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Journal of Drugs in Dermatology, May, 2008 by Kendra Gail Bergstrom, Ronald O. Perelman

TREATMENT FOR RAYNAUD'S: BEYOND CALCIUM CHANNEL BLOCKERS

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Raynaud's disease (RD), the presence of the vasospastic phenomenon without underlying systemic disease, can be troubling to patients. Raynaud's disease is relatively common; it affects 5% of men and 8% of women in a Framingham Heart Study cohort.(1) Clinical associations include migraines and angina. Raynaud's disease is usually bilateral and gangrene is rarely a complication.

The diagnosis of Raynaud's may precede diagnosis of an underlying collagen vascular disease or remain an isolated phenomenon. Raynaud's disease, or primary Raynaud's, can be distinguished from Raynaud's phenomenon (RP), or secondary Raynaud's, by the absence of an associated systemic disease in RD. The differential for RD includes a broad range of secondary causes of RP (Table 1). In 1 series, approximately 15% of patients with RP progressed to a systemic disease over a 10-year period. Raynaud's phenomenon is caused by the vasoconstriction of the small arteries and arterioles of the digits, leading to painful pallor, cyanosis, and rubor. In severe cases, digital ulceration and necrosis can occur.

Treatment

While the cornerstone of treatment is calcium channel blockers (CCBs), many patients cannot tolerate this therapy and require alternative treatment. Treatment options for RD are rarely based on large clinical trials. Much of the data on treatment of RP come from studies treating digital ulcerations in scleroderma and systemic sclerosis.

All patients with RD are advised to follow similar general measures, including avoiding cold triggers, wearing mittens and protective hand wear, abstaining from smoking, and, when applicable, changing to oral contraceptives with low estrogen or containing only progesterone. New data from the Framingham Heart Study suggest that the consumption of red wine may offer a mild protective benefit. (2)

Calcium Channel Blockers

The most commonly used initial therapy for RD is a CCB. Initial studies evaluated the use of oral nifedipine(3) 3 times per day in doses between 10 and 20 mg. This study defined efficacy as a decrease in the number of attacks and duration of each attack, and demonstrated that 50% of episodes were eliminated with this therapy. A subsequent study evaluated the efficacy of felodipine at 5 and 10 mg daily compared to that of nifedipine and a placebo, and showed an equal efficacy in terms of reducing patient-reported symptoms recorded during attacks, with felodipine having the advantage of once daily dosing. (4) Diltiazem, dosed in studies at 120 mg orally 3 times per day, has shown efficacy in RD(5) but not in RP(6) Head-to-head studies comparing short acting (3 times per day) nifedipine to felodipine showed equivalent efficacy, (4) but there are no comparative studies between long-acting daily-dosed nifedipine (Procardia XL[R]) and other CCBs.

Nitrates; Topical, Sublingual, and Transdermal Patch Delivery

Due to their vasodilator effects, nitrates have been identified as a possible treatment for RD with case reports of efficacy since the 1950s. Initial use of sublingual nitroglycerin (also called glyceryl trinitrate) evaluated Raynaud's triggered by the immersion of hands in ice water and assessed efficacy by the time it took to rewarm the hand. Sublingual nitroglycerin decreased time to rewarming to under 6 minutes from previous results of over 40 minutes. The use of sublingual nitroglycerin was limited by systemic side effects including headaches, dizziness, and hypotension.(7) More recent work has focused on the use of topical nitroglycerin paste applied locally, which causes local vasodilation for 20 to 40 minutes after induced RD attacks. Nitroglycerin ointment is sold under many brand names in strengths from 0.2% to 2%. Nitroglycerin can also be delivered via a transdermal patch applied to the chest for constant low-level systemic absorption at approximately 0.2 mg/hour. In one study, the nitroglycerin transdermal patch showed subjective efficacy in terms of a decreased number of attacks and severity on a 10-point visual analog scale over a 1-week period. Unfortunately, use was limited by treatment-refractory headaches in 8 of 42 patients. (8)

L-arginine Supplementation

L-arginine is an endogenous amino acid synthesized in the urea cycle. Arginine is the immediate precursor of nitric oxide, an endogenous gaseous signaling molecule. L-arginine is converted into nitric oxide by the enzyme nitric oxide synthase. The actions of nitric oxide are described by its previous name, endothelial-derived relaxing factor. Data from the surgical literature suggest a role in enhancing wound healing. Previous in vitro evidence that L-arginine was beneficial in coronary artery disease was reversed by a large clinical trial showing that L-arginine was associated with no mortality benefit relative to a placebo. For this reason, it is not recommended for cardiac patients.