Breastfeeding MedicineVol. 15, No. 11 LactMed® UpdateFree AccessDrug Treatment of Raynaud's Phenomenon of the NipplePhilip O. AndersonPhilip O. AndersonAddress correspondence to: Philip O. Anderson, PharmD, Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093-0657, USA E-mail Address: phanderson@ucsd.eduDivision of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, San Diego, California, USA.Search for more papers by this authorPublished Online:9 Nov 2020https://doi.org/10.1089/bfm.2020.0198AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Raynaud's phenomenon (RP) occurs in 3–5% of the population, with the rate of occurrence in women about four times that in men. It is caused by vasospasm of the blood vessels in the extremities, including the nipple. RP of the nipple can be extremely painful and result in nursing cessation. It is typically characterized by triphasic color changes of the nipple that proceed from white (blanching due to vasospasm), to blue or purple (cyanosis due to deoxygenation of static venous blood), to dark red (reactive hyperemia). It is often misdiagnosed as a Candida albicans infection and treated with antifungals. Nipple trauma, a history of RP in the hands, or personal or family history of thyroid disease have been seen in some patients.1,2 Some cases suggest that the use of labetalol for treating pre-eclampsia may cause RP of the nipple.3,4 Nursing, entering an air-conditioned room, swimming in cold water, or opening the freezer door may trigger symptoms.Nondrug treatments include optimizing breastfeeding technique, warming the nipples, stress management, and avoiding the cold. Avoidance of caffeine, nonselective beta-blockers, and vasoconstrictors (e.g., pseudoephedrine) is also recommended. Although smoking cessation is often recommended, it does not appear to be a major causal factor of RP in women.5 When these methods are not successful, drug therapy is often used. Several systemic and topical therapies have been described, although none have undergone rigorous clinical trials in patients with the nipple phenomenon.This column will review the reports of drug therapy for RP of the nipple as well as some general information on treatment of RP that might help to inform treatment of nipple symptoms. More detailed information and references on the use of specific drugs during breastfeeding can be found in the corresponding LactMed records.Calcium-Channel BlockersDihydropyridine calcium-channel blockers include amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and nisoldipine. The dihydropyridines have a greater effect on peripheral blood vessels and a lesser effect on the atrioventricular and sinoatrial nodes in the heart than diltiazem or verapamil. Diltiazem and verapamil have less effect on the peripheral vasculature than the dihydropyridines, so may not be as useful in treating RP.A 2004 meta-analysis of calcium-channel blocker trials for treating primary RP (not of the nipple) found that severity was reduced by a third and the number of attacks was reduced by 2.8–5 per week.6 A more recent Cochrane meta-analysis concluded that calcium-channel blockers reduced the frequency of attacks by around 1.7 attacks per week. Nifedipine is currently considered the first-line drug treatment for RP and the vast majority of reports of treating nipple RP have used nifedipine. Amlodipine is inherently long-acting, providing a potential advantage over nifedipine. It has been used for RP of the nipple, but with much less published evidence than nifedipine.In most studies, nifedipine doses of 20 mg three times daily were used, although some used 10–15 mg three times daily and others have used sustained-release nifedipine 30–60 mg/day. Common maternal side effects of dihydropyridines are headache, dizziness, hypotension, and tachycardia. Side effects may be lessened by starting nifedipine at 10 mg two to three times daily and then increasing weekly to a maximum dose of 60 mg/day. Amlodipine has been initiated at 5 mg/day and increased as necessary to 20 mg/day.5 Nifedipine and amlodipine milk levels are low and plasma levels in breastfed infants are undetectable. Maternal use of these drugs has not caused any adverse effects in breastfed infants.Phosphodiesterase Type 5 InhibitorsPhosphodiesterase type 5 (PDE5) inhibitors include sildenafil, tadalafil, and vardenafil. These vasodilators are used in RP refractory to calcium-channel blockers. A meta-analysis of trials of these drugs for secondary RP found that they are moderately effective in this condition, decreasing clinical severity, frequency, and duration of attacks.7 Doses that have been used are sildenafil 20 mg three times daily, tadalafil 5–20 mg once daily, and vardenafil 10 mg twice daily, although their use has not been reported in the nipple disease. Adverse effects are flushing, headache, and dizziness, and less frequently, hypotension, arrhythmias, cerebral vascular accident, and vision changes.5 Only sildenafil has information on use during breastfeeding. In two patients being treated for pulmonary hypertension, milk levels were very low in the milk of one woman, and the infant of the second woman appeared to have no adverse effects from the drug in milk.Other Oral TherapiesSeveral other drugs have evidence of benefit in RP, although they have not been studied in nipple disease. The angiotensin receptor blocker (ARB) losartan 50 mg/day reduced the severity and frequency of attacks better than nifedipine 40 mg/day in an open-label study in secondary RP. Losartan has not been studied in breastfeeding, but another ARB, candesartan, has. Preliminary evidence suggests that candesartan passes poorly into milk and is barely detectable in the plasma of breastfed infants.Fluoxetine 20 mg/day reduced the frequency of attacks in primary and secondary RP to a greater extent than nifedipine 40 mg/day in an unblinded study and a few case reports. However, fluoxetine is potentially problematic during breastfeeding. Milk levels can be high, and some infants have rather high serum levels. Adverse effects such as colic, fussiness, and drowsiness have been reported in breastfed infants whose mothers were taking the drug for depression.Topical NitroglycerinNitroglycerin ointment has a rapid vasodilator action that can treat the underlying vasoconstriction. Two recent systematic reviews of placebo-controlled studies of topical nitroglycerin for RP, mostly in the hands and fingers, found that it was quite effective.8,9 Nitroglycerin ointment is available commercially as a 2% ointment in the United States; studies used either 1% or 2% nitroglycerin ointment. Headache was the most commonly reported side effect in these studies. Reducing the nitroglycerin concentration from 2% to 1% ameliorated this side effect. Postural hypotension was reported in some patients, especially those taking other vasodilator medications. Studies in which blood pressure and heart rate were measured noted a drop in systolic blood pressure and increased heart rate. Use of nitroglycerin to treat RP of the nipple has been only sparsely reported. One woman with a history of vasoconstrictive pain in the hands and nipples who failed nifedipine treatment was treated with a low dose 0.2% nitroglycerin ointment and told to stop nursing.10 Her symptoms and nipple color returned to normal within a few weeks. Which intervention caused her improvement is unclear.Use of topical nitroglycerin by nursing mothers for anal fissures caused no adverse effects in their breastfed infants, indicating low milk levels. However, a concern with any topical therapy on the nipple is that the infant could directly ingest the drug and vehicle. Nitroglycerin could cause vasodilation and headache in the infant. In addition, the commercially available ointment in the United States (Nitro-Bid) has a base that contains white petrolatum, a petroleum product. Direct ingestion of petrolatum from the breast by the infant can result in consumption that far exceeds the acceptable daily intake of paraffins.11 It is not known if wiping excess ointment from the breast before nursing would completely eliminate these risks. Nitroglycerin ointment must never be used in any patient taking a PDE5 inhibitor, because of the drug interaction that causes severe hypotension.Dietary SupplementsSeveral dietary supplements are purportedly effective in RP of the nipple, including evening primrose oil, fish oil, vitamin B6 (pyridoxine), and l-arginine, although none are backed by high-quality studies. Pyridoxine 100 mg twice daily has been suggested for therapy of RP.4 Higher doses may decrease milk supply, so the dose should not be increased beyond this level. One woman with RP of the nipple researched this alternative and her source recommended 150–200 mg daily for 4 days followed by 25 mg/day. She stated that she did not notice any relief of her symptoms while taking pyridoxine.12Evening primrose oil and fish oil are sources of omega-3 and omega-6 fatty acids, which are precursors of prostaglandins and prostacyclin. Prostaglandin E and prostacyclin derivatives have been used intravenously to treat severe secondary RP, so there may be some rationale for using oils that increase endogenous levels of these vasodilators. These oils might also improve red cell rheology, which may improve blood flow. A few small studies in the 1980s found decreases in attacks of RP with the use of evening primrose oil with no objective changes in blood flow.13 Other small studies in the 1980s suggested fish oil supplementation might improve cold tolerance in patients with primary RP. No instances of the use these oils for RP of the nipple have been reported. These oils may take days to weeks to work, so should be viewed as prophylactic agents in those with a history of RP rather than as acute therapy. Neither of the two oils presents any special problems for the breastfed infant.l-arginine is a precursor to the physiological vasodilator, nitric oxide. There is some evidence that it improves blood flow and clinical symptoms in RP, but its use has not been reported in the nipple condition.5l-arginine has been initiated at 1–2 g/day orally and titrated to 10 g/day. l-arginine solution has also been used topically on hands and fingers with some success. Its use in nursing mothers has not been reported, but it is a normal amino acid, so serious adverse effects are not expected.Disclosure StatementNo competing financial interests exist.Funding InformationNo funding was received for this article.