Migraine Drug Therapy During Breastfeeding

Anticonvulsants

Several anticonvulsants have been used for migraine prophylaxis, but valproate and topiramate have the best evidence for efficacy. ² Valproic acid and divalproex produce low valproate breast milk levels, and infant serum levels range from undetectable to very low. Based on extensive use in mothers with seizure disorders, valproate monotherapy does not appear to adversely affect infant growth or development and no definite acute adverse reactions in breastfed infants have been reported. Less breastfeeding information is available for topiramate. Maternal doses of topiramate up to 200 mg daily produce relatively low levels in milk and infant serum.

Levetiracetam has recently been used for migraine prophylaxis. Extensive study indicates that maternal doses of levetiracetam up to 3,500 mg daily produce low levels in milk and would not be expected to cause any adverse effects in breastfed infants. Preliminary evidence suggests that levetiracetam might reduce the maternal breast milk supply in some women.

With all of these drugs, the infant should be monitored for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants.

Antidepressants

Among antidepressants, amitriptyline has the best evidence for efficacy. ² Milk levels of amitriptyline and its metabolites are low. Immediate side effects have not been reported and some follow-up has found no adverse effects on infant growth and development. However, infant sedation has been reported infrequently.

Venlafaxine has also been used for migraine prophylaxis. Infants receive venlafaxine and its active metabolite in breast milk, and the metabolite of the drug can be found in the plasma of most breastfed infants; however, infant side effects have rarely been reported. Newborn infants of mothers who took the drug during pregnancy may experience poor neonatal adaptation syndrome as seen with other antidepressants. Use of venlafaxine during breastfeeding has been proposed as a method of mitigating infant withdrawal symptoms, but this has not been rigorously demonstrated.

Serotonin reuptake inhibitors are sometimes used for migraine prophylaxis. Based on experience in depression therapy, sertraline and paroxetine are the preferred agents because of their low levels in milk and virtual lack of adverse effects in breastfed infants. Serotonin reuptake inhibitors taken during the third trimester of pregnancy can delay lactogenesis II. Other classes of antidepressants are less well studied, but some evidence indicates that tricyclic antidepressants might cause the same problem. Mothers on antidepressants at delivery for migraine prophylaxis may need extra support to establish breastfeeding.

Antihypertensives

Several beta-adrenergic blocking drugs have been used for migraine prophylaxis, including atenolol, labetalol, metoprolol, nadolol, propranolol, and timolol. Propranolol and metoprolol have the best evidence for efficacy. ² Metoprolol and propranolol are also preferred because of their low passage into milk. Atenolol has the greatest passage into milk and has caused adverse effects in breastfed infants, so it is best avoided, especially if the mother is nursing a neonate.

Verapamil has been successfully used for prophylaxis, although high-quality published evidence is lacking. ² Maternal doses of verapamil up to 360 mg daily produce low levels in milk. Newborns may have detectable verapamil serum levels, but levels are low.

Botulinum toxin

OnabotulinumtoxinA is administered intramuscularly across 31 injection sites within 7 specific head and neck muscle areas for chronic migraine prophylaxis. No data exist on the use of onabotulinumtoxinA during breastfeeding. However, it is not detectable in maternal blood after intramuscular use; thus, excretion into breast milk is unlikely. One infant was safely breastfed during maternal botulism, and no botulinum toxin was detectable in the mother's milk or infant.

Monoclonal antibodies

Three monoclonal antibodies are available that bind to the calcitonin gene-related peptide (CGRP) receptor and antagonizes CGRP receptor function. They are prophylactic medications given by subcutaneous self-injection. Erenumab is given once monthly. Fremanezumab is given once monthly or every 3 months at three times the monthly dose. Galcanezumab is given monthly after an initial loading dose of double the maintenance dose. Because of their high cost, they are usually last-line drugs for those who have failed other therapies. Oral CGRP receptor antagonists are currently under development.

Although no information is available on the use of any of these drugs in breastfeeding, the monoclonal antibodies generally are not considered contraindicated during breastfeeding. With molecular weights >140,000, the amounts in milk are likely to be very low and absorption is unlikely because they are probably destroyed in the infant's gastrointestinal tract. This issue of the journal contains a case report of erenumab use in a mother who nursed a 2-year-old twice daily with no infant adverse effects. ⁴ Until more data become available, the monoclonal antibodies should be used with infant monitoring during breastfeeding, especially while nursing a newborn or preterm infant.

Dietary supplements

Magnesium, riboflavin, and coenzyme Q10 all have some efficacy data to support prophylactic use in migraine, although the evidence is not high level. None of these products is of concern during breastfeeding. Feverfew (Tanacetum parthenium) is an herbal product used to prevent migraine. No data exist on the excretion of any components of feverfew into breast milk or on the safety and efficacy of feverfew in nursing mothers or infants. Although feverfew is generally well tolerated in adults, rebound headaches can occur with rapid discontinuation. Allergic reactions, including cross-reactions to chrysanthemums, daisies, and marigolds, occur rarely. Because of the lack of safety data during lactation, some authors recommend against its use during breastfeeding.

Analgesics

Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are generally acceptable during breastfeeding, especially short-acting drugs such as ibuprofen, which are preferred while breastfeeding a newborn. One exception is high-dose aspirin that probably caused metabolic acidosis in one breastfed infant and might predispose the infant to Reye's syndrome. Naproxen in breast milk possibly caused prolonged bleeding time, thrombocytopenia, and acute anemia in one 7-day-old infant. Ketorolac use during breastfeeding is somewhat questionable because of its potent antiplatelet effect, especially the injection, which is used in high doses that have not been studied in breast milk. Ketorolac should probably be avoided immediately postpartum.

Combination products are often used. One such combination is isometheptene, dichloralphenazone, and acetaminophen. No information is available on isometheptene during breastfeeding, but it is a vasoconstrictor, somewhat similar pharmacologically to pseudoephedrine, which can depress the milk supply. Short-term or occasional use of dichloralphenazone during breastfeeding is unlikely to adversely affect the breastfed infant, but it is broken down to chloral hydrate and then to its active metabolite, trichloroethanol. Trichloroethanol has a long half-life and repeated doses during breastfeeding could result in infant sedation, especially in a neonate or preterm infant.

Another combination product containing acetaminophen, butalbital, and caffeine was recently reported to have caused poor feeding, lethargy, and emesis for 1–2 days in a breastfed 7-day-old infant before hospital admission. The infant's mother breastfed after taking 1 tablet every 6 hours for 24 hours (200 mg of butalbital total) before the infant's symptoms.

Triptans

Only two of the triptans have information on their use in breastfeeding: sumatriptan and eletriptan. Sumatriptan milk levels have been measured after a 6 mg subcutaneous injection. A fully breastfed infant would receive only 14.4 μg in breast milk with this dose, which is 3.5% of the weight-adjusted maternal dosage. Withholding breastfeeding for 8–12 hours after a dose has been suggested to avoid infant exposure, but this might be overly cautious given the poor oral bioavailability of the drug. Three anecdotal cases found no adverse infant effects, but one other poorly documented case reported lactation cessation after a single injection of sumatriptan. Eletriptan information is limited to an unpublished study of eight women that was submitted to the Food and Drug Administration (FDA) during the approval process. With a single 80 mg oral dose of eletriptan, an average total of 12.9 μg was excreted in the 24 hours after the dose. If a triptan is needed by a nursing mother, one of these two drugs is preferable to those with no lactation information.

Opioids

Opioids have been used acutely to treat migraine, but they are discouraged because of their elevated potential to be habituating and result in medication overuse headache. ² Maternal opioids are the most frequently reported cause of serious sedation and deaths in breastfed infants, so use in this population is particularly discouraged. Codeine and tramadol have been singled out by the FDA to be avoided during breastfeeding. This is because their metabolism relies on CYP2D6, which has various genetic variants, one of which can produce an excess of active metabolites.

Ergot alkaloids

Ergot alkaloids were commonly used before the availability of the triptans. The combination of ergotamine and caffeine was used widely and methysergide was used in resistant cases. Dihydroergotamine is still sometimes used for acute therapy. Ergots should not be used to treat migraine in nursing mothers, because of their toxicity in the mother, and possibly the infant, and because they might reduce serum prolactin and milk production.

Antiemetics

Nausea and vomiting often accompany acute migraine. Although long-term therapy with some of the antiemetic drugs would not be desirable during breastfeeding, their short-term use poses few serious problems. Most of these drugs incidentally increase serum prolactin, which might help maintain the milk supply. If phenothiazines such as promethazine and prochlorperazine are used, the breastfed infant should be observed for excessive sedation and adequate feeding.

Metoclopramide is used for nausea and also increases prolactin. Most infants would receive <10% of the maternal weight-adjusted dosage, but some infants achieve pharmacologically active serum levels, with elevated serum prolactin and gastrointestinal side effects. Long-term use of metoclopramide increases the risk of tardive dyskinesia and depression in the mother, so it should only be used as a short-term therapy.

Ondansetron has very little information on use during breastfeeding, although postpartum use apparently does not adversely affect breastfeeding. No information is available on the amount in breast milk, but infants appear to tolerate the drug well when they receive it directly.