Breastfeeding-Related Adverse Drug Reactions of Triptans: A Descriptive Analysis Using Four Pharmacovigilance Databases

Abstract

Objective

: Migraine attacks are common in women of reproductive age. Although attacks are often less severe and less frequent during pregnancy, they regularly reoccur shortly after delivery. When first-line analgesic treatment is insufficient, triptans may be used for acute treatment of migraine attacks. Milk levels of occasional triptan use have shown to be low, and no adverse effects in breastfed infants have been reported. However, the available knowledge on the safety of triptans during breastfeeding is still limited.

Methods:

Four (inter)national pharmacovigilance databases were searched for breastfeeding related adverse drug reactions of triptans. These included the Dutch Pregnancy Drug Register and three databases of spontaneous reports (Netherlands Pharmacovigilance Centre Lareb, the European Medicines Agency [EudraVigilance], and the World Health Organization [VigiBase]).

Results:

A total of 26 reports on 27 breastfeeding related adverse drug reactions were identified (one report involved two separate adverse drug reactions). These involve three main complaints: painful breasts and/or nipples, painful milk ejection reflex, and a decrease in milk production.

Discussion and Conclusion:

The hypothesized pharmacological mechanism relates to the serotonin-receptor agonistic properties of triptans. These may lead to vasoconstriction in the breasts and nipples, including the vasculature surrounding the milk ducts and alveoli, and may also influence the hormonal function and levels of prolactin. The reported adverse drug reactions do not negatively impact the overall compatibility of triptans with breastfeeding. However, breastfeeding women may experience them as unsettling. Awareness of these potential adverse drug reactions is essential and should be weighed against the potential adverse effects of (untreated) symptoms of migraine attacks.

Introduction

Migraine is a common form of headache, affecting 30% of women. Although all age groups are affected, the peak incidence lies in the reproductive years.^1,2 During pregnancy, physiologically increased estrogen levels reduce the frequency and severity of migraine attacks in 70–80% of women suffering from these headaches.^3,4 A sudden drop in estrogen levels postpartum results in the frequent recurrence of migraine attacks shortly after delivery. Half of the women experience recurrence within the first month after delivery, and in almost all women, the attacks reoccur within the first year postpartum.^5–7

When traditional painkillers such as acetaminophen and nonsteroidal anti-inflammatory drugs are insufficient, triptans are often prescribed to treat migraine attacks.⁸ Triptans are selective serotonin 5-HT_1B/1D receptor agonists. Their rapid-acting properties make them useful for the acute treatment of moderate to severe migraine attacks. It is hypothesized that their effect lies in three mechanisms of action: (1) vasoconstriction of cranial blood vessels, (2) inhibition of trigeminal nerve activity, and (3) inhibition of dural neurogenic inflammation.⁹ Seven triptans are currently available for the treatment of migraine attacks: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan.

Owing to the presence of 5-HT_1B/1D receptors on tissues in- and outside the central nervous system, triptans are known to cause adverse drug reactions (ADRs) in several organ systems. The most common ADRs include paresthesia, flushing, tingling, neck pain, and a feeling of chest pressure; these are known as “triptan sensations.”^10,11

Maternal sumatriptan use during breastfeeding results in low drug levels in breastmilk, and occasional maternal use is therefore considered to be compatible with breastfeeding.^12,13 No adverse effects of the maternal intake of triptans on breastfed infants or breastfeeding have been reported. However, the documented experience in the literature of triptan use during breastfeeding is very limited. More research on the safety of triptans during breastfeeding is therefore needed.

Recently, a participant of the Dutch Pregnancy Drug Register (DPDR) reported a painful milk ejection reflex after the use of sumatriptan during breastfeeding. This report was an inducement for further exploration of breastfeeding-related ADRs of triptans. In this brief report, we provide an overview of the internationally reported breastfeeding-related ADRs of triptans.

Method

Four data sources were searched to collect (spontaneous) reports of breastfeeding related ADRs after maternal triptan (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) use. No ethical approval was needed for this retrospective, database study.

The Dutch pregnancy drug register

The DPDR is hosted by the Netherlands Pharmacovigilance Centre Lareb. The register has a prospective, observational design. The overall aim is to gain insight into the safety of drug use during pregnancy and breastfeeding and the potential effects on maternal, fetal, and infant health. Participation in the DPDR entails administering a maximum of six questionnaires during pregnancy and in the first year postpartum. Detailed information on the DPDR was previously published elsewhere.¹⁴ All women participating in the DPDR receive questions on medication use during breastfeeding. If this was the case, the following question was assessed for a positive answer: “Have you noticed an effect of the drug on your infant or breastfeeding?” The open text field in which they specified the ADR was evaluated in a qualitative way. On October 26, 2023, the DPDR was screened for women that used a triptan during breastfeeding.

Spontaneous reports of adverse drug reactions

On October 26, 2023, a search for spontaneous reports of breastfeeding-related ADRs after maternal triptan use was performed in three other databases. These included the databases of (1) the Netherlands Pharmacovigilance Centre Lareb, (2) EudraVigilance (European Medicines Agency: EudraVigilance Data Analysis System search tool), and (3) VigiBase (the World Health Organization global database of reported potential side effects of medicinal products, developed and maintained by Uppsala Monitoring Centre: Vigilyze search tool). The search terms were the high level group term (HLGT) “breast disorders” in combination with the preferred term (PT) “maternal exposure during breast feeding” or “exposure via breast milk,” based on the Medical Dictionary for Regulatory Activities.¹⁵ Available case narratives of reports including the HLGT “breast disorders” were evaluated, and reports without the PT “maternal exposure during breast feeding” or “exposure via breast milk” were included when the case narrative clearly stated that the woman was breastfeeding at the time of triptan use and the ADR. For the spontaneous reports identified in VigiBase, no case narratives were available. Duplicate reports within the different databases were identified by case numbers and duplicate reports were excluded. As the DPDR is an independent register, it was ensured that there were no duplicates between reports in the DPDR and the other databases. The date of birth, age of the reporting woman, and timing of the report were compared. This revealed no duplicates between the DPDR and the sources for spontaneous reports.

Results

The Dutch pregnancy drug register

A total of 24 women participating in the DPDR reported the use of a triptan during breastfeeding (Fig. 1). The majority of these women used sumatriptan (n = 19). Rizatriptan, zolmitriptan, eletriptan, naratriptan, and almotriptan were used by one woman each. Two women reported a breastfeeding related ADR (Table 1). One of them reported a painful milk ejection reflex, and the other woman reported painful breasts and a decrease in milk production. In both cases, it concerned an ADR after sumatriptan use (reported dose, 50 mg). Time to onset of the complaints was not reported. One woman reported that the complaint lasted for 8 hours. There were multiple positive rechallenges for both women. The ADR was the reason to either no longer take sumatriptan (n = 1) or to cease breastfeeding (n = 1). Both of the women had been breastfeeding for several months at the time of the reports.

FIG. 1.

Flowchart of the reported breastfeeding related adverse drug reactions of triptans.

Table 1.

Details of (possible) Cases

Case	Source	Triptan	Dose	Coded PT 1	Coded PT 2	Case narrative (summarized)
1	DPDR	Sumatriptan	50 mg	Not applicable	Not applicable	Very painful milk ejection reflex for approximately eight hours after sumatriptan intake. Positive rechallenge. Had been breastfeeding for 7.5 months.
2	DPDR	Sumatriptan	50 mg	Not applicable	Not applicable	Painful breasts and less milk production. Positive rechallenge. Had been breastfeeding for 7 months.
3	Lareb	Sumatriptan	50 mg	Lactation disorder	Exposure via breast milk	Very painful milk ejection reflex from about 1 hour after sumatriptan intake until effect medication wore off. Had been breastfeeding for 5 weeks.
4	EudraVigilance	Sumatriptan	100 mg	Breast pain	Exposure via breast milk	Severe pain in both breasts after drug intake. Felt like galactostasia and lasted for 6 hours. Feeding the child did not help. Happened six times. Had been breastfeeding for 3.5 months.
5	EudraVigilance	Sumatriptan	50 mg	Breast pain	Maternal exposure during breast feeding	First a burning sensation on the nipples. The pain became really strong during feeds. Pain when breastfeeding occurred regularly and reproducibly every time after intake of sumatriptan. Started 1 hour after intake.
6	EudraVigilance	Sumatriptan	50 mg	Breast pain	Maternal exposure during breast feeding	Was unable to feed the child due to severe pain in breasts.
7	EudraVigilance	Sumatriptan	50 mg	Breast pain	—	Intense pain in breasts during breastfeeding. Started 30 minutes to 1 hour after intake of sumatriptan.
8	EudraVigilance	Sumatriptan	100 mg	Beast pain	—	Severe pain in both breasts after drug intake. Both breasts became hard, burning, and very painful. This pain lasted for maximum 8 to 10 hours. Happened five times. Had been breastfeeding for 8 weeks.
9	EudraVigilance	Sumatriptan	Not available	Breast pain	Nipple pain	Burning pain in both breasts, extreme pain during use of the breast pump. Happened twice.
10	EudraVigilance	Sumatriptan	Not available	Breast pain	Nipple disorder	Painful breastfeeding, almost impossible to feed. Happened four times.
11	EudraVigilance	Sumatriptan	50 mg	Nippple pain	Raynaud’s phenomenon	Terrible pain in both nipples 2 hours after intake. Lasted a few hours. Nipples pale/white. Unable to breastfeed child due to pain. Happened twice. Had been breastfeeding for 9 weeks.
12	EudraVigilance	Sumatriptan	50 mg	Breast pain	Maternal exposure during breast feeding	Painful breasts for several hours.
13	EudraVigilance	Sumatriptan	100 mg	Nipple pain	—	Painful nipples during breastfeeding.
14	EudraVigilance	Sumatriptan	100 mg	Nipple pain	Maternal exposure during breast feeding	Nipple pain/painful to breastfeed. Happened five times.
15	EudraVigilance	Sumatriptan	100 mg	Nipple pain	Maternal exposure during breast feeding	Painful nipples. Had been breastfeeding for 15 weeks.
16	EudraVigilance	Eletriptan	20 mg	Nipple pain	Lactation disorder	Severe pain in both nipples and painful breastfeeding. Used eletriptan daily. Complaints worsen over time. Had been breastfeeding for 10 months.
17	Vigilyze	Sumatriptan	Unknown	Nipple pain	Maternal exposure during breast feeding	Not available
18	Vigilyze	Sumatriptan	Unknown	Breast pain	Maternal exposure during breast feeding	Not available
19	Vigilyze	Sumatriptan	Unknown	Breast pain	Maternal exposure during breast feeding	Not available
20	Vigilyze	Sumatriptan	50 mg	Breast pain	Maternal exposure during breast feeding	Not available
21	Vigilyze	Sumatriptan	100 mg	Suppressed lactation	Exposure via breast milk	Not available
22	Vigilyze	Sumatriptan	Unknown	Lactation insufficiency	—	Not available
23	Vigilyze	Sumatriptan	Unknown	Milk discoloration	Drug exposure via breast milk	Not available
24	Vigilyze	Naratriptan	Not available	Lactation insufficiency		Not available
25	Vigilyze	Naratriptan	2 mg	Lactation disorder	—	Not available
26	Vigilyze	Rizatriptan	Not available	Lactation disorder	Breast engorgement	Not available

PT, preferred term; DPDR, Dutch Pregnancy Drug Register; Lareb, Netherlands Pharmacovigilance Centre.

Spontaneous reports of adverse drug reactions

In the database of spontaneous ADR reports of the Netherlands Pharmacovigilance Centre Lareb, a total of seven reports with the HLGT “breast disorders” were identified (Fig. 1). One of these cases concerned a breastfeeding mother. She reported a painful milk ejection reflex after sumatriptan (reported dose, 50 mg) use (coded PT “lactation disorder”). The pain started 1 hour after sumatriptan intake and lasted until “the effect of the drug wore off” (Table 1). She had been breastfeeding for 5 weeks at the time of the report.

A search in the EudraVigilance database revealed 89 reports with the HLGT “breast disorders” (Fig. 1). Overall, 13 unique reports concerned a breastfeeding woman. There were eight reports on PT “breast pain” and five reports on PT “nipple pain.” Twelve reports were on sumatriptan (reported dose, 50–100 mg) and one on eletriptan (reported dose, 20 mg). Time to onset of the complaints was 0.5–3 hours, and the complaints lasted between 6 hours and 1 day. All women had been breastfeeding for over 2 months at the time of the report. Eight of the 13 women reported one or more positive rechallenge(s) (Table 1).

In VigiBase, a total of 167 reports including the HLGT “breast disorders” were identified. Overall, ten unique reports concerned a breastfeeding woman. The coded PTs were “breast pain” (n = 3), “lactation insufficiency/suppressed lactation” (n = 3), “nipple pain” (n = 1), “breast engorgement” (n = 1), “milk discolouration” (n = 1) and “lactation disorder” (n = 1). It concerned seven reports on sumatriptan (reported dose, 50–100 mg), two on naratriptan (reported dose, 2 mg), and one on rizatriptan (dose unknown) (Table 1). As no case narratives were available, no other details of these cases were available.

Discussion

This study investigated reports on breastfeeding-related ADRs following maternal triptan use. A total of 26 reports of breastfeeding women consisting of 27 (possible) ADRs of triptans were identified. The reported ADRs included painful breasts and/or nipples (n = 18), a decrease in milk production (n = 4), a painful milk ejection reflex (n = 2), breast engorgement (n = 1), milk discoloration (n = 1), and a lactation disorder not otherwise specified (n = 1). A positive rechallenge was reported in 10 cases. In the evaluated case narratives, there were no reports of adverse effects on infants from triptan exposure via breastmilk. However, no specific search on these effects was performed, and therefore, possible adverse effects cannot be excluded based on this study. This is the first report, to the best of our knowledge, of breastfeeding-related ADRs of triptans in the literature.

There are multiple pharmacological mechanisms by which triptans may cause breastfeeding-related ADRs.

The first mechanism is the effect of triptans on the vasculature in the breasts. The breast and nipples are vascularized by perforating branches of the internal and external thoracic arteries. The internal thoracic artery is known to express the 5-HT_1B receptor.¹⁶ Triptans acting on this receptor may cause vasoconstriction of the arteries in the breast, nipples, and the arteries surrounding the alveoli and milk ducts, causing a painful sensation and a painful milk ejection reflex. Painful breasts and nipples are ADRs that are not limited to breastfeeding women. However, as blood supply to the breasts is increased in breastfeeding women, this may make them more prone to the vasoconstrictive (side)effects of triptans in the breasts.¹⁷ Also, breastfeeding women may experience this ADR as more impactful compared to non-breastfeeding women or men.

Then, alongside the vascular effects of triptans, there are two hormonal mechanisms by which triptans may negatively affect milk production. First, the physical stimulation of the infant suckling on the mothers’ nipples induces secretion of prolactin by the anterior lobe of the pituitary gland. Prolactin stimulates milk production by the alveoli to ensure sufficient milk for the next feed. The increase in prolactin levels induces a negative feedback loop, keeping serotonin production low until the mammary glands become full of milk. In human breast tissue, when the mammary glands are full, serotonin acts by the 5-HT₇ receptor by suppressing further milk production.^18,19 Alongside the affinity for the 5-HT_1B/1D receptor, triptans have also shown to express affinity for the 5-HT₇ receptor.²⁰ Second, one of the mechanisms of action of triptans is the lowering of prolactin levels, which are elevated during migraine attacks.²¹ Triptans may therefore cause a temporary decrease in milk production, especially during the early stages of lactogenesis. It is unknown if this was the case in our study since the duration of breastfeeding (several weeks) was known in only one of the four reported cases of decreased milk production.

Although migraine itself may cause hypersensitivity to physical touch, extreme sensitivity to touch of the skin has not been described to impact breastfeeding.²² Also, especially in the early stages of breastfeeding, women often experience breastfeeding-related complaints including painful breasts and nipples. However, the case narratives included in our study describe a clear relation between the timing and duration of complaints and the use of a triptan with a positive rechallenge in 10 of the 16 cases with an available case narrative. In combination with the possible pharmacological mechanisms, there is a high probability that the complaints of painful breasts and/or nipples, a painful milk ejection reflex, and a decrease in milk production are ADRs of triptan use. One woman reported discoloration of the milk. Owing to the lack of a possible pharmacological mechanism for this observation and the absence of a case narrative, the association with triptan use is hard to substantiate.

Because of the nature of this study and the used data sources, it is not possible to make any statements on the frequency of breastfeeding related ADRs of triptan use. For six of the reports in EudraVigilance, the coded PTs did not include a term indicating a breastfeeding woman (i.e., “exposure during breast feeding” or “exposure via breast milk”). All case narratives of the EudraVigiliance reports were, however, screened, thereby limiting the chances of missed reports. However, for the reports in VigiBase, no case narratives were available. Based on these observations, it is hypothesized that the number of selected reports may be an underestimation of the exact number of cases.

Sumatriptan is the most commonly used triptan and has the best established safety profile during breastfeeding. This probably explains the high number of cases concerning sumatriptan use compared to other triptans. However, based on the proposed pharmacological mechanisms, it is expected that other triptans may cause similar ADRs in breastfeeding women. Our findings do not justify that the use of triptans during breastfeeding should be discouraged or avoided. However, awareness of potential breastfeeding-related ADRs by health care professionals is important, and breastfeeding women should be informed of the possibility of the occurrence of these ADRs of triptans, including painful breasts and/or nipples, a painful milk ejection reflex, and a decrease in milk production. Although it concerns transient and not life-threatening ADRs, it may be experienced as unsettling to breastfeeding women, and the impact of these ADRs should be weighed against the potential adverse effects of (untreated) symptoms of migraine attacks.

Footnotes

Acknowledgments

The EudraVigilance database of the European Medicines Agency was used as a data source for this article. The information in this article does not represent the opinion of the European Medicines Agency. The Global ICSR database VigiBase was used as a data source for this article. The information in VigiBase comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases. The information in this article does not represent the opinion of the UMC or the World Health Organization.

Authors’ Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by M.C. and A.M. The first draft of the article was written by M.C., and all authors commented on previous versions of the article. All authors read and approved the final article.

Author Disclosure Statement

No conflicts of interest are reported by the authors.

Funding Information

The Dutch Pregnancy Drug Register was set up with funding from The Netherlands Organization for Health Research and Development (ZonMw), project number 836012001. The funders had no role in study design, data collection and analysis, interpretation of data, decision to publish, or preparations of the article. The research activities of Michael Ceulemans are supported by the Internal Funds KU Leuven (PDMt123020).

References

, Yang

, Lv

, et al. Global, regional, and national epidemiology of migraine and tension-type headache in youths and young adults aged 15-39 years from 1990 to 2019: Findings from the global burden of disease study 2019. J Headache Pain, 2023; 24(1):023–01659.

Allais

, Chiarle

, Sinigaglia

, et al. Gender-related differences in migraine. Neurol Sci, 2020; 41(Suppl 2):429–436.

Turankar

, Sorte

, Wanjari

, et al. Relation and treatment approach of migraine in pregnancy and breastfeeding. Cureus, 2023; 15(3):e36828.

Kardes

, Hadimli

, Ergenoglu

. Determination of the frequency of migraine attacks in pregnant women and the ways they cope with headaches: A cross-sectional study. Healthcare, 2023; 11(14):2070.

Hoshiyama

, Tatsumoto

, Iwanami

, et al. Postpartum migraines: A long-term prospective study. Intern Med, 2012; 51(22):3119–3123.

Sances

, Granella

, Nappi

, et al. Course of migraine during pregnancy and postpartum: A prospective study. Cephalalgia, 2003; 23(3):197–205.

Kvisvik

, Stovner

, Helde

, et al. Headache and migraine during pregnancy and puerperium: The MIGRA-study. J Headache Pain, 2011; 12(4):443–451.

Amundsen

, Nordeng

, Nezvalová-Henriksen

, et al. Pharmacological treatment of migraine during pregnancy and breastfeeding. Nat Rev Neurol, 2015; 11(4):209–219; doi: 10.1038/nrneurol.2015.292015

Arulmozhi

, Veeranjaneyulu

, Bodhankar

. Migraine: Current concepts and emerging therapies. Vascul Pharmacol, 2005; 43(3):176–187.

10.

Antonaci

, Ghiotto

, Wu

, et al. Recent advances in migraine therapy. Springerplus, 2016; 5(637):637–2211.

11.

González-Hernández

, Marichal-Cancino

, MaassenVanDenBrink

, et al. Side effects associated with current and prospective antimigraine pharmacotherapies. Expert Opin Drug Metab Toxicol, 2018; 14(1):25–41.

12.

Wojnar-Horton

, Hackett

, Yapp

, et al. Distribution and excretion of sumatriptan in human milk. Br J Clin Pharmacol, 1996; 41(3):217–221.

13.

Amundsen

, Nordeng

, Fuskevåg

, et al. Transfer of triptans into human breast milk and estimation of infant drug exposure through breastfeeding. Basic Clin Pharmacol Toxicol, 2021; 128(6):795–804.

14.

Vorstenbosch

, Te Winkel

, van Gelder

, et al. Aim and design of pREGnant, the dutch pregnancy drug register. Drug Saf, 2019; 42(1):1–12.

15.

Brown

, Wood

. The medical dictionary for regulatory activities (MedDRA). Drug Saf, 1999; 20(2):109–117.

16.

Tanaka

, Nakamura

, Ohkura

, et al. Both 5-hydroxytryptamine 5-HT2A and 5-HT1B receptors are involved in the vasoconstrictor response to 5-HT in the human isolated internal thoracic artery. Clin Exp Pharmacol Physiol, 2008; 35(7):836–840.

17.

Geddes

, Aljazaf

, Kent

, et al. Blood flow characteristics of the human lactating breast. J Hum Lact, 2012; 28(2):145–152.

18.

Hernandez

, Stiening

, Wheelock

, et al. Evaluation of serotonin as a feedback inhibitor of lactation in the bovine. J Dairy Sci, 2008; 91(5):1834–1844.

19.

Marshall

, Hernandez

, Horseman

. Serotonin and serotonin transport in the regulation of lactation. J Mammary Gland Biol Neoplasia, 2014; 19(1):139–146.

20.

Pierce

, Xie

, Peroutka

, et al. Dual effect of the serotonin agonist, sumatriptan, on peripheral neurogenic inflammation. Reg Anesth, 1996; 21(3):219–225.

21.

Szewczyk

, Ulutas

, Aktürk

, et al. European Headache Federation School of Advanced Studies (EHF-SAS). Prolactin and oxytocin: Potential targets for migraine treatment. J Headache Pain, 2023; 24(1):023–01557.

22.

Schwedt

. Multisensory integration in migraine. Curr Opin Neurol, 2013; 26(3):248–253.