs (antipsychotic drugs)
  • Drug treatment: hyperprolactinemia
    •  Bromocriptine (Parlodel) -- very effective
      • occasional postpartum cardiotoxicity
    •  Pergolide (Permax): lactation suppression

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• Postpartum Hemorrhage:
  •  Ergot Derivatives: used to control late uterine bleeding (NEVER given before delivery, given before delivery an increase in internal and fetal mortality occur)
  • Ergot alkaloids cause uterine contractions (prolonged, powerful spasms, unlike natural labor)
•   Ergot Toxicity:
  • Most common:
    • gastrointestinal -- diarrhea, vomiting, nausea
      • Mechanism of Action:
        1. medullary vomiting center stimulation
        2. activation of gastrointestinal serotonergic receptors
      • Use of methysergide (Sansert) (prophylactic migraine agent) any limited by GI toxicities
  • Other toxicities:
    •    Vasospasm -- overdosage with drugs such as: ergotamine and ergonovine
    • Dangerous toxic effect
    • gangrene, possible amputation
      • most vasospastic reactions involves the extremities
      • Bowel infarction (secondary to mesenteric artery vasospasm) may also occur
    • Serious vasospastic reactions may be reversible by high-dose  nitroprusside or   nitroglycerin
  • Chronic toxicities:
    • Methysergide (Sansert): -- retroperitoneal fibroplasia, subendocardial fibrosis, fibroplastic changes in the pleural cavity.
      • Slowly developing
      • Presenting symptoms:
        1. hydronephrosis (ureter obstruction)
        2. cardiac murmur (valve deformation)
    • Methysergide (Sansert) CNS effects {stimulation/loose nations}
  •   Contraindications for Ergot Alkaloids Use:
    • Presence of vascular or collagen disease

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