This month’s selected commentary

Sildenafil for the treatment of

Raynaud’s phenomenon
Warren R. Heymann, MD
Based on the dialogue ‘‘Collagen Vascular Disease’’ between
Drs Melissa I. Costner and Stuart Brown

Dialogues in Dermatology, a monthly audio program from the American Academy of Dermatology,
contains discussions between dermatologists on timely topics. Commentaries from Dialogues Editor-in-
Chief Warren R. Heymann, MD, are provided after each discussion as a topic summary and are provided
here as a special service to readers of the Journal of the American Academy of Dermatology. ( J Am Acad
Dermatol 2006;55:501-2.)

T he collagen vascular diseases continue to
challenge dermatologists involved in basic
research, translational studies, and clinical
practice. In this dialogue, Dr Costner surveys some
new advances in the pathophysiology, diagnosis,
and treatment of lupus, amyopathic dermatomyosi-
tis, and scleroderma. Raynaud’s phenomenon with
attendant, recalcitrant distal ulcers is a vexing prob-
lem that may accompany any of the connective tissue
diseases. This commentary considers the use of
sildenafil (Viagra) for this condition.
Raynaud’s phenomenon may be a primary pro-
cess or secondary to collagen vascular diseases, with
the latter generally manifesting a more severe dis-
ease. According to Boin and Wigley,1 ‘‘the endothe-
lial cells actively regulate vascular tone by secreting
both vasodilative (NO, prostacyclin, prostaglandin,
and leukotrienes) and vasoconstrictive (endothelin,
angiotensin II, and thromboxane A2) mediators.
Perturbation of endothelial cell homeostasis driven
by a disturbed state (inflammation, cytokine activa-
tion, trauma/vibration) can lead to a significant
imbalance toward release of active vasoconstrictive
mediators even without underlying permanent struc-
tural vascular damage . . . Intracellular responses to
prostacyclin and NO are mediated by the cyclic
nucleotides cyclic adenosine monophosphate and
cyclic guanosine monophosphate (cGMP), respec-
tively. Phosphodiesterases are a complex group of
enzymatic molecules that contribute to the tight
regulation of intracellular cyclic nucleotides levels
by their degradation.’’ Phosphodiesterase inhibitors
The statements and opinions expressed in this commentary are
those of the Editor-in-Chief of Dialogues in Dermatology.
achieve their therapeutic effect by increasing the
concentration of vasodilating mediators. Sildenafil is
a phosphodiesterase V inhibitor that allows accumu-
lation of cGMP. cGMP causes a decrease in intracel-
lular calcium, resulting in vascular smooth muscle
relaxation and dilatation.2 These pharmacologic ef-
fects have been documented by the use of thermog-
raphy. Kamata et al3 observed that the average skin
temperature of the fingers of a 67-year-old Japanese
woman before sildenafil administration was 27.68C
and 30.78C 60 minutes after the administration of
the drug.
Lichtenstein4 was the first to utilize sildenafil
for Raynaud’s phenomenon. Ten patients, 9 women
and 1 man, were treated with 50 mg of sildenafil daily
for either primary Raynaud’s phenomenon or disease
secondary to systemic lupus erythematosus, CREST
syndrome (calcinosis, Raynaud’s phenomenon,
esophageal involvement, sclerodactyly, and telangi-
ectasia), or systemic sclerosis. Most patients failed
to respond to prior treatment with other modalities,
including calcium channel blockers. In all patients
the responses ranged from excellent to complete
relief of symptoms. Digital ulcers of the hands and
feet healed after treatment with sildenafil citrate,
although relapses occurred after the medication
was withdrawn. Side effects known to occur when
the drug is prescribed for erectile dysfunction—
hypotension, arrhythmias, myocardial infarctions,
cerebrovascular accidents, flushing, headaches, diz-
ziness, blurred vision, and altered colored vision—
were not observed in this study.
Kumana, Cheung, and Lau5 reported improved
digital ischemia in 3 women treated with silden-
afil: one patient for lupus, one for amyopathic

501
502 Dialogues in Dermatology
dermatomyositis, and one for malignancy-associated
dermatomyositis. The patient with amyopathic der-
matomyositis ultimately died of pulmonary tubercu-
losis. Of interest, this patient had worsening of her
digital ischemia following rifampin administration
for her tuberculosis. The authors suspect that rifam-
pin, an inducer of P450 enzymes capable of enhanc-
ing sildenafil elimination, may result in decreased
efficacy of sildenafil.
Fries et al6 reported a double-blind, placebo-
controlled, fixed-dose, crossover study of 16 patients
with symptomatic secondary Raynaud’s phenome-
non resistant to vasodilatory therapy. Patients were
treated with 50 mg of sildenafil or placebo twice daily
for 4 weeks. While the patients were taking silden-
afil, the mean frequency of Raynaud’s attacks was
significantly lower, the cumulative attack duration
was significantly shorter, and the mean Raynaud’s
Condition Score was significantly lower. Capillary
blood flow velocity increased in each patient, and the
mean capillary blood flow velocity of all patients
more than quadrupled after treatment with sildenafil.
Two patients receiving sildenafil withdrew because
of side effects, including treatment-related head-
aches and muscle pain in the leg. In the authors’
estimation, sildenafil is an effective and well-toler-
ated treatment for patients with Raynaud’s phenom-
enon. In an editorial accompanying this article,
Mahler and Baumgartner7 opined that the effect of
sildenafil is not restricted to the corpora cavernosa;
because the report by Fries et al described data in a
controlled trial, ‘‘it appears that sildenafil has now
made its entrance into circulatory therapy.’’
Further refinements in phosphodiesterase inhibi-
tion therapy are on the horizon. Indeed, Baumhae-
kel, Scheffler, and Boehm8 have noted that tadalafil
(Cialis) has a half-life of 17 hours compared with 3.8
hours for sildenafil. The authors described a 53-year-
old man with Raynaud’s phenomenon secondary to
chemotherapy with carboplatin for oral squamous
cell carcinoma who failed to respond to sildenafil,
but improved with tadalafil.
As the phosphodiesterase inhibitors have
been labeled ‘‘lifestyle’’ drugs by the lay press, it is
gratifying to see that these medications may also
J AM ACAD DERMATOL
SEPTEMBER 2006
improve the quality of life for those afflicted with one
of the most confounding, intractable, dermatologic
disorders.
REFERENCES
1. Boin F, Wigley FM. Understanding, assessing and treating
Raynaud’s phenomenon. Curr Opin Rheumatol 2005;17:752-60.
2. Gore J, Silver R. Oral sildenafil for the treatment of Raynaud’s
phenomenon and digital ulcers secondary to systemic sclerosis.
Ann Rheum Dis 2005;64:1387.
3. Kamata Y, Kamimura T, Iwamoto M, Minota S. Comparable
effects of sildenafil citrate and alprostadil on severe Raynaud’s
phenomenon in a patient with systemic sclerosis. Clin Exp
Dermatol 2005;30:451.
4. Lichtenstein JR. Use of sildenafil citrate in Raynaud’s phenom-
enon: comment on the article by Thompson et al. Arthritis
Rheum 2003;48:282-3; author reply 283.
5. Kumana CR, Cheung GT, Lau CS. Severe digital ischaemia
treated with phosphodiesterase inhibitors. Ann Rheum Dis
2004;63:1522-4.
6. Fries R, Shariat K, von Wilmowsky H, Böhm M. Sildenafil in the
treatment of Raynaud’s phenomenon resistant to vasodilatory
therapy. Circulation 2005;112:2980-5.
7. Mahler F, Baumgartner I. More potential for sildenafil than
potency. Circulation 2005;112:2894-5.
8. Baumhaekel M, Scheffler P, Boehm M. Use of tadalafil in a
patient with secondary Raynaud’s phenomenon not respond-
ing to sildenafil. Microvasc Res 2005;69:178-9.
Additional topics from the August 2006 issue
of the Dialogues in Dermatology:
1. Mesotherapy
With Lisa Donofrio, MD, interviewed by Gary
Brauner, MD
2. Managing the teenage patient
With Hillary E. Baldwin, MD, interviewed by
Stuart Brown, MD
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