Brief Communication

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Labetalol for Prophylactic Treatment of Intractable Migraine During Pregnancy

Ranjan Dey, MD; Sajid Khan, MD; Vimal Akhouri, MD; Joshua Wootton, PhD; Zahid H. Bajwa, MD

Headaches tend to improve in the majority of migraineurs during pregnancy, but some patients report a wors-ening of migraine and present a management challenge because of the restrictions of pharmacotherapy duringpregnancy. Treatment options become even more limited for pregnant migraineurs who develop preeclampsia.Labetalol was tried successfully in reducing the frequency, duration, and intensity of migraine attacks in a preg-nant woman with preeclampsia. There were no significant side effects and the patient delivered a healthy babywithout complications.

Key words: migraine, prophylaxis, preeclampsia, Labetalol

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The majority of sufferers of migraine report a sub-stantial reduction in migraine attacks after the first tri-mester of pregnancy,

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but a considerable minority ofthese patients nevertheless report persistent or evenworsening migraine symptoms during pregnancy.Given the limitations of pharmacotherapy, treating mi-graineurs whose symptoms worsen during pregnancypresents a considerable challenge. We report the suc-cessful treatment of a patient with disabling migraineattacks during the second half of her pregnancy, whichwas further complicated by preeclampsia. Labetalol inescalating doses resulted in significant improvement inthe frequency, duration, and severity of her migraineattacks within 10 days of starting treatment.

CASE HISTORY

A 32-year-old women, gravida 1, para 0, was re-ferred to our clinic in her 28th week of pregnancy withcomplaints of progressively worsening migraine head-ache over a period of 6 weeks, requiring treatmentwith opioids and antiemetics.

The patient reported a history of migraine sincethe age of 13, when her headaches would occur everyfew months. Gradually, her headaches became morefrequent, and she was treated with over-the-counteranalgesics. She continued to have headaches withvariable frequency that would meet the InternationalHeadache Society Criteria for migraine without aura,through her teens and twenties.

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Her attacks becamemore frequent, again, when she was 28 years old, oc-curring two to three times a month. These headacheswere unilateral and associated with photophobia, phono-phobia, nausea, and occasional vomiting, each attacklasting 12 to 24 hours.

She was treated with acetaminophen, ibuprofen,codeine, combination analgesics, and sumatriptan tab-lets, without significant benefit. Verapamil and Pro-pranolol were each tried for several months with vari-able effect on reducing the frequency, duration, andseverity of her attacks, but she stopped all medica-

From the Arnold Pain Center, Department of Anesthesia andCritical Care, Beth Israel Deaconess Medical Center, HarvardMedical School, Boston, Massachusetts.

Address all correspondence to Dr. Zahid H. Bajwa, Depart-ment of Neurology, Harvard Medical School, Arnold PainCenter, Department of Anesthesia and Critical Care, Beth Is-rael Deaconess Medical Center, 330 Brookline Avenue, Bos-ton, MA 02115.

Accepted for publication March 28, 2002.

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tions when she started planning pregnancy at age 32.During the first and early part of her second trimes-ter, she experienced hyperemesis, resulting in dehy-dration and headaches, which tended to improve withoral rehydration and bed rest. She also had occa-sional migraine headaches of moderate severity re-quiring analgesics and antiemetics. Around her 24thweek of pregnancy, her migraine attacks became worsethan ever, occurring up to 5 days a week. She describeda sharp, throbbing, left periorbital pain lasting up to 3days. Her visual analogue scale of pain at its worstduring this period was 10 of 10 and averaged 6 to 7 of10. Her headaches would not wake her from sleep;but she was while awake, they were associated withphotophobia, phonophobia, nausea, and occasionalvomiting. She reported that her symptoms were simi-lar to her prepregnancy migraine attacks, but they oc-curred now with increased frequency, and instead ofher usual right side of the temple and periorbital areabeing affected, her left side was now more commonlyinvolved. Her medical history was significant for hy-pothyroidism and endometriosis, and she had no sig-nificant family history of migraine or other neuro-logic disorder. Her medications were levothyroxine0.075 mg/day, oxycodone 5 to 10 mg as needed forheadache, and multivitamins. She had no known drugallergies, other than a dystonic reaction to prochlor-perazine, and her physical examination revealed ahealthy, well-nourished, alert, attentive, and coopera-tive woman with a good recall of events. She was 65inches tall and weighed 156 pounds. Her heart ratewas 104 beats per minute, with a regular rhythm anda blood pressure of 148/90 mm at the time of evalua-tion. She also had mild bilateral pedal edema. Herneurologic examination was normal, along with nor-mal fundoscopy. Musculoskeletal examination of thehead, neck, and face revealed no significant tender-ness, tightness, or trigger points. Her urinalysis showed3

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proteins at the first two visits.After reassuring the patient, we recommended bio-

feedback, relaxation, avoidance of headache triggers,and acetaminophen and oxycodone on an as-needed ba-sis for moderate to severe headache. After consultingwith her primary care physician and obstetrician, we rec-ommended Labetalol 50 mg, once a day for 2 days, in-creasing to 50 mg b.i.d. She was monitored weekly, in-

creasing her Labetalol by 50 mg every 3 days until shereached a 150-mg b.i.d. dose. She reported improve-ment in headache frequency and intensity once shereached a 100-mg b.i.d. dose, without any change inher blood pressure or pulse. Weekly visits included he-modynamic monitoring, urinalysis, fetal monitoring, anda review of her headache diary, which included the date,time, severity, location, and duration of headache, asso-ciated symptoms, pulse, blood pressure, medicationused (including total dosage), and the subjectively as-sessed effect of the medications. Her visual analoguescale for headache pain at the beginning of the La-betalol treatment was 6 to 10 of 10, with headache ep-isodes occurring up to 5 days a week. After 1 week ofLabetalol treatment, she reported that the intensityof her headaches was reduced to 5 of 10 and the fre-quency was reduced to three times a week. We alsoswitched her oxycodone on her second weekly visit tohydromorphone 2 to 4 mg on as needed basis to im-prove analgesia. By the end of the 6th week on La-betalol, she was taking 300 mg per day (150 mg b.i.d.)without significant change in her blood pressure andpulse, and she reported more than 50% improvementin her headache symptoms. Her requirement of hy-dromorphone was also reduced from 8 to 10 mg to 2to 4 mg per migraine attack and her sensitivity to lightand sound improved.

Her liver function tests, along with other fetal andobstetrical parameters, remained within normal lim-its. Of note, there was a reduction in proteinuria from3

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at her 28th week of gestation to negligible at her34th week. The patient was followed at weekly inter-vals and remained on 150 mg b.i.d. of Labetalol untilshe delivered a normal healthy baby in her 38th week.

COMMENTS

Migraine is primarily a clinical diagnosis, basedon history and physical and neurologic examination,that meets the International Headache Society crite-ria.

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The exact incidence of migraine during pregnancyis not well documented, and many reported cases haveinvolved migraine with aura or prolonged aura.

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Ap-proximately 60% to 70% of migrainers improve spon-taneously during pregnancy,

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principally in the 2ndand 3rd trimester, with improvement more likely tooccur in women with perimenstrual migraine. A smaller

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percentage of women (4% to 8%) undergo a worsen-ing of migraine during pregnancy, particularly womenexperiencing migraine with aura.

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Our patient contin-ued to experience migraine attacks during the firsthalf of her pregnancy, with clear worsening during herearly third trimester.

If migraine headaches persist during pregnancy,migraine prophylaxis is usually not recommended, de-spite changing patterns possibly resulting from hor-monal and hemodynamic fluctuations during the variousstages of pregnancy.

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However, the use of prophylacticmedications may be justified when there is increased fre-quency and severity of migraine with associated nauseaand vomiting, potentially causing dehydration and otherharmful effects to the mother and fetus.

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Our patienthad a frequency of four to five migraine attacks perweek, with associated photophobia, phonophobia, in-tractable nausea, and intermittent vomiting. The pain in-tensity of her migraine attacks also worsened duringpregnancy, with the result that her established regi-men of 5 to 10 mg oxycodone with acetaminophen ev-ery 4 hours merely dulled her headaches, which nowsometimes lasted for more than 24 hours. Our patientalso developed tachycardia, hypertension, pedal edema,and proteinuria. Because she had two pathophysiologi-cal entities, namely migraine and pregnancy-inducedhypertension with gradually worsening headaches, weopted to treat her prophylactically with Labetalol.

Silberstein,

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in his review on migraine and preg-nancy, suggests that “if a patient has coexistent illnessthat requires treatment, one drug that will treat both dis-orders should be used.” We considered Labetalol overcommonly used prophylactic agents, including otherbeta-blockers, because Propranolol alone has a greaterlikelihood of causing unopposed alpha effect, perpetu-ated by the presence of circulating thromboxane inpreeclampsia. Labetalol is a combined alpha and beta-adrenergic blocker that has met with the greatest successamongst all other beta-blockers and has generated thefewest related side effects in pregnancy-induced hyper-tension and preeclampsia.

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Moreover, the transitionfrom oral to intravenous administration and vice versacan be easily carried out without any complications.

Labetalol is a unique parenteral and oral antihy-pertensive drug that exhibits selective alpha-1 andnonselective beta-1 and beta-2-adrenergic antagonist

effects. Presynaptic alpha-2 receptors are spared by La-betalol, with the result that released norepinephrine cancontinue to inhibit further release of catecholamines viathe negative feedback mechanism occurring with thestimulation of alpha-2 receptors.

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Labetalol is one-fifthto one-tenth as potent as Phentolamine in its ability toblock alpha-receptor sites and is approximately one-fourth to one-third as potent as Propranolol in blockingbeta-receptors. In humans subjects, the beta-to-alphablocking potency ratio is 3:1 for oral Labetalol and 7:1for intravenous Labetalol.

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Furthermore, Labetalol is the most commonlyused single antihypertensive agent for treating hyper-tension during pregnancy.

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It decreases systemicvascular resistance with little or no change in cardiacoutput, is considered safe during pregnancy, and isassociated with good fetal outcome.

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It does not ap-pear to impair placental blood flow to the fetus orcause fetal malformation, and it may have a beneficialeffect on the fetal lung maturation.

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In the study byLamming et al,

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after 2 weeks of treatment with La-betalol, renal function had significantly improved, witha markedly lower incidence of proteinuria.

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Morepatients went into spontaneous labor following La-betalol than following Aldomet,

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and in our patient’scase, urine protein diminished substantially after start-ing her on Labetalol treatment (refer to Table 1).

In 60% to 70% of cases, beta-blockers are effec-tive in reducing the frequency of headache by at least50%. Among the beta-blockers, Propranolol, Timolol,Nadolol, Metaprolol, and Atenolol are considereduseful for migraine.

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Bisoprostol has also been foundto be effective in reducing the frequency of migraineattacks,

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yet neither the mode nor even the site of ac-tion of these drugs has been conclusively identified.The proposed mechanism of action includes periph-eral vascular effects, central actions, including 5HT

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antagonism, and anxiolytic effect.

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Beta-blockers alsoblock catecholamine-induced platelet aggregation, de-crease platelet adhesiveness, prevent alteration of co-agulation factor during epinephrine release, shift thehemoglobin-oxygen dissociation curve, promotingrelease of oxygen to tissues, and block catecholamine-induced lipolysis. Blocking lipolysis decreases the pro-duction of arachidonic acid, a precursor of prostaglan-dins accounting for inhibition of platelet aggregation.

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Vatz et al

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demonstrated that alpha-1-adrenergicblocking drugs Terazocin or Doxazocin decreased mi-graine frequency, severity, or both.

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In view of the unique alpha and beta blockadeactivity of Labetalol, and because our patient exhib-ited pregnancy-induced hypertension associated withmigraine, we found it appropriate to treat her with in-creasing doses of this drug. In the first 6 weeks of grad-ually escalating the dosage of Labetalol to 300 mg/day,the severity and duration of her migraine attacks wasreduced by 50%, with a corresponding reduction in as-sociated symptoms and proteinurea.

Besides resulting in beta blockade activity, La-betalol also has alpha-1 receptor and 5HT

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antagonistactivity.

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Therefore, our rationale for its use was anattempt to create a synergistic multireceptor block-ade that would both reduce the severity of migrainesymptoms and treat pregnancy-induced hypertension.To our knowledge, Labetalol has not been reported asa prophylactic treatment for migraine, but our anec-dotal experience has prompted a large scale study ofthis drug for migraine prophylaxis. Labetalol may proveto be a particularly useful prophylactic agent when mi-graine persists or worsens during pregnancy.

REFERENCES

1. Silberstein SD. Migraine and pregnancy.

NeurolClin.

1997;15:209-231.2. Headache Classification Committee of the Interna-

tional Headache Society. Classification and diagnos-tic criteria for headache disorders, cranial neuralgia,and facial pain.

Cephalalgia.

1988;8:1-96.3. Aube M. Migraine in pregnancy.

Neurology.

1999;53(suppl 1):S26-S28.

4. Sibai BM. A comparison of no medication versus

methyldopa or labetalol in chronic hypertension dur-ing pregnancy.

Am J Obstet Gynecol.

1990;162:960-966.5. Steolting RK. Alpha and beta adrenergic receptor

antagonists. In: Steolting RK, ed. Pharmacology andPhysiology in Anesthetic Practice. Baltimore, Md:Lippincott, Williams & Wilkins; 1999:288-301.

6. Lund-Johansen P. Pharmacology of combined al-pha-beta blockade: II. Haemodynamic effects of La-betalol.

Drugs.

1984;28:35-50.7. Lourwood DL. Treatment of chronic disease during

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Clin ExpHypertens.

1980;2:865-895.9. Cruinkshank DJ. Does labetalol influence the devel-

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-Adrenoceptor blockade and mi-graine.

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graine effect of ergotamine: a role for alpha-adren-ergic blockade?

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Correo S, Licata G. The effects of terazosin hydro-chloride and buflomedil in patients with hemicraniawithout aura [in Italian].

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Table 1.—Advantages of Labetalol over Propranolol for Prophylactic Treatment of Migraine During Pregnancy

Labetalol Propranolol

Additional

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-blockade effect Only

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-blocking effectSynergistic effect due to

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/

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combination No synergismHelpful in treating comorbid conditions like

pregnancy-induced hypertensionIsolated

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-blocker, not used for pregnancy-induced hypertension

Improves proteinuria No effect on proteinuriaNo untoward fetal effect Fetal bradycardia, hypoglycemia, and acidosis possibleDepression unlikely Depression is a possible side effect