See my new special section on New Treatments for Migraine.

Preventive therapy should be based on general principles including the following (Silberstein and Lipton):{9}
1) When two or more attacks occur per month and produce disability lasting more than three days
2) When symptomatic medications are contraindicated or ineffective.
3) When abortive medication is required more than twice a week or for when special circumstances that exist, that is, a rare headache attack that produces profound disruption.
The major medication groups include: calcium channel antagonists, beta adrenergic blockers, antidepressants, serotonin antagonists, and anticonvulsants. (Table 10):

Table 10. Preventive therapy for migraine

Drug	Daily oral dosage range
BOTOX (see new Rx )	30-200 Units
Beta-Blockers
Propranolol*	40-240 mg
Nadolol*	20-80 mg
Atenolol**	50-150 mg
Timolol*	20-60 mg
Metoprolol**	50-300 mg
Calcium channel blockers
Verapamil	120-480 mg
Diltiazem	90-180 mg
Nifedipine	30-120 mg
Serotonin antagonists/agonists
Cyproheptadine	4-8 mg
Methysergide	4-6 mg
Methylergonovine	0.2 mg tid or qid
Tricyclic antidepressants
Amitriptyline	10-200 mg
Nortriptyline	10-150 mg
Doxepin	10-200 mg
Imipramine	10-200 mg
MAO inhibitors
Phenelzine	30-90 mg
Serotonin-reuptake inhibitors
Fluoxetine	10-30 mg
Trazodone	50-300 mg
Anticonvulsants
Phenytoin	300-800 mg
Carbamazepine	200-800 mg
Divalproex sodium	250-1,500 mg
Gabapentin	300-1800 mg
Topamax*®	25-200 mg
Keppra**®	250 mg bid -> 3.0 gm
*Topamax is not yet FDA approved for Migraine  ( as of 5/14/2001) Increase dose slowly, e.g. 25 mg/wk
**Keppra is not yet FDA approved for Migraine ( as of 5/15/2001) Increase dose , e.g. 500 mg/wk to 1.5-3.0 gm
NSAIDs
Naproxen	550-1,100 mg (eg, 275 mg tid)
Meclofenamat	100-400 mg (eg, 50 mg tid)
Flubiprofen	50-200 mg
Ibuprofen	300-1,200 mg
Alpha-Adrenergic blockers
Clonidine	0.1 mg bid or tid
KEY * Nonselective. ** Selective. MAO: Monamine oxidase. NSAIDs: Nonsteroidal anti-inflammatory drugs.

Cost Review in Medical Letter

For cluster headache, if these drugs fail, methysergide or lithium may be utilized. Methysergide is an extremely effective agent for cluster. It is related chemically to ergotamine tartrate and closely to lysergic acid, but it is relatively free of vasoconstrictor effect and is believed to be an antagonist of serotonin. Acutely, it may rarely cause a confusional state requiring its withdrawal. The major concern as to its chronic use is the development of retroperitoneal fibrosis.{228,229} This complication develops after long-term (usually more than 1 year) continuous methysergide therapy, often at doses of 8 to 16 mg per day. It is currently believed that such complications can be avoided by gradually discontinuing the drug (to avoid rebound) over 2 to 3 weeks and stopping it for 3 to 4 weeks every 6 months.

Calcium Channel Blocking Drugs
Specific calcium channel blockers were originally intended for use in cardiovascular disease but show great promise as prophylactic agents in the treatment of migraine. Diltiezam,{230} verapamil,{231} nifedipine,{232} nimodipine,{160,233,234} and flunarizine{235} have all been reported to be effective in migraineurs. The mechanism of action of this class of drug in headache is unknown but may relate to their antivasoconstrictor activity{236} or to non-vascular processes such as inhibition of platelet aggregation, serotonin release,{231} or serotonin and histamine receptor blockade. Calcium entry blockers do not necessarily share common molecular structures and may act at different sites on the calcium channel. For instance, nimodipine, nifedipine and nitrendipine are dihydropyridines, flunarizine is a piperazine derivative and verapamil is structurally related to papaverine. It is now known that many other drugs have calcium channel blocking activity including some useful for migraine, such as amitriptyline and cyproheptadine.{236}
Data suggest that there may be a delay of up to 8 weeks before any response to these agents is seen.{160,230,233} Verapamil may be an exception with improvement occurring within one or two weeks of initiation. At the current time verapamil is my first choice for most patients with migraine headaches. Therapy is initiated with 80mg/d for 2 days, then 80mg 2/d for two days, and then 80mg 3/d for two days, and then switch to the 240mg sustained release form. Sometimes patients report an initial increase in headache and headache improvement often requires weeks of treatment. The dose of verapamil may then be increased to 240mg sustained release in the morning and 120mg sustained release in the evening, and later to 240mg sustained release twice per day. The primary side effect of verapamil is constipation which may be avoided with the use of stool softeners such as Fiber-Con. Other side effects vary and depend upon the individual drug, but do include dizziness, headache (particularly with nifedipine), depression, vasomotor changes, tremor, orthostatic hypotension, and bradycardia. Calcium channelers are especially useful in patients with comorbid hypertension and in patients with a contraindication to beta-blockers, such as asthma and Raynaud's disease. These agents, particularly verapamil, may have a particular advantage in patients with prolonged aura or vertibular vascular migraine. There is little comparative data on the efficacy of various calcium channel blockers.

Beta-blockers
Beta-blockers, particularly propranolol have been the most widely used prophylactic agents in migraine. They have shown to be 60-80% effective in producing greater than 50% reduction in attack frequencies. Many controlled studies{237} have shown that propranolol, metoprolol, timolol, nadolol, and atenolol reduce the frequency of attacks in patients who have migraine with and without aura.{158,219} All beta-blockers do have side effects such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depression and, rarely esophageal spasm. Less common side effects include orthostatic hypotension, significant bradycardia, impotence, and aggravation of intrinsic muscle disease. Such drugs have specific contraindications including asthma, heart block and congestive heart failure. Long acting forms of propranalol may be helpful in some patients, but are significantly more expensive and less flexible in dosage. Studies have been carried out with other beta-blocking agents but none have been superior to propranalol. There are clearly some patients who are responsive to one and not to other drugs in this class, so if a patient does not respond to propranalol it is reasonable to proceed with nadolol, (80-240 mg), atenolol (50-100 mg) or timolol (20-100 mg). Determination of plasma propranolol concentrations have demonstrated that different responses to the same oral dose do not depend on different plasma levels of the drug.{238} Therefore, clinical response to such agents would seem to be linked to individual sensitivity. Several articles and text discuss the overall approach to the treatment of vascular headaches.{14,15,207,238}

Tricyclic Antidepressants
Propranolol was compared to amitriptyline by Zieglar et al.{239} and found to be equally effective but that has not been my experience. Many regard amitriptyline to be the drug of choice in mixed headache particularly when there is a muscle contraction and depression factor. Time and experience will indicate whether tricyclic antidepressants are really as effective as the beta blocking drugs in pure vascular headaches. "The ideal prophylactic agents for the therapy of migraines should be early active, possess long-term efficacy with few side effects and a convenient dosing schedule, and truly prevent attacks from occurring rather than merely decreasing their severity."{240} The fact is that no such ideal agent has been found.
The tricyclic antidepressants most commonly used for migraine and tension-type headache prophylaxis include amitriptyline, nortriptyline, doxepin, and protryptyline.{219} Side effects of tricyclic antidepressants are common and involve antimuscarinic effects such as dry mouth and sedation. These drugs also increase appetite and therefore produce weight gain. One should also be aware of potential cardiac toxicity and orthostatic hypotension. Tricyclics have also been used cautiously in combination with MAO inhibitors and with beta-blockers. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline are the newest types of antidepressants that may be effective in some headache patients.

Serotonin Antagonists
Methysergide is a semisynthetic ergot 5-HT2 receptor antagonist that displays affinity for the 5-HT1 receptor.{9 } Methysergide (Sansert) is an effective migraine prophylactic in 60% or more of migraineurs and may be especially effective in cluster headache. The side effects of methysergide include transient muscle aching, claudication, abdominal distress, nausea, weight gain, and hallucination. The major complication is the rare (1 in 5000) development of retroperitoneal, pulmonary, or endocardial fibrosis.{241,242} It is believed that this major complication may be prevented by having a medication-free interval of four weeks following each six months of continuous treatment. The dosage should not exceed three of the 2mg pills (6mg total daily dose).
Other agents such as cyproheptadine, pizotifen, and the use of anticonvulsant medications is discussed further elsewhere.{9, 207}
Another approach to migraine therapy is that of vigorous bilateral compression and massage of the frontal branch of the superficial temporal artery, started at the first sign of visual aura. The technique was successful in blocking 81% of attacks in 15 patients.{243} The authors speculated that the blood vessels of the extra cranial circulation as well as those of the Circle of Willis have perivascular nerve fibers of trigeminal origin. It may well be that these nerve fibers, rather than the dilation of blood vessels with release of vasoactive substances mediate the pain syndrome of migraine. Digital massage might stimulate the nerve endings and for some reason stop the ensuing pain phase of the headache.
As pointed out by Silberstein and Lipton,{9} the goals of treatment are to relieve or prevent pain in the associated symptoms of migraine and optimize the patient's ability to function normally. The patient should learn to identify and avoid headache triggers. The wide variety of drug therapies available, numbering over 400, attest to the fact that no particular therapy or combination of drugs is completely effective. The management of the patient with migraine is a complex problem requiring evaluation and elimination of possible precipitating factors, including psychogenic ones, as well as vigorous management of the acute attack and attempts at prevention of recurrent episodes. The care of the migraine patient continues to represent, in many instances, a major therapeutic challenge.

  Therapy for Chronic Daily Headache

First one must be sure of the diagnosis, that is, that the chronic daily headache with which the patient suffers is not due to some other specific cause.  One must know that the condition is primarily a rebound phenomenon. The headaches may have initially been standard common migraine ( Migraine without aura) which have been transformed by analgesic abuse, trauma, subarachnoid hemorrhage, or brain surgery into chronic daily headache.  If it is clear that analgesic overuse is the major cause a detailed history of prior headaches and particularly the amount and type of medication that the patient is taking must be elicited.  Often patients are receiving analgesic medication from a variety of physicans and every effort must be made to keep all health care providers in communication.  If one assumes care of the patient, both patient and physican should agree that there should be only one prescribing physician involved.  Following suggestions from Ninan Matthews I have had patients keep a daily chart of headache intensity and a detailed listing of all analgesic preparations being used, including all Over the Counter (OTC) medications, vitamins, alternative medical therapies and acute emergency room visits.  The patients need to be firmly convinced that a gradual reduction in medication  ( 10% reduction in number of pills taken each week ).

Patients should be started on a preventive regimen which may include calcium channel blocking medications, anticonvulsants, beta-blockers, and BOTOX.  Combination therapy may be appropriate, for example:  verapamil, Topamax and BOTOX. The patient should be made to understand that no preventive regimen is likely to be effective until a MAJOR reduction in analgesic medication is achieved.  In some situations, when out-patient "detox" is ineffective an in-patient stay in a facility or service that understands analgesic abuse  may be needed.  Again, coordination and communication among all health care providers is mandatory.