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Migraine Prophylactic Guideline
Summary for Primary Care Physicians -
Section IV
Tamara Pringsheim1, W. Jeptha Davenport1, Gordon Mackie2, Irene
Worthington3, Michel Aubé4, Suzanne N. Christie5, Jonathan Gladstone6, Werner J. Becker1 on behalf of the Canadian Headache Society Prophylactic Guidelines Development Group Can J Neurol Sci. 2012; 39: Suppl. 2 - S41-S44 months at the target or optimal dose (or at the maximum Many of the recommendations in this guideline are tolerated dose if the usual target dose is not tolerated) before summarized here to provide a compact source of information for a prophylactic drug is considered inef ective. the primary care physician. More detailed discussion can be i . A daily headache diary (available for download from found in the main guideline document. Section 3, Table 2 can be is useful for assessing response to consulted for more detailed information on drug dosages, precautions, and side effects. The evidence for efficacy of individual drugs is based on a systematic review. Statements When should prophylactic therapy be considered effective?
regarding other aspects of migraine prophylaxis are based on a i. A prophylactic medication is usual y considered ef ective if general literature review and expert opinion (Expert consensus).
headache frequency is reduced by 50% or more, although Al patients for whom migraine drug prophylaxis is being lesser reductions in headache frequency may be worthwhile, considered should be educated regarding the common migraine particularly if the drug is wel tolerated. triggers and the important lifestyle factors which may potential y i . In addition to reduction in headache frequency, reductions in influence their headache frequency.
headache intensity and migraine-related disability need to be considered when judging the ef ectiveness of prophylactic To assist the physician in choosing an appropriate i i. Patients on migraine prophylaxis require periodic re- prophylactic medication for an individual with intermit ent evaluation both to monitor potential side ef ects, and to assess migraine headaches (headache on ≤ 14 days a month).
Who should receive prophylaxis?
How long should successful prophylaxis be continued?
i. Migraine prophylactic therapy should be considered in i. After six to 12 months of successful prophylactic therapy, patients whose migraine at acks have a significant impact on consideration should be given to tapering and discontinuing their lives despite appropriate use of acute medications and the prophylactic medication in many patients, although others trigger management / lifestyle modification strategies. may benefit from a much longer duration of prophylactic i . Migraine prophylactic therapy should be considered when the therapy. If headache frequency increases as the prophylactic frequency of migraine at acks is such that reliance on acute drug dosage is reduced, the dosage can be increased again or medications alone puts patients at risk for medication overuse the drug restarted if it has been discontinued. (rebound) headache. Medication overuse is defined as use of opioids, combination analgesics, or triptans on ten days a What advice should be given the patient with medication
month or more, or use of simple analgesics (acetaminophen, overuse when prophylaxis is being considered?
ASA, NSAIDs) on 15 days a month or more, i. When prophylactic drug therapy is started, the patient should i i. Migraine prophylaxis should be considered for patients with also be evaluated for the presence of medication overuse (see greater than three moderate or severe headache days a month when acute medications are not reliably ef ective, and for patients with greater than eight headache days a month even when acute medications are optimal y ef ective because of the risk of medication overuse headache. From the 1University of Calgary and the Hotchkiss Brain Institute, Calgary, AB; 2Richmond Hospital, Richmond, BC; 4McGil University, Montreal, QC; 5Ot awa Headache Centre, Ot awa; 6Gladstone Headache Clinic; 3Sunnybrook Health Sciences What constitutes an adequate prophylactic trial?
Centre, Toronto, ON, Canada.
i. Unless side ef ects dictate that the drug be stopped sooner, A RECEIVED NOVEMBER 9, 2011. FINAL REVISIONS SUBMITTED NOVEMBER 26, 2011.
Correspondence to: W.J. Becker, Division of Neurology, Foothil s Hospital, 1403 29th prophylactic medication trial should consist of at least two St. NW, Calgary, Alberta, T2N 2T9, Canada.
THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES definition above) and cessation of medication overuse should daily in the morning. The dose can be increased slowly (every be strongly encouraged to optimize the chances for success. one to two weeks) as necessary and tolerated, up to a maximum of 160 mg daily. Which prophylactic drug should be used?
iv. For metoprolol, the usual starting dose is 50 mg twice a day. In this section, prophylactic drugs are divided into those with The dose can be increased slowly (every one to two weeks) as a strong recommendation for use, and those with a weak necessary and tolerated to a maximum dose of 200 mg daily. recommendation. A strong recommendation means that the The long acting form may also be used. intervention could be used for most patients, and that the benefits b. Tricyclic strategy: amitriptyline (nortriptyline)
of therapy outweigh the potential risks. A weak recommendation i. Amitriptyline is a good initial migraine prophylactic drug. It indicates that the intervention could stil be applied to a majority may be particularly useful in patients with insomnia or of patients, but it would not be appropriate for many, often associated tension-type headache. because of potential side effects. With a weak recommendation, i . When starting amitriptyline prophylaxis for migraine, a low the balance between risks and benefits is closer or more uncertain, initial dose should be used in most patients (10 mg) and the and whether the intervention is suitable for a patient depends a dose should be built up slowly (10 mg every week or every two great deal on the clinical situation and the nature of the patient.
The medication may stil be very useful for selected patients. For i i. In patients without insomnia or in those who cannot tolerate more details, please consult Section 2 of the main guideline amitriptyline, nortiptyline in similar doses may be bet er tolerated and possibly ef ective. Al of the fol owing medications are recommended for migraine prophylaxis: 2. Low side effect strategy
• Strong recommendation: a. Drug: candesartan, lisinopril
i. High quality evidence for ef icacy: Topiramate, propranolol, i. Candesarten and lisinopril have evidence for ef icacy in i . Moderate quality evidence: nadolol, gabapentin, candesartan, migraine prophylaxis, and general y have few side ef ects, although each has only one control ed trial to date supporting i i. Low quality evidence: riboflavin, coenzyme Q10, magnesium its use. The target dose for candesartan is 16 mg daily, for lisinopril 20 mg daily. Candesarten is preferred because of fewer side ef ects, and because clinical experience with • Weak recommendation: lisinopril is more limited. Given the limited data for ef icacy i. High quality evidence for efficacy: divalproex sodium, and the limited clinical experience with both these drugs at this time, they should not be considered as substitutes for the i . Low quality evidence: venlafaxine, verapamil, lisinopril. more established drugs in the "first time strategy" under most A prophylactic drug should be chosen for an individual patient based on evidence for drug efficacy, side-effect profile, and the b. Herbal / vitamin / mineral: Mg citrate, riboflavin,
presence of any co-existing medical and psychiatric disorders.
but erbur, Coenzyme Q10 Prophylactic strategies: The prophylactic drugs can be
i . But erbur, riboflavin, magnesium, and co-enzyme Q have very organized into treatment strategies which are based on patient few side ef ects, and are evidence based options for migraine clinical features. These strategies are listed below. Note that drugs prophylaxis. These compounds are felt to have only modest in brackets have insufficient evidence from randomized trials to ef icacy, and should not be considered substitutes for "First recommend them for routine use. For more information on time" strategy drugs under most circumstances. dosages, precautions, and side effects, see Section 3, Table 2.
i i. Target doses are: but erbur 75 mg twice a day; riboflavin 400 mg daily; magnesium 300 mg (elemental magnesium) of 1. First time strategy (for the patient who has not had
magnesium citrate twice a day; co-enzyme Q10 100 mg three prophylaxis before). Although other drugs may be used for the times a day. initiation of prophylaxis in a patient for the first time (ie topiramate, gabapentin, low side effect strategies), the 3. Increased body mass index strategy: topiramate
fol owing appear particularly suited for first time prophylaxis.
i. Topiramate is a migraine prophylactic drug which, because of a. Beta-blocker strategy: propranolol, nadolol, and metoprolol
its propensity to promote weight loss, is particularly useful in patients who are overweight, in patients who are particularly i. Propranolol, nadolol, and metoprolol are good initial concerned about weight gain, and in patients with co-existent prophylactic drug choices for many patients with migraine. il nesses which might be exacerbated by weight gain (ie Some other beta blockers may also be useful, but have not been reviewed for this guideline. i . Topiramate should be started at a low dose (15 or 25 mg i . For propranolol the usual starting dose is 20 to 40 mg twice daily), and the daily dose should be increased slowly (by 15 daily. The dose can be increased slowly (every one to two every week or 25 mg every two weeks in order to improve drug weeks) as necessary and tolerated up to a maximum of 160 mg daily. The long acting form may also be used. i i. The usual target dose for topiramate in migraine prophylaxis i i. For nadolol, the usual starting dose is 20 to 40 mg given once is 100 mg daily. LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES 4. Hypertension strategy: propranolol, nadolol, metoprolol,
Although traditional y beta-blockers have been considered to candesarten, lisinopril predispose to depression, more recent studies suggest that this i. For patients with hypertension and migraine, refer to the is not the case. Canadian Hypertension Education Program's (CHEP) clinical practice recommendations which are updated 6. Additional monotherapy drug strategies: topiramate,
annual y and can be found at . The divalproex, gabapentin, pizotifen, flunarizine, (verapamil).
fol owing recommendations for managing patients with both i. Topiramate is a useful migraine prophylactic drug. Although migraine and hypertension have been reviewed with CHEP used for first time prophylaxis by some clinicians, it is not and are consistent with those evidence based included here in the "First time" strategies because of its recommendations. The specific angiotensin receptor blockers potential side ef ect profile. An exception is when it is used as and angiotensin converting enzyme inhibitors listed below are part of the increased body mass index strategy. For dosages, those with evidence for ef icacy in migraine prophylaxis. see increased body mass index strategy (Strategy 3). i . Simplification of medical regimens is known to improve i . Divalproex sodium (500 to 1500 mg daily) is a useful migraine adherence, and the use of the same medication for both prophylactic drug in patients when other prophylactic drugs migraine and hypertension may reduce the potential for drug have failed. Given its teratogenicity, it should general y be side ef ects and interactions. Recommended options are: avoided in women with child bearing potential and if used, a. Propranolol, nadolol, or metoprolol (for patients under age should only be used when the benefits are felt to outweigh the 60). (Some other beta-blockers may also be effective, but risks, and with appropriate contraception in place. have not been reviewed in this guideline.) i i. Gabapentin (1200 to 1800 mg daily) can be considered in b. Candesartan (Candesartan has also demonstrated efficacy patients when other prophylactics have failed. It has the for patients with isolated systolic hypertension) advantage of few drug interactions. Evidence for ef icacy is c. Lisinopril (ACE inhibitors have been found to be less less strong than for some other prophylactics. effective for lowering blood pressure as monotherapy in iv. Flunarizine (10 mg daily) can be a useful prophylactic when patients of African (black) origin).
other prophylactics have failed, but should be avoided in patients with a significant history of depression. Patients on i i. Combination therapy is often required to achieve blood flunarizine should be monitored for onset of depression. pressure targets. For patients requiring additional medication v. Pizotifen (1.5 to 4 mg daily) is an option for migraine for blood pressure control, adding a thiazide diuretic and / or prophylaxis when other drugs have failed. a calcium channel blocker to one of the above medications is vi. Verapamil (240 to 480 mg daily) can be considered for indicated (combinations of beta blockers and non- migraine prophylaxis when other drugs have failed, but the dihydropyridine calcium channel blockers like verapamil quality of evidence for ef icacy of verapamil is low. should be avoided due to the risk of heart block). iv. If adequate migraine prophylaxis is not achieved and the 7. Refractory patient strategy: multiple drugs (lower doses
blood pressure is at target, other migraine prophylactic than those usual y used are often used in combination therapy medications may be added. for at least one of the drugs to reduce side effects).
5. Depression / anxiety strategy: amitriptyline, venlafaxine,
i. The simultaneous use of more than one prophylactic drug may (nortriptyline) (dual therapy) be of benefit in patients with migraine refractory to i. Because of the advantages of monotherapy (less potential for i . The fol owing drug combinations may be useful in patients drug interactions and side ef ects), monotherapy with one of with refractory migraine, based primarily on non-randomized amitriptyline (individualize dose, build up slowly) or trials and clinical experience: beta-blockers and topiramate, venlafaxine (target dose 150 mg daily) should be considered in beta-blockers and divalproex sodium, beta-blockers and patients with anxiety and /or depression who require migraine amitriptyline, and amitriptyline and topiramate. prophylaxis. Experience with venlafaxine in migraine i i. Patients requiring prophylactic polypharmacy should be prophylaxis is limited. Nortriptyline may be an alternative considered for specialist referral. although less evidence-based choice. i . In some patients, particularly if good control is not achieved 8. Migraine during pregnancy strategy:
with monotherapy or if the patient is unable to tolerate adequate doses of the tricyclic, clinicians may need to treat the i. Migraine drug prophylaxis is best avoided during pregnancy migraine and the anxiety and / or depression with separate if at al possible. Strategies involving trigger management, maintenance of good hydration, regular meals, regular sleep i i. If SSRI – tricyclic co-therapy is planned, sertraline should be and at ention to other lifestyle factors should be considered. considered because of less potential for drug interactions. i . Magnesium is considered the safest migraine prophylactic Most other SSRIs, in particular fluoxetine, fluvoxamine, and during pregnancy. paroxetine, have a greater potential for significant drug i i. If migraine drug prophylaxis is necessary during pregnancy, interactions with amitriptyline and nortriptyline. the best choice is a beta-blocker (propranolol or metoprolol) iv. Certain prophylactic drugs can precipitate or exacerbate or if these are contraindicated or inef ective, amitriptyline or depression, and should be typical y be avoided (flunarizine), or used with caution (topiramate) in patients with depression. THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES 9. Migraine during lactation strategy:
i. Migraine prophylaxis should be avoided during breast Prophylactic migraine therapy is general y underutilized. If feeding, if possible. at ention to life style factors, trigger management, and acute drug i . Magnesium and the beta-blockers (propranolol, metoprolol, therapy does not provide sufficient relief from symptoms, and nadolol) are the preferred choices if migraine prophylaxis prophylactic drug therapy should be strongly considered.
is necessary during lactation. i i. Amitriptyline and nortriptyline may be considered for prophylaxis during lactation if magnesium and beta-blockers are contraindicated or inef ective. iv. Although divalproex sodium is considered compatible with breastfeeding, it may be best avoided due to the possibility of pregnancy in this population. Other Drugs
1. Methysergide is an effective migraine prophylactic, but
because of side-effects is not recommended for routine use.
When methysergide is used, specialist supervision is 2. Imipramine, trimipramine, desipramine, clomipramine, and doxepin are not recommended for routine use for migraine 3. Although there is good evidence for efficacy in chronic migraine, botulinum toxin type A is not recommended for prophylaxis of episodic migraine in patients with less than 15 headache days per month. We found high quality evidence that botulinum toxin type A is no bet er than placebo for the prophylaxis of migraine in such patients.
4. Feverfew is not recommended for the prophylaxis of migraine.
We found moderate quality evidence that feverfew is no bet er than placebo for the prophylaxis of migraine.
5. Selective serotonin reuptake inhibitors and clonidine are not recommended for the prophylaxis of migraine.



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