Dovepress In a randomized, double-blind, crossover study enrolling 109 patients with moderate to severe primary or secondary RP (mean baseline RCS 3.9), treatment with MQX-503 0.9% applied immediately before or within 5 minutes of onset of an attack was associated with a lower mean RCS than placebo (2.92 vs 3.17; P = 0.009). An improvement in RCS of at least 2 points was achieved in 42% of patients with MQX-503 compared with 23% of patients with placebo. Mean measures of pain and numbness were also lower with MQX-503 compared with placebo.17 In combined data from three phase 3 studies of MQX-503 assessed for safety and tolerability, adverse events occurred with similar frequency with MQX-503 and vehicle placebo: headache (17% and 15%), dizziness (6% and 5%), and skin irritation (2% and 2%).18 Prostaglandin analogs For patients with an insufficient response to traditional vasodilators, prostaglandin analogs are sometimes given. Most of the literature involves the investigational use of iloprost, a stable analog of epoprostenol (prostaglandin I2), which has demonstrated variable activity in RP associated with systemic sclerosis. Iloprost is a potent vasodilator and inhibitor of platelet aggregation. In a 1998 Cochrane review, intravenous iloprost was reported to be effective in the treatment of RP secondary to scleroderma – decreasing the frequency and severity of attacks and preventing or heal- ing digital ulcers.19 Results have not been consistent across all studies though. Intermittent iloprost infusions reduced the frequency and severity of RP attacks in patients with RP secondary to systemic sclerosis in a large randomized, placebo-controlled, double-blind study; however, there was no difference between treatments in digital ulcer healing.20 Iloprost was also associated with reduced frequency and severity of attacks in two small crossover studies.21,22 In another small study also enrolling patients with systemic sclerosis iloprost had no effect on RP severity or frequency, but was associated with improved ulcer healing.23 In another small study improvement in the frequency of RP attacks was observed, with no difference in duration or severity.24 High and low dose regimens were associated with a reduction in frequency, severity, and duration of RP attacks in a double- blind study and in an open-label study. A reduction in digital ulcers was also reported in the latter.25,26 Other small studies compared intravenous iloprost with nifedipine in patients with RP associated with systemic sclerosis. Short term intravenous iloprost infusions produced a reduction in the number, duration, and severity of RP attacks comparable to Vascular Health and Risk Management 2010:6 Treatment of Raynaud’s phenomenon oral nifedipine.27 Intermittent iloprost infusions improved skin scores and RP severity scores to a greater extent than oral nifedipine in a long-term comparative study.28 Table 1 summarizes the key studies with the intravenous iloprost. Other case reports, case series and observational studies have also described reduced RP attack severity, duration, and frequency, and improved ulcer healing with intermittent iloprost infusions.29–34 Iloprost was associated with a high incidence of adverse reactions during infusion, including headache, flushing, nausea, jaw pain, diarrhea, vomiting, injection site reactions, and myalgia; however, intermittent administration is possible.20,22,23,28 Other studies have also assessed an investigational oral iloprost in patients with RP secondary to systemic sclerosis, again with variable results. In one large study, oral iloprost 50 mcg twice daily for 6 weeks was no more effective than placebo in reducing the frequency, duration, or severity of RP attacks.35 In a smaller study, oral iloprost 150 mcg twice daily for 10 days was also no more effective than placebo in reducing RP attack duration or severity, was but preferred by patients.36 In another smaller study, oral iloprost 50 mcg and 100 mcg twice daily for 6 weeks was associated with reduced RP attack duration and severity, but no change in frequency.37 Reduced duration and severity of RP attacks was also reported in a series of 20 patients with primary or secondary RP treated with inhaled iloprost.38 Other prostaglandin analogs have also been assessed, without demonstrating consistent benefit. In a small open- label assessment, daily infusion of alprostadil for six days was associated with a reduced frequency and severity of RP attacks in patients with systemic sclerosis;39 however, in a double-blind, placebo-controlled study enrolling patients with primary RP or RP secondary to systemic sclerosis, IV alprostadil was no more effective than placebo.40 A double- blind study revealed no differences between oral beraprost and placebo in the treatment of primary RP.41 Endothelin receptor antagonists More recently studies have assessed the use of oral endothelin receptor antagonists as an alternative to prostaglandins in patients with severe RP not responding to other therapies. Endothelin-A (ETA) receptors are found primarily in vascu- lar smooth muscle cells and mediate vasoconstriction and cell proliferation. Endothelin-B (ETB) receptors are found primarily on endothelial cells and mediate vasodilatation via nitric oxide. Bosentan acts as an antagonist primarily at ETA receptors, reducing vasoconstriction mediated by endogenous endothelin. In the United Kingdon and Ireland, bosentan is submit your manuscript | www.dovepress.com Dovepress 169