Pediatric Raynaud Phenomenon Medication

Updated: Jun 23, 2022
  • Author: Suzanne C Li, MD, PhD; Chief Editor: Lawrence K Jung, MD  more...
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Medication Summary

Medications are used to reduce severity of Raynaud phenomenon (RP) episodes if modifications in lifestyle are ineffective. Medications are more likely to be used to treat secondary Raynaud phenomenon rather than primary Raynaud phenomenon. Adult patients with scleroderma and systemic lupus erythematosus generally have the highest risk for developing digital ischemia. [9]

A Cochrane review of oral vasodilators did not find evidence to support the use of any other class of medications besides calcium channel blockers for treating primary Raynaud phenomenon. [91] This was largely due to limited methodology of studies and small number of studied patients. [91] A EULAR review recommended that dihydropyridine-type calcium channel blockers (usually nifedipine) be first-line treatment for Raynaud phenomenon in systemic sclerosis patients, intravenous prostanoids considered for treatment of systemic sclerosis patients with severe Raynaud phenomenon, and bosentan considered for those in whom both calcium channel blockers and prostanoids fail. [92]

A recent report from scleroderma experts found high agreement on using phosphodiesterase inhibitors to treat secondary Raynaud phenomenon not sufficiently responsive to calcium channel blockers. [93]

General categories of medications used to treat Raynaud phenomenon include the following: [17, 7]

  • Vasodilators (eg, calcium channel blockers, nitric oxide [NO] supplementation/NO donors/L-arginine (includes phosphodiesterase inhibitors, topical nitroglycerin), prostanoids, calcitonin gene–related peptides [CGRP], phosphodiesterase inhibitors)

  • Drugs that reduce vasoconstriction (eg, ACE inhibitors, angiotensin II receptor antagonists, α-adrenergic blockers, endothelin-1 receptor antagonists, serotonin reuptake inhibitors)

  • Other drugs with effects on vasculature (eg, antioxidants, statins, rho-kinase inhibitors)

  • Platelet inhibitors affect blood viscosity (eg, salicylates, dipyridamole, prostaglandins, pentoxifylline)

  • Miscellaneous agents (eg, rituximab, anakinra, botulinum toxin A)

Details for the most commonly used drugs (ie, calcium channel blockers, α-adrenergic blockers, nitroglycerin ointment, nitroprusside) are described in the specific medication tables provided below.

Angiotensin inhibitors

ACE inhibitors and angiotensin II receptor blockers can affect endothelial function but randomized placebo-controlled trials of 3 ACE inhibitors (quinapril, captopril, enalapril) have not shown any significant benefit for Raynaud phenomenon patients. [93, 91]

Selective serotonin receptor inhibitors

Serotonin receptor antagonists have been studied in patients with Raynaud phenomenon. Fluoxetine (Prozac) administered at a dose of 20 mg PO qd decreased frequency and severity of primary Raynaud phenomenon and secondary Raynaud phenomenon in adult patients in some studies but did not in others. [7, 5] Their use has not been reported in pediatric patients with Raynaud phenomenon. Dosing for children older than 5 years for other conditions has been 5-10 mg orally daily, not to exceed 20 mg/day. [94]

Ketanserin was not shown to be beneficial for patients with secondary Raynaud phenomenon (patients with systemic sclerosis) in a meta-analysis and is not marketed in the United States or United Kingdom. [7]

Sarpogrelate hydrochloride administered 3 times per day was reported to reduce digital ulcers in systemic sclerosis patients after 3 months in an open-label study. [87]


Prostanoids can have several beneficial effects in patients with Raynaud phenomenon including vasodilation, inhibiting platelet aggregation, suppressing profibrotic cytokine connective tissue growth factor, and affecting vascular remodeling. [7]

The prostacyclin analogue iloprost has been shown to be beneficial in reducing the frequency and severity of ischemic attacks and in digital ulcer healing in adult patients with Raynaud phenomenon but only via the intravenous route. [2, 7, 5] Iloprost has been shown to be beneficial in children with Raynaud phenomenon at doses of 2 (±0.3) ng/kg/min IV for 6 h/d for 10.7 (±5.7) days for each cycle. [95] Intravenous iloprost is not available in the United States; only the inhalation product (Ventavis) is available in the United States and is indicated for pulmonary hypertension. [5, 96]

Prostaglandin E1 (alprostadil [Prostin VR]) administered at 6-10 ng/kg/min IV for 72 hours was not found to have a clear benefit in adults with Raynaud phenomenon. [5] However, another study comparing iloprost with alprostadil (20 mcg/h for 5 d, then 1 d/mo) showed similar efficacy between the 2 medications. [97]

Epoprostenol was reported to be beneficial in treating pediatric patients with severe Raynaud phenomenon digital ischemia when administered at 4-20 ng/kg/min IV. [14] The cost and complicated continuous IV infusion limits the clinical use of this agent.

A transdermal prostaglandin analogue, CL115.347.cyanamid (500 mcg q12h) was reported to be helpful in children with Raynaud phenomenon. [14] In adults, 1000 mcg was optimal for treating primary Raynaud phenomenon and secondary Raynaud phenomenon. [98]

Phosphodiesterase inhibitors

Nitric oxide (NO) is a strong vasodilator. Phosphodiesterase inhibitors increase the availability and/or effect of NO and several studies have evaluated their effectiveness for Raynaud phenomenon, primarily secondary Raynaud phenomenon. [87] Most report improvement during the 4- to 6-week treatment periods. A meta-analysis of 6 randomized clinical trials found moderate but significant improvement in symptoms, with insufficient data to evaluate their effectiveness for treating or preventing digital ulcers. [99]

Sildenafil (Revatio, Viagra) has been reported to decrease the frequency, severity, and duration of Raynaud phenomenon attacks and aids in the healing of digital ulcers in adults. [100, 101] Two randomized, double-blind, placebo-controlled trials have been conducted, one using sildenafil 50 mg PO bid in 15 secondary Raynaud phenomenon patients for 4 weeks and another using a modified-release sildenafil at 100 mg PO once a day for 3 days and then dosed at 200 mg/day for a total of 4 weeks in 57 patients with limited systemic sclerosis. Both studies reported improvement, either a decrease in in Raynaud phenomenon symptoms or in frequency of attacks. [100]

Randomized, double-blind, placebo-controlled trials have been conducted of 2 other phosphodiesterase inhibitors, vardenafil and tadalafil. Vardenafil was dosed at 10 mg PO bid in 6 primary and 47 secondary Raynaud phenomenon patients for 6 weeks after being studied in an open-label trial. Both studies reported benefit. [102, 103] Two randomized, double-blind, placebo-controlled trials of tadalafil reported different findings. In one trial, tadalafil dosed at 20 mg/day in 39 secondary Raynaud phenomenon patients for 4 weeks was reported to have no benefit, while in the other, tadalfil was dosed at 20 mg on alternate days in 24 seondary Raynaud phenomenon patients for 6 weeks and reported to decrease symptoms and improve ulcers. [104, 105] Adverse effects of these medicines include flushing and headache. [87]

Dosing of sildenafil for pediatric patients has not been established. A recent study reported a mean dose of 3.4 ± 1.1 mg/kg/d to treat children (aged 4-18 y) with pulmonary hypertension. [106] Tadalafil was given at 1 ± 0.4 mg/kg/day in these patients. [106]

Endothelin inhibitors

Bosentan may be most helpful for secondary Raynaud phenomenon patients with severe vascular disease. It was found to prevent the occurrence of digital ulcers in systemic sclerosis patients in 2 randomized placebo-controlled clinical trials, reducing the occurrence rate by 30% compared to placebo. [107, 108] Bosentan, however, did not improving healing of existing ulcers. [107, 108] Potential adverse effects include liver toxicity and teratogenicity, and it may reduce the effectiveness of hormonal contraceptives. [92]

In adults, it has been dosed at 62.5 mg PO bid for 4 weeks initially, then 125 mg bid for 12 weeks. [107, 108] No information on its use in pediatric Raynaud phenomenon has been reported. Three different dosing regimens were used to treat children (aged 3-15 y) who had pulmonary hypertension. [109] Children who weighed 10-20 kg were treated with 31.25 mg PO bid, those who weighed 20-40 kg were treated with 62.5 mg PO bid, and those who weighed more than 40 kg were treated with 125 mg PO bid. [109] It was used to treat an 11-year-old girl with systemic sclerosis with Raynaud phenomenon and pulmonary hypertension with improvement in both conditions; dosing was begun at 62.5 mg/day, increased to 125 mg/day, and then to 250 mg/day. [110]

Another ET1A-R inhibitor, ambrisentan, was reported effective in a small open-label study and is currently being evaluated in a larger trial. [4]


Limited studies have been done of antioxidants. Probucol (Lorelco) given at 500 mg PO qd for 12 weeks decreased the frequency and severity of primary Raynaud phenomenon and secondary Raynaud phenomenon episodes in adults and increased their low-density lipoprotein oxidation lag time compared with nifedipine. [111] N -acetylcysteine (NAC) increases levels of glutathione, an endogenous antioxidant, and has also been reported to have vasodilation effects. [112] In an open-label prospective study, 50 systemic sclerosis patients received intravenous NAC 15 mg/kg/hour x 5 hours every 14 days for a median of 3 years and were reported to have a significant decrease in the number of ulcers, decrease in attack symptoms, and over 50% decrease in attack frequency. [112] No major adverse effects were reported.

Miscellaneous agents

Statins may improve endothelial dysfunction, reduce the coagulation of blood, and have anti-inflammatory effects. [113] One randomized placebo-controlled trial has been conducted in 84 systemic sclerosis patients who either received atorvastatin 40 mg/day or placebo for 4 months. Patients who received atorvastatin had a significant decrease in developing new digital ulcers, improved patient function, and showed improvement in endothelial markers of activation. [113] More study is needed to evaluate this class of drugs.

RhoA/Rho kinase inhibitor

A double-blind, placebo-controlled, randomized, cross-over study of a Rho kinase inhibitor did not find a significant difference in digital blood flow between a single dose of fasudil and placebo following a cold challenge. [114]

Other drugs, such as pentoxifylline (Trental), decrease blood viscosity and may help in mild, but not severe, Raynaud phenomenon. [2] An older study reported a reduction in adult Raynaud phenomenon symptoms with subcutaneous low molecular weight heparin, but no follow-up studies have been done. [4]

A few studies have reported that botulinum toxin A can improve blood flow and reduce ischemia, ulceration, and pain in secondary Raynaud phenomenon associated with systemic sclerosis, but studies have been done without controls and using a range of doses. [115] Botulinum toxin may block smooth muscle depolarization and vasoconstriction. [115]

Treatment of the underlying disease can improve Raynaud phenomenon symptoms. Rituximab (Rituxan) was found to decrease severe Raynaud phenomenon symptoms in an adult female with mixed connective tissue disease who had failed treatment with iloprost, bosentan, and tadalafil, and digital sympathectomy. She was treated with rituximab (1000 mg) and had good response with retreatment when her symptoms flared. [116]

The interleukin1-receptor antagonist anakinra was reported to decrease Raynaud phenomenon symptoms in a patient with familial cold autoinflammatory syndrome (FCAS); the anakinra controlled the FCAS symptoms, and no further Raynaud phenomenon episodes occurred while taking anakinra. [45]


Calcium channel blockers

Class Summary

A meta-analysis of all studies using calcium channel blockers (most commonly nifedipine) to treat Raynaud phenomenon reported a benefit, with a moderate reduction in mean number of attacks and a 35% improvement in severity in systemic sclerosis–related Raynaud phenomenon. A smaller, but significant, benefit was observed for primary Raynaud phenomenon. [117, 118] The primary Raynaud phenomenon trials did not use maximum dosage, which may have caused the lesser response.

Most studies involve the dihydropyridine class of calcium channel blockers (eg, amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine). [2, 5] Limited studies suggest felodipine, amlodipine, and isradipine may be as effective as nifedipine, whereas diltiazem and verapamil are less potent. [5] Adverse effects (eg, edema, flushing, tachycardia, headache, hypotension) may occur in 15% of patients. [7, 5, 9]

The adult dose for nifedipine is typically 10-30 mg PO tid/qid for the prompt release formulation or 30-90 mg PO qd for sustained release. [5] In pediatric patients, nifedipine doses may range from 0.2-1 mg/kg/d PO divided tid/qid. Initiate with small doses and increase as tolerated and needed. [14, 119, 1]

Doses of other calcium channel blockers include the following:

- Amlodipine: Administer 2.5-10 mg PO qd initially and adjust as needed up to 20 mg/d in adults. [5] Pediatric dosing for hypertension is 0.1-0.2 mg/kg PO qd but may increase up to 0.3 mg/kg/d. [94]

- Felodipine: Administer 2.5-10 mg PO qd in adults. [120, 5]

- Isradipine: Administer 2.5-10 mg PO qd bid in adults. [5]

- Nicardipine: Administer 50 mg PO qd in adults. [5]

Nifedipine (Procardia)

Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Also causes peripheral vasodilation.


Alpha-adrenergic blockers

Class Summary

Smooth muscle α2-adrenergic receptors respond to the cold and were found to have increased reactivity in patients with systemic sclerosis. [7, 121] A randomized placebo-controlled trial of an α2C -adrenoreceptor antagonist was recently completed. No benefit on digital rewarming following a cold challenge was found from administering a single oral dose of 30 or 100 mg of ORM-12741 to 12 systemic sclerosis patients, with blow flow assessed by temperature probe, LDI, and IT. [122] Other studies on medications that block these receptors are limited. [5, 7]

Phenoxybenzamine was reported to be beneficial in a case series of Raynaud phenomenon in children who were given 0.25-1 mg/kg/d PO divided tid. [14] Adult doses of phenoxybenzamine range from 10 mg PO qid to 30 mg PO tid. [5] Adult doses of prazosin range from 1-3 mg PO bid or tid. [5, 123]

Prazosin (Minipress)

Prazosin treats prostatic hypertrophy. Improves urine flow rates by relaxing smooth muscle, which is caused by blocking α 1-adrenoceptors in the bladder neck and prostate. When increasing dose, administer first dose of each increment at bedtime to reduce syncopal episodes. Although doses >20 mg/d usually do not increase efficacy, some patients may benefit from as much as 40 mg/d.

Phenoxybenzamine (Dibenzyline)

Long-acting, adrenergic, α -receptor blocker that can produce and maintain a chemical sympathectomy. Lowers supine and upright blood pressures. Does not affect the parasympathetic nervous system.


L-arginine and nitric oxide pathway supplementation

Class Summary

NO is a strong vasodilator, L-arginine is precursor for NO, and topical glyceryl trinitrate is an NO donor. [7]

Topical nitrates have been used to decrease frequency and severity of primary Raynaud phenomenon and secondary Raynaud phenomenon. [9] Nitroglycerin 1% ointment has been applied to affected fingers in children with Raynaud phenomenon (< 4 mm/kg) bid or tid as tolerated. [1] In adults, nitroglycerin 2% ointment (0.25-0.50 inch) has been applied locally. [5] The topical glyceryl trinitrate patch can be effective in adults but has a high frequency of systemic adverse effects, which limits its use. [124] A topical preparation of a novel formulation of nitroglycerin MQX-503 was found effective for reducing symptoms in a placebo-controlled trial in secondary and primary Raynaud phenomenon patients, but it is not commercially available. [87, 125]

Intravenous L-arginine and sodium nitroprusside were effective in patients with secondary Raynaud phenomenon. [7] In pediatric patients with Raynaud phenomenon, nitroprusside has been anecdotally given at 0.5-5 mcg/kg/min IV. [14] No benefit was found for PO L-arginine in a trial of adult patients with primary Raynaud phenomenon and secondary Raynaud phenomenon (scleroderma-related). [7]

Nitroglycerin topical (Nitro-Bid ointment)

Causes relaxation of vascular smooth muscle by stimulating intracellular cyclic guanosine monophosphate production. The result is vasodilation and decreased blood pressure.

Nitroprusside (Nitropress)

Rapidly acting, easily titrated, antihypertensive. Produces vasodilation and increases inotropic activity of the heart. At higher dosages, may exacerbate myocardial ischemia by increasing heart rate.


Platelet inhibitors

Class Summary

Salicylates are administered to decrease platelet aggregation and activation. No adult trial has shown a clear benefit for their use, but they are still recommended for adult patients with systemic sclerosis (80-975 mg aspirin/d). [5]

Salicylates have also been administered to children with Raynaud phenomenon. Nigrovic et al reported that low-dose aspirin was given to patients with Raynaud phenomenon who had antiphospholipid antibodies. [28] Burns et al reported that salicylates were used in patients whose platelets showed spontaneous aggregation (2.5 mg kg/dose PO every other day or dipyridamole 5 mg/kg/d PO divided tid). [14]

No clear benefit has been demonstrated for low molecular weight heparin in adult studies. [5]


Odorless, white, powdery substance available in 81 mg, 325 mg, and 500 mg for oral use. When exposed to moisture, aspirin hydrolyzes into salicylic acid and acetic acids.

Stronger inhibitor of both prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives. Acetyl group is responsible for inactivation of cyclooxygenase via acetylation. Aspirin is hydrolyzed rapidly in plasma, and elimination follows zero-order pharmacokinetics.

Irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to PGI2 (potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (potent vasoconstrictor and platelet aggregate). Platelet-inhibition lasts for life of cell (approximately 10 d).

May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. Reduces likelihood of myocardial infarction. Also very effective in reducing risk of stroke. Early administration of aspirin in patients with AMI may reduce cardiac mortality in first month.

Dipyridamole (Persantine)

Platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine, itself an inhibitor of platelet reactivity. In addition, may inhibit phosphodiesterase activity, leading to increased cyclic-3',5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2. May enhance effects of aspirin.