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Journal compilation 2008 American Headache Society Expert Opinion
Beta-Blockers for Migraine
Randolph W. Evans, MD; Paul Rizzoli, MD; Elizabeth Loder, MD, FACP; Dhirendra Bana, MD Sometimes the observations by one astute clini- blood pressures are similarly elevated. There is no cian of one patient lead to new treatments. In 1966, prior history of hypertension. Screening blood tests Rabin et al1 in a study of propranolol to prevent angina, noted that a 59-year-old man reported that his Would propranolol be a good choice for preven- migraines and angina improved on propranolol but tion of her migraines and treatment of her hyperten- the migraines returned after a crossover to placebo sion? Are other beta-blockers effective for migraine medication. Since then, propranolol has become a prevention? What titration schedule do you recom- first-line agent for migraine prevention with increas- mend? What are the lower limits of blood pressure ing caveats, some real, others questionable.
and pulse at which you will initiate treatment with abeta-blocker for migraine prevention? Does propra-nolol have an increased risk of stroke when used for CLINICAL HISTORY
the treatment of hypertension? Is propranolol con- A 38-year-old woman has had migraine without traindicated in migraine with prolonged aura? Are aura of moderate to severe intensity for 15 years.
there other contraindications for beta-blocker use? Is For the last 2 years, the headaches have been occur- propranolol use associated with weight gain? Depres- ring about 1-2 times per week with an inconsistent sion? Is propranolol still a first-line treatment for response to triptans. She is otherwise healthy except for a history of moderate depression 3 years previ-ously when she got divorced. She occasionally feels EXPERT OPINION
“down.” She walks for exercise and does some weight This patient is experiencing 4-8 headaches a training. Her examination is normal except for a month, a frequency well above the threshold of 2 to 3 sitting blood pressure of 146/98 with a pulse of 76; attacks per month beyond which preventive headache height 5′3″, weight 110 pounds. Several repeated treatment is encouraged. Many physicians might rec-ommend treatment with a beta-adrenergic blocker forthis patient. Traditional reasons for preferring beta- Case submitted by: Randolph W. Evans, MD, 1200 Binz #1370,
Houston, TX 77004.
blockers in this case might include the fact that 2beta-blockers, propranolol and timolol, are Food and Expert opinion by: Paul Rizzoli, MD, John R. Graham Head-
ache Center, Brigham and Women’s/Faulkner Hospitals,
Drug Administration-approved for migraine prophy- Boston, MA, USA; Elizabeth Loder, MD, FACP, Chief, Divi-
laxis, a status that reflects the level of evidence sup- sion of Headache and Pain, Department of Neurology,
porting their efficacy in migraine treatment. They also Brigham and Women’s/Faulkner Hospitals, Boston, MA, USA;
are among a handful of drugs considered by treatment Dhirendra Bana, MD, John R. Graham Headache Centre,
Brigham and Women’s/Faulkner Hospitals, Boston, MA, USA.
guidelines to be first-line choices for prophylaxis.2 Additionally, this patient has stage 1 hypertension, increase the risk of ischemic stroke in some patients making it attractive to choose a possible “two-fer” who have migraine with aura, as discussed below.
drug that might benefit both hypertension and head- Assumption No. 2: “Beta-blockers only cause
ache. Finally, beta-blockers are inexpensive and widely reversible, nuisance side effects like fatigue, but have
perceived as safe, despite well-known “nuisance” side few or no serious side effects.”—Evidence is emerg-
effects such as exercise intolerance and fatigue.
ing that beta-blocker use may be associated with This patient does not have one of the few condi- some important health risks, including diabetes, tions historically considered contraindications to the weight gain, and ischemic stroke in patients who have use of beta-blockers, such as asthma, congestive heart failure (CHF), or aura. Her history of depression Diabetes.—It is widely recognized that beta- might give some physicians pause because of case blockers should be avoided in patients with diabetes, reports suggesting a link between beta-blocker treat- because adrenergic blockade may impede recognition ment and the onset or exacerbation of depression.3,4 of sympathetically mediated symptoms of hypoglyce- Others, however, might conclude that the depression mia. Emerging evidence suggests, though, that beta- was moderate, situational, and has resolved. Who blocker therapy also may have unfavorable effects on would not feel “down” having 1-2 headaches a week? glucose metabolism, and perhaps increase the risk of Because new information has emerged regarding type II diabetes.9 A recent meta-analysis examined the long-term risks and benefits of beta-blockers, it is the risk of new-onset diabetes associated with various worth re-examining the evidence, or lack of evidence, antihypertensive medications. New onset diabetes that underlies many commonly held beliefs and was least likely to occur in subjects treated with assumptions about beta-blockers before deciding angiotensin-converting enzyme inhibitors and angio- whether they are a reasonable treatment choice for tensin receptor blockers, followed by calcium channel blockers and placebo. It was most likely to occur in Assumption No. 1: “Beta-blockers are a first-line
subjects treated with beta-blockers or diuretics.10 The treatment for hypertension.”—Current treatment
association of diuretic and beta-blocker use with guidelines do include beta-blockers among the first- diabetes is also supported by the results of another line choices for treatment of hypertension, but this trial.11 Risks may differ depending upon which beta- has recently come under considerable fire.5-7 Their blocker is used.12,13 Until this issue is settled, a prudent original use in hypertension was based on the belief approach is to avoid the use of beta-blockers in that they might lower the risk of hypertensive com- patients who have risk factors for diabetes such as plications such as heart attack and stroke. This elevated body mass index or a family history of dia- assumption was not based on direct evidence from betes. Our case patient has a body mass index of 19.5 controlled trials; rather, it was an extrapolation of the confirmed benefit of beta-blockers in lowering the Weight Gain.—An association has been sug- risk of these events in patients who had already suf- gested between the use of beta-blockers and weight fered a cardiovascular event. A recent meta-analysis gain. Most patients view weight gain as a highly unde- concluded that in patients with primary hypertension, sirable side effect of migraine treatment; excess beta-blockers in fact are not as effective as other anti- weight may also worsen the clinical course of hypertensives in preventing the secondary complica- migraine.14,15 A systematic review of 8 randomized tions of hypertension, including stroke.8 Migraine is controlled trials of patients receiving beta-blockers an established risk factor for stroke, so this particular for hypertension found that body weight was higher disadvantage of beta-blockers, if it withstands scru- in the beta-blocker than the control group at 6 tiny, might warrant reconsideration of their favored months, with a median weight increase of 1.2 kg.
status in migraineurs with hypertension or other Weight gain seemed to occur during the early part of stroke risk factors. Additionally, there is at least some treatment and then plateau.16 One open, prospective evidence to suggest that beta-blockers may actually study assessed weight gain at 6 months in migraine patients using various prophylactic medications.
with stroke in patients with migraines, we feel a strong Three of 15 patients treated with atenolol gained a case can be made against the indiscriminate use of mean of 1.7 kg, and one of 13 patients treated with propranolol for prophylaxis in migraine . . . the same propranolol gained 6 kg. The authors suggested that prudence should extend to the use of propranolol as the weight gain, at least with atenolol, was “modest.”17 to the use of ergotamines and oral contraceptive pills The authors of another review of migraine drugs and weight gain concluded that “it is not clear whether Assumption No. 3: “Beta-blockers might cause or
there is any difference in associated weight gain” exacerbate depression.”—An association between
between different types of beta-blockers.18 the use of beta-blockers and major depression has Prolonged Aura or Stroke.—Case reports have been suggested, based on case reports and clinical suggested that beta-blocker treatment may precipi- observation, but has never been validated in well- tate or prolong migraine aura, or even cause ischemic conducted clinical trials.26,27 A meta-analysis of 15 stroke.19-22 The single clinical trial that sheds light on trials with over 35,000 subjects did not show evidence these concerns was conducted to compare metoprolol of an increase in depressive symptoms in subjects with placebo for the treatment of classic migraine treated with beta-blockers. The pooled incidence of (which would now be termed “migraine with aura”).
depression in those trials was 6/1000.28,29 Most of the Detailed, prospective information was obtained trials examined in the meta-analysis were carried out about aura symptoms and frequency, including scoto- for conditions other than migraine; an additional criti- cism is that adverse event information data collection paresthesias, paresis, ataxia, and speech disturbances.
in clinical trials is generally poor. It is possible that Metoprolol was effective in decreasing headache fre- patients with migraine may be particularly suscep- quency and pain compared with placebo, but subjects tible to drug-induced depression, as migraineurs are in the metoprolol group had a statistically significant already at higher than average risk of depression increase in the percentage of attacks with pre- and other affective disorders.30-33 However, no high headache scintillations, paresthesias, and speech quality evidence exists to support or refute a con- disturbances, although there were no differences nection between beta-blocker use and depression in between the 2 groups on any other studied aura the general population of patients or any subgroup.
Despite this, the assumption that beta-blockers cause The study authors did not consider the increased depression has proved to be remarkably enduring.
frequency in some aura symptoms to be of concern. In One author has referred to the persistent belief in the fact, they commented that their data did not support connection as a “myth without evidence.”34 the hypothesis that beta-blockers constrict cranial Assumption No. 4: “Beta-blockers are absolutely
vessels, as “if this is so, it is likely that aura symptoms contraindicated in patients with asthma, chronic
would be prolonged and aura without headache obstructive
pulmonary
(migraine equivalents) would occur more frequently CHF.”—Randomized clinical trials show that cardi-
during beta-blockade. Our data do not support this.”23 oselective beta-blockers prolong life in patients with Despite this, worry lingers about the possible dangers CHF, and they are now indicated for that condition of beta-blockers in patients who have migraine with in all but the most seriously compromised patients.35 aura. For this reason, many headache experts report Similarly, cardioselective beta-blockers do not appear that they prefer to avoid beta-blockers in patients to increase disease exacerbations or worsen airway with aura, and warn against their use in this function in patients with COPD.36 Cardioselective setting.24-25 This cautious attitude is probably best beta-blockers also appear to have a reasonable short- summarized by Bardwell, who comments that “Given term safety profile in patients who have reversible the action of beta-blockers on cerebral vascular auto- airway disease such as asthma, although the long- regulation and given the appearance of several case term safety remains to be established.37 The beta- reports linking the initiation of propranolol treatment blockers most commonly used to treat migraine are not cardioselective, so it still is prudent to be cautious compelling to suggest that depression, if present, is a in their use to treat headache in these patients. It is, strong contraindication to the use of beta-blockers if however, equally important to be aware that beta- they are otherwise an appropriate treatment choice.
blocker use may be far less dangerous in these con- In addition to headache, this patient’s most pressing medical concern is hypertension. There isnow considerable controversy about whether beta- APPLYING THE EVIDENCE TO
blockers are an appropriate first-line choice for treat- OUR PATIENT
ment of hypertension. In view of this, the patient and What is the bottom line for this patient and her physician will need to decide whether they still others like her? Many longstanding beliefs about have a preference for a single drug to treat both con- the harms, benefits, and contraindications of beta- ditions, or whether they wish to treat both conditions adrenergic blocker therapy have been flatly contra- separately. In making this decision, several drawbacks dicted or called into serious question over the past of treating 2 conditions with a single drug should be decade. This case thus illustrates the maxim that “half considered.The first is that it may prove difficult to find of what you’ll learn in medical school will be shown to a single dose that optimally treats both problems. This be either dead wrong or out of date within 5 years of increases the likelihood that treatment of one condi- your graduation; the trouble is that nobody can tell tion, or possibly both, will be suboptimal. Another disadvantage is that use of a single drug may lead to Several possible complications of beta-blockers confusion about who is responsible for managing the arguably should not weigh heavily in the decision patient’s hypertension over time. If a headache spe- about this patient’s treatment. Her body mass index is cialist initiates the beta-blocker, counseling about well within the normal range, so there is little need to other blood pressure control measures may not occur, worry about a possible risk of beta-blocker-induced and the patient or other physicians caring for her may diabetes or weight gain. Similarly, she does not have a assume that the headache specialist is also treating chronic respiratory condition or heart failure. She hypertension. If the patient lapses from headache care, may be depressed, and it would be prudent to evalu- needed follow-up of hypertension may not occur, par- ate this possibility carefully. However, evidence is not ticularly if she does not have a primary care physician.
Table.—Typical Titration Schedules for Selected Beta-Blockers Used to Treat Migraine†
†Typical dose ranges based on information contained in: Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM.
Evidence-based guidelines for migraine headache in the primary care setting: Pharmacological management for prevention ofmigraine. 2000. Accessed Despite this, if the physician and patient are 6. Beevers DG. The end of beta blockers for uncom- aware of these potential problems and take steps to plicated hypertension? Lancet. 2005;366:1510-1512.
avoid them, a beta-blocker is a reasonable treatment 7. Lindholm LH, Carlberg B, Samuelsson O. Should choice for this patient. Other drugs with evidence of beta blockers remain first choice in the treatment efficacy for both migraine and hypertension include of primary hypertension? A meta-analysis. Lancet.
2005;366:1545-1553.
verapamil, lisinopril, and candesartan. However, 8. Rudd P. Review: Beta blockers are less effective the evidence for these drugs is not as impressive as than other antihypertensive drugs for reducing risk that for several of the beta-blockers, especially of stroke in primary hypertension. Evid Based Med.
propranolol.40-43 The Table lists common dose ranges and titration schedules for several beta-blockers fre- 9. Sarafidis PA, Bakris GL. Antihypertensive treat- quently used to treat migraine. In considering the use ment with beta-blockers and the spectrum of glycae- of beta-blocker therapy in patients who are not mic control. QJM. 2006;99:431-436.
hypertensive, most physicians avoid their use in 10. Elliott WJ, Meyer PM. Incident diabetes in clinical patients with pre-existing orthostatic symptoms or trials of antihypertensive drugs: A network meta- low blood pressure and pulse. In the absence of evi- analysis. Lancet. 2007;369:201-207.
dence about “how low is too low,” a reasonable clini- 11. Cooper-Dehoff R, Cohen JD, Bakris GL, et al.
cal practice is to adjust the beta-blocker dose based Predictors of development of diabetes mellitus in on the patient’s symptoms, blood pressure, and pulse.
patients with coronary artery disease taking anti-hypertensive medications (findings from the IN- Most physicians aim to avoid systolic blood pressures below 80 mmHg and a resting pulse lower than 60 [INVEST]). Am J Cardiol. 2006;98:890-894.
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tion between dose and efficacy, or dose and side Effects of metoprolol and carvedilol on preexisting effects. Thus, trial and error may be necessary to and new on-set diabetes in patients with chronic determine the effective and tolerated dose for each heart failure {inverted exclamation}V data from the Carvedilol or metoprolol European Trial (COMET).
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