Specific Migraine-Preventive Agents: Serotonin Antagonists

By | January 31, 2015

The antiserotonin, migraine-preventive drugs are potent 5-HT2B- and 5-HT2C-receptor antagonists, whereas metachlorophenyl piperazine (mCPP), a 5-HT2B- and 5-HT2C-receptor agonist, induces migraine in susceptible individuals. Methysergide, cyproheptadine, and pizotifen, effective migraine prophylactic drugs, are 5-HT2B-and 5-HT2C-receptor antagonists, whereas ketanserin, a selective 5-HT2A- and a poor 5-HT2B- and 5-HT2C-receptor antagonist, is not.

mCPP, a major metabolite of the antidepressants trazodone and nefazodone, induces migraine hours after the immediate pharmacologie response to the drug (monitored by elevation of plasma cortisol and prolactin) is over. Gordon et al. found that mCPP induced headache in both migraineurs (five of eight) and non-migraine controls (four of 10). No significant differences were found between the migraineurs and normal subjects in terms of their neuroendocrine or headache responses to mCPP, but there were highly significant associations between the cortisol responses and headache severity and duration.

Pizotifen and methylergometrine are potent rabbit jugular vein endothelial cell 5-HT2-receptor antagonists. Activation of 5-HT2B or 5-HT2C receptor by mCPP or endogenously released 5-HT could dilate cerebral vessels. Vasodilation, however, is neither necessary nor sufficient to cause headache, but endothelium-derived NO can activate sensory trigeminovascular fibers resulting in CGRP release, which mediates pial artery vasodilation and neurogenic inflammation. mCPP itself can produce extravasation in the durai membrane, which can be blocked by selective 5-HT2B antagonists.

Methysergide is also a 5-HT1-receptor agonist, but has lower affinity for the 5-HT1- than for the 5-HT2-binding site. Methysergide-induced contraction of the isolated saphenous vein of dog is also mediated by 5-HT1B receptors. Chronic, but not acute, treatment with methysergide attenuates durai plasma extravasation following electric stimulation of the rat trigeminal ganglion in the Moskowitz model. The difference between acute and chronic drug administration could be due to the accumulation of the active metabolite, methylergometrine. Methysergide (or methylergometrine) presynaptically could inhibit the release of CGRP from perivascular sensory nerves.


Methysergide is a semisynthetic ergot alkaloid that is structurally related to methylergonovine. It is a 5-HT2-receptor antagonist and 5-HT1B/D agonist. It was probably the first drug developed for migraine prevention, but its usefulness is limited by reports of retroperitoneal and retropleural fibrosis associated with long-term, mostly uninterrupted, administration.

The AHCPR Technical Report identified 17 controlled trials of methysergide for migraine prevention. Four placebo-controlled trials suggested that methysergide was significantly better than placebo at reducing headache frequency.

Four comparison trials showed no statistically significant differences between methysergide and pizotifen. Two trials that directly compared methysergide and propranolol failed to demonstrate any statistically significant differences between these treatments. The only trial that compared methysergide with metoprolol reported an unusually low response to metoprolol (6%) and thus a mis-leading relative increase in methysergide efficacy.

Methysergide was associated with a higher incidence of AEs than was placebo. AEs noted in trials and clinical practice include transient muscle ache, claudication, gastrointestinal complaints (nausea, vomiting, abdominal pain, and diarrhea), leg cramps, hair loss, weight gain, dizziness, giddiness, drowsiness, lassitude, paresthe-sia, and hallucinations. Frightening hallucinatory experiences after the first dose are not uncommon. AEs were no more common with methysergide than with pizotifen. The major complication of methysergide is the rare (1/W) development of retroperitoneal, pulmonary, or endocardial fibrosis. The duration of the trials reviewed here was too short to detect them.

Methysergide is indicated for the treatment of migraine and cluster headache. The dose ranges from 2 to 8 mg/day, with the higher doses being given two or three times a day. Some clinicians find that they can use higher doses, up to 14 mg/day, without AEs and with higher efficacy. To minimize early AEs, patients can start with a dose of 1 mg/day and increase the dose gradually by 1 mg every two to three days. (This can be accomplished by breaking the 2mg tablets if 1 mg tablets are not available.) Methysergide, in generai, should not be taken continuously for long periods, because doing so may produce retroperitoneal fibrosis. Instead, the drug should be given for six months, stopped for one month, and then restarted. To avoid an increase in headache when methysergide is stopped, the patient should be weaned off the drug over a one-week period. Some authorities use methysergide on a continuous basis with careful monitoring, which includes auscultation of the heart and yearly echocardiography, chest X-ray, and abdominal MRI. The drug should be discontinued immediately on suspicion of pulmonary or cardiac retroperitoneal fibrosis.

Contraindications to methysergide use include pregnancy, peripheral vascular disorders, severe arteriosclerosis, coronary artery disease, severe hypertension, thrombophlebitis or cellulitis of the legs, peptic ulcer disease, fibrotic disorders, lung diseases, collagen disease, liver or renal function impairment, valvular heart disease, debilitation, or serious infection. Patients who receive methysergide should remain under the supervision of the treating physician and be examined regularly for development of pulmonary/cardiac or peritoneal fibrosis or vascular complications.

Methysergide is an effective migraine preventive medication that is an appropriate consideration in resistant headaches with a high attack frequency. All of the open and controlled studies attest to its efficacy. In addition to being effective in reducing attack frequency, it often acts synergistically with ergotamine for break-through attacks. Due to its AEs profile, it should be reserved for severe cases in which other migraine-preventive drugs are not effective.


Cyproheptadine, an antagonist at the 5-HT2, histamine Hl5 and muscarinic cholinergic receptors, is widely used in the prophylactic treatment of migraine in children. Curran and Lance found cyproheptadine more effective than placebo but less effective than methysergide. Cyproheptadine is available as 4mg tablets. The total dose ranges from 12 to 36 mg/day (given two to three times a day or at bedtime). Common AEs are sedation and weight gain; dry mouth, nausea, lightheadedness, ankle edema, aching legs, and diarrhea are less common. Cyproheptadine may inhibit growth in children and reverse the effects of SSRIs.


Pizotifen, a 5-HT2-receptor antagonist structurally similar to cyproheptadine, is not available in the United States. The U.S. Headache Consortium Guidelines found that evidence was inconsistent for its efficacy from 11 placebo-controlled trials and 19 comparisons with other agents (). Analysis of the placebo-controlled trials suggested a large clinical effect that was statistically significant. In direct comparisons with other agents known to be efficacious for migraine prevention, no significant differences were demonstrated between pizotifen and flunarizine, methysergide (), naproxen sodium, or metoprolol. However, in the 26 trials reviewed, pizotifen was generally poorly tolerated. Substantial weight gain, tiredness, and/or drowsiness were frequently reported. Pizotifen was associated with a high rate of withdrawals due to AEs. Controlled and uncontrolled studies in Europe have shown this drug to be of benefit in 40% to 79% of patients. The dose recommendation is 0.5 to 1 mg, one to three times daily by titration. Side effects include drowsiness and weight gain.