Medication Summary
Drugs in a variety of classes have been studied for use in Raynaud syndrome. None is currently approved for this indication by the US Food and Drug Administration (FDA).
Drugs with clear evidence of benefit shown through randomized controlled trials include calcium channel blockers and the vasodilator iloprost. Other agents used in treatment of Raynaud phenomenon include the following:
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Topical nitroglycerin
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The selective serotonin reuptake inhibitor (SSRI) fluoxetine
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Phosphodiesterase-5 enzyme inhibitors
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The endothelin antagonist bosentan
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The angiotensin receptor blocker (ARB) losartan
Calcium channel blockers
Class Summary
These agents are used for vasodilation and possible antiplatelet effects. Calcium channel blockers of the dihydropyridine class contain potent vasodilators and are the first line of treatment after nondrug therapy. Of the dihydropyridines, nifedipine has been extensively studied; however, in the same category, felodipine, amlodipine, and isradipine seem to be equally effective.
Nifedipine (Adalat, Procardia, Nifediac CC, Nifedical XL)
Nifedipine inhibits transmembrane influx of extracellular calcium ions across myocardial and vascular smooth muscle cell membranes without changing serum calcium concentrations; this results in inhibition of cardiac and vascular smooth muscle contraction, with consequent dilation of main coronary and systemic arteries. Vasodilation with decreased peripheral resistance and increased heart rate result.
For Raynaud phenomenon, the extended-release form of nifedipine is most often selected. Treatment should be initiated at the lowest dose available and titrated upward as tolerated, with the goal of diminishing the frequency and/or severity of attacks.
Nicardipine (Cardene, Cardene SR)
Nicardipine is used for vasodilatation and possible antiplatelet effects. Start with lowest dose available. Extended-release preparations are preferred.
Prostaglandins
Class Summary
Agents in this class have potent vasodilatory effects.
Iloprost (Ventavis)
Iloprost is a synthetic analogue of prostacyclin (prostaglandin I2 [PGI2]) that dilates systemic and pulmonary arterial vascular beds. It is approved for use in pulmonary arterial hypertension, but has been found effective for secondary Raynaud syndrome, administered either orally or intravenously.
Epoprostenol (Flolan, Veletri)
Epoprostenol is an analogue of PGI2 that has potent vasodilatory properties, immediate onset of action, and a half-life of approximately 5 minutes. In addition to producing vasodilation, it also contributes to inhibition of platelet aggregation and plays a role in inhibition of smooth muscle proliferation.
Alprostadil (Prostin VR)
Alprostadil (Prostaglandin E1) is used primarily to keep patency of ductus arteriosus but also has a mild pulmonary vasodilatory effect. It is reported to inhibit macrophage activation, neutrophil chemotaxis, and release of oxygen radicals and lysosomal enzymes. It affects coagulation by inhibiting platelet aggregation and possibly by inhibiting activation of factor X. It may promote fibrinolysis by stimulating production of tissue plasminogen activator. Has been found to be effective for secondary Raynaud syndrome.
Nitrates, Angina
Class Summary
Topical nitroglycerin is used in Raynaud phenomenon for its local vasodilatory effects.
Bosentan (Tracleer)
Topical nitroglycerin is used in Raynaud phenomenon for its local vasodilatory effects.
Phosphodiesterase-5 Enzyme Inhibitors
Class Summary
Phosphodiesterases are a complex group of enzymes that help to tightly regulate the degradation of intracellular cyclic nucleotides. Intracellular responses to both NO and prostacyclin are mediated by the cyclic nucleotides cGMP and cyclic adenosine monophosphate (cAMP), respectively. So, by bolstering the vasodilatory effect of both NO and prostacyclin, these agents may be useful in the treatment of Raynaud phenomenon.
Sildenafil (Revatio)
Studies of sildenafil in Raynaud phenomenon have used in doses ranging from 25 mg three times daily to 50 mg twice daily.
Tadalafil (Adcirca)
Studies of tadalafil in Raynaud phenomenon have used in doses ranging from 20 mg dailiy to 20 mg three times a week. Doses may need to be adjusted for renal or hepatic impairment.
Vardenafil (Levitra, Staxyn ODT)
Vardenafil has been used in dosages of 10 mg twice daily for Raynaud phenomenon
Antidepressants, SSRIs
Class Summary
Serotonin is a potent vasoconstrictor that is released from nerve endings and during platelet activation. SSRIs do not have consistent evidence showing sustained benefit in Raynaud phenomenon, but they may be chosen if hemodynamic side effects develop with calcium channel blockers or prostacyclin analogues. However, some case reports describe exacerbation of Raynaud syndrome following the initiation of SSRI treatment.
Fluoxetine (Prozac)
Fluoxetine selectively inhibits presynaptic serotonin reuptake with minimal or no effect in the reuptake of norepinephrine or dopamine. Doses of 20 mg daily have been used in treatment of Raynaud phenomenon, with better results reported in primary Raynaud phenomenon.
Sertraline (Zoloft)
Sertraline selectively inhibits presynaptic serotonin reuptake, with minimal or no effect on reuptake of norepinephrine or dopamine.
Citalopram (Celexa)
Citalopram enhances serotonin activity through selective reuptake inhibition at the neuronal membrane. No head-to-head comparisons of SSRIs have been done; however, on the basis of metabolism and adverse effects, citalopram is considered the SSRI of choice for patients with head injury.
Escitalopram (Lexapro)
Escitalopram is an SSRI and an S-enantiomer of citalopram. It is used for the treatment of depression. Its mechanism of action is thought to be potentiation of serotonergic activity in the CNS, resulting from inhibition of CNS neuronal reuptake of serotonin. The onset of depression relief may be obtained after 1-2 weeks—sooner than is possible with other antidepressants.
Endothelin Antagonists
Class Summary
These agents inhibit vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 (ET-1) receptors ETA and ETB in endothelium and vascular smooth muscle.
Bosentan (Tracleer)
Bosentan is approved for use in the treatment of pulmonary arterial hypertension, but has been used off-label in patients with severe Raynaud phenomenon unresponsive to other therapies. Bosentan is approved in the United Kingdom for the prevention of new digital ulcers in patients with systemic sclerosis. [27]
ARBs
Class Summary
These agents are used for vasodilation and for their possible antifibrotic and anti-inflammatory effects.
Losartan (Cozaar)
Losartan is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Short-term treatment at 50 mg/day has proved useful, with better results in patients with systemic sclerosis than in those with primary Raynaud phenomenon.
Candesartan (Atacand)
Candesartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. In addition, candesartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.
Eprosartan (Teveten)
Eprosartan is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. In addition, eprosartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.
Irbesartan (Avapro)
Irbesartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II at the tissue receptor site In addition, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.
Losartan (Cozaar)
Losartan blocks the vasoconstrictive and aldosterone-secreting effects of angiotensin II. In addition, Losartan does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.
Olmesartan (Benicar)
Olmesartan blocks the vasoconstrictive effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptors in vascular smooth muscle. Its action is independent of the pathways for angiotensin II synthesis.
Valsartan (Diovan)
Valsartan is a prodrug that produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from AT1 receptors and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.
In addition, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.
Local Anesthetics, Amides
Class Summary
Local anesthetics are used for local pain relief. Local infiltration of lidocaine or bupivacaine at the base of the involved digits decreases sympathomimetic input, reduces ischemic pain, and improves blood flow.
Lidocaine (Xylocaine)
Lidocaine is an amide local anesthetic; it inhibits depolarization of type C sensory neurons by blocking sodium channels.
Bupivacaine (Marcaine)
Bupivacaine decreases permeability to sodium ions in neuronal membranes. This results in the inhibition of depolarization, blocking the transmission of nerve impulses.
Metabolic & Endocrine, Other
Class Summary
Agents in this class may be used in patients with systemic sclerosis and digital ulcers.
Acetylcysteine (Acetadote)
Acetylcysteine may prevent worsening of baseline renal insufficiency. It may scavenge oxygen-derived free radicals and improve endothelium-dependent vasodilation.
Neuromuscular Blocker Agents, Botulinum Toxins
Class Summary
These agents produce symptomatic improvement in strength, autonomic symptoms, or both in some patients.
Botulinum toxin type A (BOTOX)
This agent binds to receptor sites on motor nerve terminals and inhibits the release of acetylcholine, which in turn inhibits the transmission of impulses in neuromuscular tissue.
Anticoagulants, Hematologic
In patients with rapidly advancing ischemia, anticoagulant therapy may be necessary. Anticoagulants prevent recurrent or ongoing thromboembolic occlusion of the vertebrobasilar circulation.
Heparin
Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse thrombi but is able to inhibit further thrombogenesis. Heparin prevents recurrence of a clot after spontaneous fibrinolysis.
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A 9-year-old with Raynaud phenomenon. Notice the discoloration of the fingers.
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Photo of a patient with Raynaud phenomenon that resulted from working with a jackhammer. Courtesy of the CDC.
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Raynaud phenomenon showing demarcation of color difference.
