Part II: The treatment of primary and

secondary Raynaud’s phenomenon

Paul Curtiss, MD,a Katerina Svigos, MD,a Zachary Schwager, MD,b Kristen Lo Sicco, MD,a and
Anrdew G. Franks, Jr, MDa,c

Learning objectives
We seek to describe evidence-based approaches to the management of primary and secondary Raynaud’s Phenomenon including established and emerging therapies, and provide an
algorithmic approach to proposed treatment strategies.

Disclosures
Editors
The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with
commercial interest(s).

Planners
The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved
with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Reviewers
David Fivenson, MD, FAAD is an investigator for Bristol-Myers Squibb and receives grants/research funding; an investigator and speaker for Eli Lilly and Company and receives grants/
research funding and honoraria; and an investigator and speaker for Pfizer Inc. and receives grants/research funding and honoraria. Ellie Choi, MBBS, IFAAD receives grants/research
funding from Pfizer Inc.
Staff
The staff involved with this CME activity have reported no relevant financial relationships with commercial interest(s).
All relevant financial relationships have been mitigated.

Raynaud phenomenon (RP) presents with either primary or secondary disease, and both have the potential
to negatively impact patient quality of life. First-line management of RP should include lifestyle
modifications in all patients. Some patients with primary RP and most with secondary RP require
pharmacologic therapies, which may include calcium channel blockers, topical nitrates, phosphodiesterase
5 inhibitors, or endothelin antagonists. Additional approaches to treatment for those with signs of critical
ischemia or those who fail pharmacologic therapy include botulinum toxin injection and digital
sympathectomy. Herein, we describe in detail the treatment options for patients with RP as well as
provide treatment algorithms for each RP subtype. ( J Am Acad Dermatol 2024;90:237-48.)

Key words: connective tissue disease; medical dermatology; Raynaud phenomenon; scleroderma; systemic
lupus.

From The Ronald O. Perelman Department of Dermatology, New Ó 2022 by the American Academy of Dermatology, Inc.
York University Grossman School of Medicine, New York, New https://doi.org/10.1016/j.jaad.2022.05.067
Yorka; Department of Dermatology, Lahey Hospital and Medical Date of release: February 2024.
Center, Burlington, Massachusettsb; and Division of Rheuma- Expiration date: February 2027.
tology, Department of Internal Medicine, New York University
Grossman School of Medicine, New York, New York.c
Scanning this QR code will direct you to
Dr Curtiss and Dr Svigos contibuted equally to this article as
the CME quiz in the American Academy
co-first authors.
of Dermatology’s (AAD) online learning
Dr Lo Sicco and Dr Franks contributed equally to this article as
center where after taking the quiz and
co-senior authors.
successfully passing it, you may claim 1
Funding sources: Supported by the Frances & Benjamin Benenson
AMA PRA Category 1 credit. NOTE: You
Foundation and The William Silverman Fund.
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signed in on your device in order to be
Accepted for publication May 25, 2022.
directed to the CME quiz. If you do not
Correspondence and reprint requests to: Kristen Lo Sicco, MD, The
have an AAD account, you will need to
Ronald O. Perelman Department of Dermatology, 240 E 38th
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0190-9622/$36.00

237
238 Curtiss et al
Abbreviations used:
5HT: serotonin
BoNT: botulinum toxin
CCB: calcium channel blocker
NO: nitric oxide
PDE-5: phosphodiesterase 5
RCT: randomized controlled trial
RP: Raynaud phenomenon
SRP: secondary Raynaud phenomenon
SSc: systemic sclerosis
INTRODUCTION
Raynaud phenomenon (RP) is a relatively com-
mon vasospastic condition affecting the digital ar-
teries in the hands and feet resulting in characteristic,
well demarcated color changes in response to cold or
stress. RP is largely divided into 2 distinct subty-
pesdprimary and secondary. Primary RP is common
and occurs in approximately 5% to 7% of most
populations. Although it is relatively benign and
not associated with underlying systemic disease,
undertreated primary RP has a significant negative
impact on quality of life.1
Secondary Raynaud phenomenon (SRP) occurs
most commonly in the context of autoimmune and
connective tissue disease, is associated with progres-
sive biochemical and structural changes in vascula-
ture, and may result in tissue necrosis and loss of
digits. Additionally, cutaneous vasoconstriction
often occurs concurrently with visceral vascular
pathology.2,3 It is therefore of utmost importance to
recognize and treat SRP early to help prevent not
only digital necrosis but possible associated internal
organ damage as well.
The goal of this article is to provide (1) an effective
summary of current standard of care treatments used
in both primary and secondary RP, and (2) a
systematic approach to the management of these
disorders in heterogeneous patient populations.
ASSESSING THE EFFICACY OF TREATMENT
Evaluating the impact and efficacy of treatment is
important in managing RP, particularly in SRP.
Treatment response may be measured by following
patient reported clinical severity markers or objec-
tive measurements of digital blood flow.
Clinical severity markers include frequency,
severity, duration, and quality of life metrics or a
‘‘Raynaud Condition Score,’’ which allows patients to
use a diary of daily self-assessment on an ordinal
scale accounting for these factors.4,5
A variety of objective blood flow metrics have
been used to assess the severity of attacks based on
changes in perfusion including infrared thermog-
raphy, photoplethysmography, laser Doppler
J AM ACAD DERMATOL
FEBRUARY 2024
imaging, and laser Doppler flowmetry.6,7 These
modalities are used to assess flux, heat, and volu-
metric changes as a measure of digital blood flow at
regular intervals to track the progress of the disease
and its treatment over time.
LIFESTYLE INTERVENTIONS
As RP most commonly occurs in response to
stimuli such as cold exposure, lifestyle interventions
are critical in the initial management of RP. This is
particularly so in primary RP, which is often
adequately controlled through lifestyle interventions
alone.
Patients should be counseled extensively on
avoidance of cold exposure and other triggers for
attacks. Appropriate full body covering, with special
attention to the hands and feet, should be worn in
cold temperatures and during the winter months.8,9
Mittens offer superior insulation and protection from
the cold compared with gloves and should be
favored.10 If possible, the forehead should be covered
as well, as cold air across the forehead produces a
vasomotor or ‘‘diver’s’’ reflex that can induce periph-
eral vasospasm.11 Protective garments may also be
used in cold indoor spaces to minimize attacks.
When feasible, medications associated with RP
exacerbation should be avoided or discontinued.12
b-blockers are thought to induce a reflexive increase
in a-mediated adrenergic tone, exacerbating RP
(Table I).13 A meta-analysis including 1013 patients
and 13 studies found a prevalence of RP in 14% of
patients receiving b-blockers.14 Similarly, a variety of
other medications including caffeine have been
implicated through different mechanisms. Smoking
tobacco is strongly associated with RP, and smokers
have a higher incidence of more severe phenotypes
including digital ulcers and gangrene.15 All patients
with RP should be extensively counseled on the
importance of smoking cessation.
A variety of maneuvers may be used to help
patients abort acute attacks of RP. These techniques
are often more effective in patients with primary RP
because no structural disease is present. A ‘‘Frisbee
maneuver’’ may be performed in patients with
musculoskeletal limitations whereby the arm is
extended laterally, with a simultaneous snapping
motion of the wrist in rapid succession, as though
tossing a frisbee.16 Alternatively, a windmill or swing
arm maneuver may be performed by rotating the arm
rapidly in a softball pitching motion.17
Biofeedback training and relaxation techniques
may be helpful in patients whose attacks are
triggered by stress as well as those without tissue
damage. Multiple small studies have suggested
benefit in both RP subtypes.18,19
J AM ACAD DERMATOL Curtiss et al 239
VOLUME 90, NUMBER 2

Table I. Primary versus secondary Raynaud phenomenon: Epidemiology, etiology and exacerbating factors
Characteristics Primary Secondary
Epidemiology
Sex predilection Female* None
Time at presentation \30 yy [30 y
Pathogenesis
Vasoconstriction Yes Yes
Biochemical and structural abnormalities No Yes
within the microvascular system
Endovascular remodeling, fibrosis, or stenosis No Yes
Exacerbating factors
Smoking Yes Yes
Nonselective b-blockers Yes Yes
Migraine therapies (ie, ergotamine) Yes Yes
Estrogen replacement therapy Yes Yes
Caffeine Yes Yes
Vinyl chloride (occupational exposure) Yes Yes
High intensity vibratory stimuli Yes Yes
Frostbite Yes Yes
Associated conditions, medications, and infections
Vasospastic disorder associations Prinzmetal variant No
coronary angina
Migraine disorder
ACTD disease association No SSc (limited and diffuse)z
SLE
MCTD
DM
Other rheumatologic diseases No RA
€gren syndrome
Sjo
Vasculitis
Vascular occlusive diseases No Arteriosclerosis
Buerger disease
Thromboembolic disease
Hematologic syndromes No Cryoglobulinemia
Cryofibrinogenemia
Paraproteinemia
Polycythemia
Cold agglutinin disease
Protein C, protein S
Antithrombin III deficiency
Factor V Leiden, Prothrombin gene mutations
Medications No Amphetaminesx
Bleomycin
Cisplatin
Cyclosporine
Interferon alfa
Vinblastine
Infections No Hepatitis B/C (cryoglobulinemia associated)
Parvovirus B19
Mycoplasma infections (cold agglutinins)
Anatomic syndromes No Scalenus anticus syndrome
Cervical rib

ACTD, Autoimmune connective tissue disease; DM, dermatomyositis; MCTD, mixed connective tissue disease; RA, rheumatoid arthritis; RP,
Raynaud phenomenon; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.
*More even distribution in men and women after menopause.
y
Secondary RP in the setting of systemic sclerosis often presents in younger patients.
z
Patients with systemic sclerosis who test positive for RNA polymerase III antibody are often antinuclear antibody negative.
x
Literature regarding psychostimulants in the exacerbation of RP is limited to retrospective analyses and case reports, and no randomized
controlled trial exists specifically comparing psychostimulant subtypes. Two such subtypes are: (1) methylphenidate, a catecholamine
reuptake inhibitor, and (2) mixed salt amphetamines, which inhibit the reuptake of catecholamines as well as lead to release of
catecholamines. Based on these reported mechanisms and empiric evidence, the mixed salt amphetamines have been identified as a more
common culprit compared with methylphenidate.13
240 Curtiss et al
Fig 1. Algorithm for the treatment of primary Raynaud phenomenon.
PHARMACOLOGIC INTERVENTIONS
In the past decades, a variety of pharmacologic
agents have been developed for the treatment of RP.
These include specific targeted therapies for
patients with SRP and systemic sclerosis (SSc) who
often suffer additional morbidity due to digital ulcers
and tissue necrosis. As such, the underlying disease
process is relevant when considering pharmacologic
intervention for RP.
J AM ACAD DERMATOL
FEBRUARY 2024
Given its nonprogressive nature, primary RP
should initially be managed with conservative lifestyle
interventions as previously detailed. For refractory
primary RP, pharmacotherapy is indicated and should
be initiated with calcium channel blockers (CCBs) or
topical nitrates as tolerated. In SRP, an aggressive
approach with early pharmacotherapy may be taken
to prevent irreversible tissue damage. For those with
digital ulcers or tissue necrosis, concurrent use of more
J AM ACAD DERMATOL
VOLUME 90, NUMBER 2
Fig 2. Algorithm for the treatment of secondary Raynaud phenomenon.
proactive treatments (eg, interdigital botulinum toxin
[BoNT ]) is often warranted. Our structured treatment
algorithms are outlined above and below (Figs 1, 2).
CCBs
CCBs are the most extensively studied medication
in both primary and secondary RP and are generally
considered to be the preferred first-line systemic
agent. A Cochrane review and meta-analysis
including 7 randomized controlled trials (RCTs) and
296 patients showed that CCBs were effective in
reducing the frequency, severity, and duration of
attacks in both subtypes.20
CCBs fall broadly into 2 categories based on their
affinity for cardiac muscle or vascular smooth mus-
cle. Dihydropyridine (amlodipine, nifedipine) are
less cardioselective, exert greater peripheral effects
on vascular smooth muscle, and are preferred over
nondihydropyridine CCBs (verapamil, diltia-
zem).20,21 While generally well-tolerated, both dihy-
dropyridine and nondihydropyridine CCBs have the
potential to cause lower extremity edema in 12.3%
and 3.1% of patients, respectively, and may necessi-
tate the use of alternative agents.22
Curtiss et al 241
Topical nitrates
Topical nitrates are a second line agent to patients
who fail CCB monotherapy. Following application,
topical nitrates are metabolized to nitric oxide (NO)
and thereby provide potent exogenous vasodila-
tion.23 Exogenous NO functions by increasing the
concentration of cyclic guanosine monophosphate
in vascular smooth muscle, resulting in decreased
tone and increased blood flow.
Placebo-controlled trials have demonstrated the
efficacy of topical nitrates in improving perfusion to
digital arteries as well as reducing the severity of RP
symptoms.24-30 Our study group’s recent meta-
analysis further validated the effectiveness of topical
nitrates in both primary and secondary RP.31
In higher concentrations, topical nitroglycerin is
absorbed systemically and may result in side effects
including headache.23 To mitigate this adverse effect,
2% topical nitroglycerin may be mixed with hydro-
philic ointment to obtain a 1% mixture.21
Additionally, application may be restricted to
severely involved distal areas, mitigating a ‘‘steal’’
phenomenon, whereby less diseased vessels more
easily dilate and shunt blood from more severely
affected areas. A variety of other formulations have
242 Curtiss et al
been proposed with the goal of limiting systemic
absorption.27,28 Caution should be used in initiating
treatment with topical nitrates in patients already
taking phosphodiesterase 5 (PDE-5) inhibitors as
detailed below.
PDE-5 inhibitors
Generally, PDE-5 inhibitors should be pursued as
systemic therapy in patients refractory to CCBs. PDE-
5 inhibitors inhibit the degradation of cyclic guano-
sine monophosphate, potentiating the effects of
endogenous and exogenous NO and nitrates.
Sildenafil and vardenafil have short half-lives (3 to
5 hours) and should be dosed up to 3 times daily,
while tadalafil has a longer half-life (18 hours)
allowing for more convenient daily or less frequent
dosing.32
Both RCTs and meta-analyses support the efficacy
of short- and long-acting PDE-5 inhibitors in
decreasing the frequency and duration of attacks in
SRP.33-36 Multiple small observational studies have
suggested benefit with regard to healing of digital
ulcers as well.37,38 One RCT, termed the SEDUCE trial
(Sildenafil Effect on Digital Ulcer Healing in
sClerodErma), included 83 patients and showed a
statistically significant benefit in the healing of digital
ulcers at 8 and 12 weeks secondary to sildenafil
when compared with placebo.39
Importantly, caution should be used when coad-
ministering PDE-5 inhibitors and topical nitrates.
When combined, the synergistic vasodilatory
response may result in profound hypotension.40
However, in refractory patients, this compounded
effect may be harnessed if topical nitrate doses are
fractionated. In such cases, 1% nitroglycerin may be
applied sparingly to severely affected digits while
monitoring blood pressure.
Endothelin receptor antagonists
Endothelins are pathologically elevated in SSc and
are implicated in underlying disease processes
including pulmonary hypertension and severe RP
phenotypes. Endothelin receptor antagonists
thereby limit endothelin-mediated vasoconstriction
and promotion of pathologic vascular lumen remod-
eling.41 In 2 major clinical trials (‘‘Randomized,
double-blind, placebo-controlled study with bosen-
tan on healing and prevention of ischemic digital
ulcers in patients with systemic sclerosis’’ [RAPIDS] 1
and RAPIDS 2), bosentan, an endothelin 1, and 2
receptor antagonist, was found to decrease forma-
tion of digital ulceration, most prominently in those
with existing ulcers.42,43 These studies failed to show
a benefit in healing preexisting digital ulcers or the
frequency and severity of attacks. A subsequent
J AM ACAD DERMATOL
FEBRUARY 2024
Fig 3. Pretreatment effects in a systemic sclerosis patient
with a robust response to interdigital Botox.
long-term cohort study suggested up to 24 months
may be necessary to achieve a reduction in the
number of digital ulcers.44 Selective endothelin 1
receptor antagonists have also been studied in
patients with SSc-related SRP with digital ulceration.
In 2 small studies, ambrisentan, an endothelin A
antagonist, was associated with a reduction in new
digital ulceration.45,46
BoNTs
BoNTs are an important local therapy for patients
with SRP who are refractory to initial interventions,
or those with severe phenotypes including refractory
pain, digital ulcers, or gangrene, and should be used
prior to consideration of surgical sympathectomy.
They function by degrading soluble N-ethylmalei-
mide-sensitive fusion attachment protein receptor
proteins that allow exocytosis of acetylcholine into
the neuromuscular junction. The supported thera-
peutic mechanism of BoNT in RP is through
blockade of sympathetic adrenergic nerves, thus
inhibiting vascular smooth muscle contraction.47
This restores distal blood flow and limits vasospastic
response (Figs 3, 4). BoNT may also inhibit endo-
thelial exocytosis of endothelin 1 and ultralarge von
Willebrand factor, thus attenuating vasospasm and
preventing capillary microthrombosis and patho-
logic vascular remodeling.48 Additionally, the
blockade of substance P release by sensory nerve
fibers caused by BoNT often improves symptoms
more rapidly.
Multiple small, uncontrolled studies have shown
significant benefit in RP symptoms and healing of
digital ulcers in patients unresponsive to other
treatments.47,49-54 One retrospective study of 19
patients showed BoNT-A injections were associ-
ated with rapid pain relief and healing of chronic
ulcers within 60 days after injections. Further, an
RCT showed that after 6 weeks, digital pulp tem-
perature in the fingertips was dramatically
improved compared with patients who were
J AM ACAD DERMATOL
VOLUME 90, NUMBER 2
Fig 4. Posttreatment effects in a systemic sclerosis patient
with a robust response to interdigital Botox.
injected with normal saline, suggesting an increase
in digital blood flow and decrease in vasospasm.55
Another RCT using BoNT-B (Myobloc) showed
significant improvement in digital blood flow
during a cold water immersion challenge.56 We
routinely recommend BoNT-A injections for pa-
tients with severe SRP phenotypes, including
digital ulcers.
Most commonly, BoNT is injected at the middle of
web spaces where the bifurcations of the superficial
digital arteries occur. BoNT may also be injected
along the palmar neurovascular bundles of the
metacarpophalangeal joint. However, the latter tech-
nique is less favored given increased risk of hand
weakness.57 Injection volumes ranging from 6 to 100
units per hand have been used.49-53,55,58 The authors
recommend slowly injecting 10 units of BoNT-A into
the bilateral matched interdigital web spaces and/or
neurovascular bundles surrounding each affected
digit (Fig 5).
L-arginine
L-arginine is a semiessential amino acid and
precursor to NO. Abnormal metabolism of NO
contributes to both fibrosis and vasospasm in SRP,
and multiple small studies have demonstrated
benefit in SRP phenotypes but often fail to show
benefit in primary RP.59-61 This likely relates to the
high levels of endogenous methylarginines in SRP,
which may be counteracted by therapeutically
increasing circulating L-arginine.62
Given its relatively favorable side effect profile, L-
arginine should be included in SRP regimens, start-
ing at 1 to 2 g daily and titrating to 8 to 9 g daily.
Alternatively, citrulline, an arginine precursor, is
absorbed more efficiently and may increase arginine
concentrations by a greater degree when trialed in
similar doses.62,63 Primary RP studies have failed to
Curtiss et al 243
Fig 5. Injection of interdigital Botox at a 308 angle,
targeting the interdigital arteries.
show the same benefit. L-arginine is often useful in
patients who are unable to tolerate conventional
vasodilators (eg, CCBs, PDE-5 inhibitors) because of
low systemic blood pressure.
Prostanoids
Intravenous prostanoids may be considered in
patients with digital necrosis refractory to oral
medications and as an addition or alternative to
intralesional BoNTs. A Cochrane systematic review
and meta-analysis of 7 RCTs including 332 patients
with SSc-related SRP showed the efficacy of intrave-
nous iloprost in improving the frequency and
severity of attacks as well as digital ulcer healing
and prevention of new digital ulcer formation.64
However, these treatments typically require hospi-
talization or regular visits to an infusion center,
proving costly and burdensome. As such, the authors
do not routinely use them in clinical care.
ALTERNATIVE AGENTS AND TREATMENTS
OF SPECIFIC POPULATIONS
Anticoagulants and antiplatelet agents
Anticoagulants may be particularly useful in
patients with SRP who have an underlying coagul-
opathy. This most commonly occurs within the
context of systemic lupus erythematosus, in which
patients may have underlying antiphospholipid
antibodies.65 Although such patients should gener-
ally be treated with first-line therapies, they may
benefit from anticoagulation or antiplatelet agents.
Small studies have suggested that routine anticoagu-
lation with low molecular weight heparin or low
dose warfarin may beneficial.66,67
There are few studies formally evaluating cyclo-
oxygenase 1 inhibition (aspirin) in RP; however, it is
often used given its favorable side effect profile.68 It
244 Curtiss et al
may have additional benefits in patients with anti-
phospholipid syndrome or coagulopathic disorders.
Interestingly, clopidogrel, a P2Y12 inhibitor and
more potent antiplatelet agent, was recently shown
to worsen endovascular pathology and digital ulcer-
ation.69 As such, we do not recommend the use of
antiplatelet agents except aspirin.
Pentoxifylline is a methyl-xanthine with vasoac-
tive properties and has been successfully used for the
treatment of nonoperative ischemic claudication. Its
inhibitory effects on cyclic adenosine monophos-
phate phosphodiesterase contribute to vasodilation
through vascular smooth muscle relaxation. It has
been reported to aid in the treatment of SSc-related
SRP, although more research is needed to confirm its
effectiveness.70
Angiotensin pathway inhibitors: Angiotensin-
converting enzyme inhibitors and angiotensin
II receptor blockers
Blockers of the renin-angiotensin-aldosterone
axis have been studied in the context of SSc and
SRP. Two large RCTs involving angiotensin-
converting enzyme inhibitors (captopril and quinap-
ril) failed to show benefit in digital ulcer formation or
RP severity.71,72
One RCT comparing losartan, an angiotensin II
receptor blocker with nifedipine, showed reduced
severity and frequency of RP attacks, with the most
significant improvement seen with losartan.73 We
therefore favor the selection of angiotensin II recep-
tor blockers over angiotensin-converting enzyme
inhibitors as a potential adjunct agent.
Statins
The pleiotropic effects of statins may aid in
improving endothelial dysfunction in SSc, possibly
increasing the vasodilatory capacity of SSc blood
vessels and decreasing the levels of proinflammatory
cytokines.74 A small laboratory-based study suggests
that statins improve abnormal vascular remodeling
in SSc-related SRP by downregulating abnormally
elevated angiogenic growth factors.75 Additionally,
an RCT suggested atorvastatin improved clinical RP
symptoms when compared with placebo.76 Given
their favorable tolerability profile, statins should be
considered as a useful adjuvant in select patients
with SRP including those with low blood pressure.
a-blockers
Prazosin is an a receptor antagonist with vaso-
dilatory effects that has been studied in the treatment
of RP. A Cochrane review and meta-analysis
including 2 studies showed modest benefit over
placebo in patients with SRP treated with
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FEBRUARY 2024
prazosin.77-79 Although it is not routinely used, it
may be an alternative or adjuvant if other treatments
fail.
Serotonin (5HT) inhibitors
5HT signaling is mediated by the family of 5HT
receptors, and 5HT plays an active role in the
vascular endothelium, both as a vasoconstrictive
peptide and by promoting platelet activation.80
Additionally, 5HT likely plays a role in neural vaso-
regulation, although its precise role in the pathogen-
esis of RP is not clear.
Selective serotonin receptor inhibitors,
commonly prescribed antidepressants and anxieto-
lytics, have been explored as treatments given their
tolerability, particularly in patients with low blood
pressure.81 Several small studies including one
randomized cross-over controlled study suggested
a benefit of selective serotonin receptor inhibitors
in RP.82-84 Interestingly, their vasodilatory effects
may induce erythromelalgia in some patients with
RP.85 Although more high quality studies are
needed prior to regular use, selective serotonin
receptor inhibitors remain an option in patients
with RP and low blood pressure.
Several other 5HT inhibitors have been studied as
well. A Cochrane meta-analysis of ketanserin, a 5HT-
2 receptor blocker, concluded that there was insuf-
ficient evidence to support its efficacy in the
treatment of SRP.86 Sarpogrelate is a 5HT-A receptor
blocker, with antiplatelet and vasodilatory effects,
found to be beneficial in symptom reduction and
improvement of digital ulcers in several small studies
in Japan.87,88
Tissue plasminogen activator
Several case reports have suggested the use of
thrombolytics in acute digital ischemia with impend-
ing necrosis.89,90 Importantly, administration occurs
with significant risk of hemorrhage and should only
be considered in low bleed risk individuals with
evidence of acute ischemia who do not respond to
vasodilators such as intravenous iloprost or interdi-
gital botulinum toxin.
Rho kinase inhibitors
While efficacious for other vasospastic conditions,
the Rho kinase inhibitor, fasudil, has not been shown
to be beneficial in the treatment of RP.91
Antioxidants
N-acetylcysteine, an antioxidant, has shown some
benefit in 2 studies looking at oral and intravenous
formulations, respectively.92,93 These effects are
modest compared with other alternatives.
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Sympatholytics
Reserpine and guanethidine both block sympa-
thetic tone and have both been studied in the
treatment of RP. Despite their previous routine use,
they are less effective than other treatments, and
there is insufficient controlled data to support their
effectiveness in RP.21,94
SURGICAL INTERVENTIONS
Multiple surgical approaches have been explored
in the treatment of SRP, usually in patients with
refractory disease or impending digital necrosis.
Early approaches included the ligation of sympa-
thetic tracts at the level of the thoracic nerve.95
Although there is limited randomized trial data,
prospective studies indicate this is likely beneficial
in cases where patients are refractory to pharmaco-
logic interventions. Currently, endoscopic ap-
proaches may minimize the morbidity of thoracic
sympathectomy.96
Importantly, for many patients with refractory SRP
and digital ulcers, vascular remodeling plays a prom-
inent role. External compression of arterial vessels
from a fibrotic tunica adventitia may limit the ability
of digital vessels to dilate effectively, regardless of
chemical stimuli.97 In these patients, periarterial
sympathectomy including surgical stripping of the
tunica adventitia is favored to restore blood flow and
improve healing of digital ulcers.98
CONCLUSION
Management of RP should include lifestyle mod-
ifications in all patients. Some patients with primary
RP and most with SRP require pharmacologic ther-
apies, which may include CCBs, topical nitrates,
PDE-5 inhibitors, or endothelin antagonists.
Additional approaches to treatment for those with
signs of critical ischemia or those who fail pharma-
cologic therapy include BoNT injection and digital
sympathectomy.
Conflicts of interest
None disclosed.
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