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Drug Information Pharmacist and Clinical Assistant Professor, Pharmacotherapy Department, College of Pharmacy, Washington State University Spokane, PO Box 1495, Spokane, WA 99210-1495, fax 509/358-7744, Levient{at}wsu.edu
Reprints: Dr. Levien
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DATA SOURCES: Searches of MEDLINE (1966-March 2006) and Web of Science (1980-March 2006) were conducted; search terms were sildenafil, tadalafil, vardenafil, phosphodiesterase, and Raynaud. Studies and case reports published in English were retrieved. Additional references were identified in bibliographic reviews.
DATA SYNTHESIS: Several small studies and a number of case reports have described the use of PDE5 inhibitors in patients with either primary or secondary Raynaud's phenomenon. The data from the best designed study show a reduced attack frequency and duration, reduced Raynaud Condition Score, and increased capillary blood flow in patients with secondary Raynaud's phenomenon.
CONCLUSIONS: Available evidence suggests that sildenafil may be associated with improved microcirculation, symptomatic relief, and ulcer healing in patients with secondary Raynaud's phenomenon. Limited information suggests similar effects with tadalafil and vardenafil. Improved blood flow and clinical improvements have also been observed in some patients with primary Raynaud's phenomenon treated with PDE5 inhibitors; however, studies have yielded conflicting results.
Key Words: Raynaud's phenomenon, sildenafil, tadalafil, vardenafil
Published Online, July 11, 2006. www.theannals.com, DOI 10.1345/aph.1H005
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Primary Raynaud's phenomenon is characterized by symmetric attacks; the absence of tissue necrosis, ulceration, or gangrene; the absence of a secondary cause; normal nailfold capillaries; a negative test for antinuclear antibody; and a normal erythrocyte sedimentation rate. Symptoms are generally mild, and the median age at onset is 14 years.1 In contrast with primary Raynaud's phenomenon, a secondary cause is suggested by age of onset greater than 30 years; episodes that are intense, painful, asymmetric, or associated with ischemic skin lesions; concomitant symptoms suggestive of a connective tissue disease; specific autoantibodies; and evidence of microvascular disease on microscopy of nailfold capillaries.1 Up to 90% of patients with systemic sclerosis have secondary Raynaud's phenomenon.2
Nonpharmacologic therapy includes avoidance of cold temperatures, emotional
stress, and
smoking.3
Pharmacologic therapy includes calcium-channel blockers,
1-adrenergic blockers, angiotensin II receptor
antagonists, topical nitroglycerin, and pentoxifylline. Despite therapy, some
patients with severe attacks will develop intense pain, ulceration and
ischemic skin lesions, and gangrene and may ultimately require therapy with
intravenous prostaglandins. Patients with severe symptoms or intolerance to
available therapies have prompted exploration of alternative therapies,
including the PDE5 inhibitors.
Raynaud's phenomenon occurs as a result of vasoconstriction of the digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts.1 Nitric oxide vasodilates and inhibits platelet activation by generating cyclic guanosine 5'-monophosphate (cGMP),4 which is hydrolyzed by phosphodiesterases, particularly the cGMP-specific PDE5 isoenzyme. Sildenafil, tadalafil, and vardenafil are selective inhibitors of cGMP-specific PDE5, which increases cGMP, resulting in enhanced cGMP-dependent microvascular and macrovascular dilation.3,4 The use of PDE5 inhibitors is being explored in patients with Raynaud's phenomenon because of their potential effects on the microvascular and macrovascular circulation.
LITERATURE REVIEW
Sildenafil, tadalafil, and vardenafil have been assessed in several studies
and numerous case reports in patients with Raynaud's phenomenon. In several
case reports and case series describing the use of PDE5 inhibitors in patients
primarily with secondary Raynaud's phenomenon
(Table 1), symptomatic
improvement, ulcer healing, and objective improvement in blood flow have been
reported.2,5-14
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In addition to these case reports, several small studies have assessed
these agents in the treatment of Raynaud's phenomenon
(Table 2). The investigations
include a single-dose crossover study with sildenafil and
-tocopherol,15
an open-label uncontrolled trial of
vardenafil,16
a small study comparing tadalafil with
pentoxifylline,17
and 2 crossover studies comparing sildenafil with
placebo.3,18
Three of these studies have been presented only in meeting
abstracts.15,17,18
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One trial compared the physiologic effects of single-dose sildenafil and
-tocopherol in 15 patients with Raynaud's
phenomenon.15
Forearm blood flow, blood pressure, and plasma cGMP concentrations were
measured before and 1 hour after a single dose of sildenafil 50 mg or
-tocopherol 100 mg. Following sildenafil, basal forearm blood flow was
increased 75% and plasma cGMP was increased 32%. Sildenafil was also
associated with a reduction in systolic and diastolic blood pressure;
-tocopherol had no effect on any of these parameters. Because this
study has only been presented as an abstract, details are not available.
Raynaud's phenomenon was not specified as either primary or secondary by the
investigators. Although this was only a single-dose trial, the results did
demonstrate an improvement in blood flow with sildenafil in patients with
Raynaud's phenomenon. Clinical effects were not assessed.
Clinical and blood flow effects of vardenafil were assessed in 40 patients with Raynaud's syndrome.16 Patients with either primary or secondary Raynaud's phenomenon were included. All vasoactive medications (eg, calcium-channel blockers, nitrates) were discontinued at least one week prior to study entry; prior therapy was not described. Peripheral blood flow in the index finger was measured by Laser-Doppler flowmetry at room temperature at study entry, 1 hour after initial vardenafil dosing, and after 2 weeks of continuous therapy. Cold testing, with measurements of contralateral blood flow and microscopy, was also performed at the same time points. Laser-Doppler measurements revealed improved digital blood flow in 70% of the subjects. Among patients responding, peripheral blood flow was increased at room temperature and in the cold-exposure test at both 1 hour and 2 weeks. At room temperature, blood flow increased 21% at 1 hour and 30% at 2 weeks; in the cold-exposure test, blood flow increased 18% at 1 hour and 35% at 2 weeks (all p < 0.01 vs baseline). In conjunction with improvement in Raynaud's Condition Score (RCS), 27 of 40 patients (68%) reported distinct symptomatic improvement. A reduction in the total daily duration of attacks was reported in 24 patients (60%), the number of daily attacks was reduced in 20 patients (50%), and the severity of attacks was reduced in 21 patients (53%). Improved blood flow with vardenafil was observed in patients with either primary or secondary Raynaud's phenomenon. Although this study was open-label and not comparative, blood flow response would not be expected to be subjective and is unlikely to have been influenced by the study design. The duration of the trial was only 2 weeks, but improvement in blood flow and a reduction in the frequency and duration of attacks was evident in this short time.16
Tadalafil has been compared with pentoxifylline in the treatment of Raynaud's phenomenon in a study enrolling men with severe Raynaud's phenomenon associated with autoimmune diseases.17 All patients completed daily diaries, recording the frequency and duration of Raynaud's attacks, using the RCS. RCS demonstrated greater improvement in the tadalafil-treated patients. Attack frequency declined 59% with tadalafil treatment compared with a 36% reduction with pentoxifylline treatment. Attack duration was also significantly reduced with tadalafil therapy compared with pentoxifylline treatment. Also, both physician and patient assessments of Raynaud's phenomenon were improved after 4 weeks of therapy with tadalafil (p < 0.05 compared with 2 wk, and p < 0.05 vs controls). Results after 4 weeks of therapy were better than those achieved after 2 weeks of therapy.
This study has also only been presented as an abstract and lacks details such as previous therapies and descriptions of the blinding and randomization methods. In addition, it enrolled a very small number of patients. Despite these limitations, tadalafil did appear more effective than pentoxifylline with continued improvement evident over the 4 week treatment period.17
In a well designed study conducted in Germany in the summer of 2003, sildenafil was assessed in the treatment of Raynaud's phenomenon resistant to vasodilatory therapy.3 This assessment included 18 patients after 2 patients discontinued therapy due to adverse effects. Sixteen patients had secondary Raynaud's phenomenon (14 with systemic sclerosis, 2 with mixed connective tissue disease) and 2 had primary Raynaud's phenomenon. Six patients with secondary Raynaud's phenomenon had chronic digital ulcerations. Inclusion criteria were the regular occurrence of painful attacks and resistance to therapy with at least 2 conventional vasodilators. Therapy prior to study entry included calcium-channel blockers in 94% of patients, nitroglycerin in 39%, pentoxifylline in 28%, angiotensin-converting enzyme inhibitors in 22%, intravenous prostaglandins in 17%, and bosentan in 6%. All other vasodilatory agents were discontinued prior to study entry; concomitant drugs for the treatment of rheumatic disease remained unchanged throughout the course of the study.
Primary outcome variables were frequency and duration of Raynaud's attacks, capillary flow velocity detected by nailfold capillary microscopy using a Laser-Doppler anemometer, and evolution of digital lesions. Mean capillary flow velocity increased with sildenafil but not with placebo. Overall, mean capillary blood flow velocity increased by more than 400% during sildenafil treatment (from 0.13 to 0.53 mm/sec; p = 0.0004). In addition, attack frequency and duration were substantially reduced, as reflected by reductions in the RCS. The beneficial effects with sildenafil on attack duration and frequency, RCS, and capillary blood flow velocity were comparable regardless of the order of treatment. In all 6 patients with chronic digital ulcerations, healing was observed during sildenafil treatment. In 2 patients, ulcerations completely cleared during sildenafil treatment but reappeared or progressed on discontinuation of sildenafil therapy.3
During the study, all patients reported that they were certain they knew which agent they were receiving. When the blinding was removed, all patients had correctly identified the agents at the time they were received. Sixteen patients (89%) subsequently requested off-label continuation of sildenafil therapy. Reporting of symptoms may have been biased by apparent subject knowledge of the assigned therapy; however, objective measurement of capillary flow velocity also exhibited significant improvement. Although improved blood flow velocity and clinical improvement were observed in patients with either primary or secondary Raynaud's phenomenon in this study, too few patients with primary Raynaud's phenomenon were included in this assessment to draw conclusions on the effectiveness of sildenafil therapy in this population.3
In contrast with the benefits reported in the above studies, no benefit was observed in patients with primary Raynaud's phenomenon treated with sildenafil. Patients received sildenafil or placebo for 2 weeks, with a one week washout period between study phases.18 The dosage regimen was identical to that used in the preceding study.3 Patients recorded the frequency and duration of Raynaud's attacks in daily diaries, utilizing the RCS. The Isolated Cold Stress Test, Scanning Laser-Doppler, Digital Brachial Index, and Vital Capillaroscopy were used to monitor blood supply to the digits upon exposure to cold. No difference between sildenafil and placebo was observed in these measures. The percentage of patients with more than 3 attacks per day also did not differ (19% with sildenafil, 16% with placebo; p > 0.05), nor did the median RCS scores.
All of the patients enrolled in this study had primary disease rather than secondary disease, which is often more severe. As this study also has been presented only as an abstract, information on the baseline frequency and severity of disease was not reported. Information provided did not address whether these patients were refractory to other therapies or what additional therapies had been previously administered.18
Limited adverse effect information was reported in these small studies and case reports. Adverse effects reported with sildenafil and vardenafil therapy in patients with Raynaud's phenomenon have included headache, muscle pain, flushing, facial heat sensation, rhinorrhea, nausea, dyspepsia, dizziness, and visual abnormalities.3,6,15 These adverse effects are similar to those observed with PDE5 inhibitors in the treatment of erectile dysfunction.
SUMMARY
The use of sildenafil in patients with secondary Raynaud's phenomenon has
been associated with improved microcirculation, symptomatic relief, and ulcer
healing. Limited information suggests similar beneficial effects with
tadalafil and vardenafil. Improved blood flow and symptomatic improvement have
also been observed in some patients with primary Raynaud's phenomenon treated
with PDE5 inhibitors; however, studies have yielded conflicting results.
Although additional clinical studies are necessary to validate the efficacy of
these agents in Raynaud's phenomenon, the limited clinical data, oral
availability, and favorable tolerability profile suggest that a trial of a
PDE5 may be appropriate in patients with severe symptoms associated with
Raynaud's phenomenon despite traditional vasodilator therapy. Doses exhibiting
activity in clinical studies included sildenafil 50 mg twice daily, vardenafil
10 mg twice daily, and tadalafil 20 mg every 2-3 days; however, additional
studies are necessary to determine the optimal doses.
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This article has been cited by other articles:
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  A. L. Burnett Molecular Pharmacotherapeutic Targeting of PDE5 for Preservation of Penile Health J Androl, January 1, 2008; 29(1): 3 - 14. [Abstract] [Full Text] [PDF]
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 M. Colakoglu, V. Cobankara, and T. Akpolat Effect of Clonazepam on Raynaud's Phenomenon and Fingertip Ulcers in Scleroderma Ann. Pharmacother., September 1, 2007; 41(9): 1544 - 1547. [Abstract] [Full Text] [PDF]
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