Dovepress and P  0.05 vs controls). Results after 4 weeks of therapy were better than after 2 weeks of therapy.57 In a well-designed, randomized, double-blind, placebo- controlled, crossover study, sildenafil was assessed in the treatment of RP resistant to vasodilatory therapy.5 This assessment included 16 patients with secondary RP and 2 patients with primary RP. Inclusion criteria were the regu- lar occurrence of painful Raynaud attacks and resistance to therapy with at least two conventional vasodilators. Therapy prior to study entry included calcium channel blockers in 94% of patients, nitroglycerin in 39%, pentoxifylline in 28%, ACE inhibitors in 22%, intravenous prostaglandins in 17%, and bosentan in 6%. All vasodilatory agents were discon- tinued prior to study entry. Mean capillary flow velocity increased with sildenafil, but not placebo. In addition, attack frequency and duration were substantially reduced with sildenafil. In all six patients with chronic digital ulcerations, healing was observed during sildenafil treatment. In two patients, ulcerations completely cleared during sildenafil treatment, but reappeared or progressed upon discontinua- tion of sildenafil therapy. Responses with tadalafil were observed in a randomized, double-blind, crossover study enrolling 25 patients with secondary Raynaud. The daily frequency, duration, and RCS scores were improved during tadalafil therapy. In addition all preexisting fingertip ulcers healed during the tadalafil phase, and fewer ulcers developed during the tadalafil phase than during the placebo phase.59 In contrast with the benefits observed in the above stud- ies and case reports, no benefit was observed in 20 patients with primary RP treated with sildenafil in a randomized, double-blind, crossover study. Patients received sildenafil 50 mg twice daily or placebo for 2 weeks, followed by a 1-week washout period, and administration of the alternate agent for 2 weeks; this dosage regimen was identical to the regimen used in the preceding sildenafil study. No differences between sildenafil and placebo was observed in frequency and duration of Raynaud attacks, or measurements of blood supply to the digits upon exposure to cold.58 Another randomized, double-blind, placebo-controlled study of tadalafil in 39 patients with secondary Raynaud revealed no significant differences from placebo in RCS, or frequency and duration of RP.60 Similarly, tadalafil did not improve digital blood flow or attenuate cold-induced vasoconstriction in a population of patients mostly with primary Raynaud.81 Limited adverse effect information was reported in these small studies and case reports. Adverse effects reported with Vascular Health and Risk Management 2010:6 Treatment of Raynaud’s phenomenon sildenafil and vardenafil therapy in patients with RP have included headache, muscle pain, flushing, facial heat sensation, rhinorrhea, nausea, dyspepsia, dizziness, and visual abnormali- ties.5,56,68 These adverse effects are similar to those observed with PDE5 inhibitors in the treatment of erectile dysfunction. Serotonin receptor antagonists and serotonin reuptake inhibitors The role of serotonin in the pathophysiology and management of RP is not clearly established. Remission of RP symptoms has been described in a patient treated with fluoxetine; possibly as a result of depletion of platelet serotonin.82 Other case reports have described improvement with sertraline and escitalopram83,84 A crossover study has also compared fluoxetine with nifedipine in the treatment of 26 patients with primary and 27 patients with secondary RP. Patients received fluoxetine 20 mg daily or nifedipine 40 mg daily for 6 weeks, followed by a 2-week washout period and then therapy with the alternate agent. Attack frequency and sever- ity were reduced with either therapy; however, the effect was significant only during the fluoxetine therapy.85 Numerous other reports, however, have described exacerbation of RP symptoms following initiation of therapy with a serotonin reuptake inhibitors and serotonin partial agonists (fluoxetine, fluvoxamine, citalopram, reboxetine, tegaserod).86–90 Sarpogrelate is a selective serotonin 5HT2 receptor antagonist that is undergoing evaluation in the treatment of RP. In a small study enrolling 7 patients with systemic sclerosis, sarpogrelate 300 mg once daily for 12 months was associated with a decreased frequency and duration of RP, as well as the coldness, numbness and pain of RP. The effect appeared to be mediated by reduction in the plasma concentration of fibrinopeptide A (FPA), beta thromboglobu- lin (beta-TG), and platelet factor 4 (PF4), and prevention of platelet aggregation.91 Improvement in the frequency and duration of RP and symptoms of coldness and pain were also described in a Japanese report including 32 patients with secondary RP treated with sarpogrelate 300 mg once daily for 8 weeks, and in a meeting abstract reporting on 12 patients with secondary RP treated with sarpogrelate 300 mg once daily for 12 weeks.92,93 Antioxidants N-Acetylcysteine has also demonstrated activity in patients with RP secondary to systemic sclerosis. The use of N-acetylcysteine in the treatment of RP has been described in an open-label pilot study enrolling 22 patients with RP secondary to systemic sclerosis. The study was conducted submit your manuscript | www.dovepress.com Dovepress 173