Levien mediators, nitric oxide, endothelin-1, serotonin, thromboxane, and angiotensin have been suggested to play a role. Numerous neural mediators, including calcitonin gene-related peptide and neuropeptide Y, and agents interacting with alpha-adr- enoreceptors have also been implicated through impairment of vasodilation and increased vasoconstriction. In addition, platelet activation, fibrinolysis, and oxidative stress may contribute.2,3 Nonpharmacologic therapies include avoidance of cold temperatures, emotional stress, caffeine, and smoking, as well as avoidance of vasoconstrictive medications.3,5 Phar- macologic therapy has historically included dihydropyridine calcium channel blockers, alpha1-adrenergic blockers, angiotensin II receptor antagonists, topical nitroglycerin, and pentoxifylline.3,5 Patients with primary RP only occa- sionally require pharmacologic therapy; while such therapy is more common in patients with secondary RP. Despite therapy, some patients with severe attacks will develop intense pain, ulceration and ischemic skin lesions, and gangrene, and may ultimately require therapy with intra- venous prostaglandins. Patients with severe symptoms or intolerance to available therapies have prompted exploration of alternative therapies, including endothelin antagonists, phosphodiesterase type 5 (PDE5) inhibitors, antioxidants, and newer vasodilators. No guidelines have been published for the therapy of RP, and many of the agents used in the treatment of RP are used off-label. Historical treatments and newer variations Calcium channel blockers remain the most widely used class of drugs in the management of RP.3 The dihydropyridine cal- cium channel blockers are most effective; nifedipine has been the most extensively studied. In a meta-analysis in primary RP, calcium channel blockers reduced frequency of attacks by 2.8 to 5 fewer attacks per week and severity by 33%.6 In another meta-analysis in RP secondary to systemic sclerosis, calcium channel blockers reduced RP attack frequency by 8.3 attacks over 2 weeks and severity by 35%.7 Calcium chan- nel blockers typically used include nifedipine, nicardipine, felodipine, and amlodipine; once daily and sustained release dosage forms are preferred.3 A recent Cochrane review identified no other oral vasodi- lators with established efficacy in primary RP.8 Studies with angiotensin converting enzyme (ACE) inhibitors have not dem- onstrated a clear benefit. The angiotensin II receptor antagonist losartan reduced the severity and frequency of RP to a greater extent than nifedipine in primary RP in one small comparative 168 submit your manuscript | www.dovepress.com Dovepress Dovepress study.9 The alpha1-adrenergic blocker prazosin was found to be modestly effective in the treatment of RP secondary to sclero- derma in another Cochrane review.10 The vasodilator fasudil, a rho-kinase inhibitor, is also undergoing evaluation for the treat- ment of RP in patients with systemic scleroderma.11 Nitroglycerin ointments, sublingual tablets, and trans- dermal patches have also been used in the therapy of RP, demonstrating improvements in finger temperature and perfusion, but with a high incidence of side effects including headache and dizziness. Topical nitroglycerin reduces the severity and frequency of vasospastic episodes in primary and secondary RP.12–14 A new formulation of topical nitroglycerin is currently undergoing evaluation in clinical trials and has been submit- ted for approval in the United States. MQX-503 (MediQuest Therapeutics, Inc., Bothell, Washington, USA) consists of nitroglycerin in a microemulsion of approximately 50% lecithin-based organic phase and 50% water phase. It is rapidly absorbed, and has a rapid onset of action. MQX-503 0.5% and 1.25% were compared with placebo gel applied to fingers immediately prior to a cold challenge in 36 patients with primary or secondary Raynaud. Improvements in blood flow as assessed by laser Doppler were observed as early as 5 minutes after the cold challenge. The mean time to achieve baseline blood flow was shorter with MQX 1.25% applica- tion; although there was no difference in time to achieve 50% or 70% baseline skin temperature or in pain/numbness/tin- gling scores between the 3 groups.15 MQX-503 reduced the severity of RP, but not the dura- tion or frequency, in a randomized, double-blind, placebo- controlled study enrolling 219 patients with primary or secondary RP who experienced at least 5 RP episodes in a 7-day period during a placebo run-in phase. Over 90% of patients were female, with a mean age of 46 years. Over two- thirds had secondary RP, primarily associated with systemic sclerosis. Patients received MQX-503 0.9% or placebo with instructions to apply gel to the affected finger immediately before or up to 5 minutes after the onset of a RP event. The change in mean daily Raynaud’s Condition Score (RCS) from baseline, the primary endpoint, was 0.48 with MQX-503 (14.3%) compared with 0.04 (1.3%) with placebo (P  0.04). The mean number and duration of RP events did not differ between treatments. In patients with systemic sclerosis, new digital ulcers developed with similar frequency in the two groups (9% with MQX-503 and 13% with placebo; P = 0.51). Adverse effects did not differ between groups; headache occurred in 23% of MQX-503 treated patients and 21% of placebo recipients.16 Vascular Health and Risk Management 2010:6