RAYNAUDS PHENOMENON

Botulinum Toxin A Treatment of Raynauds Phenomenon:

A Review
Matthew L. Iorio, MD, Derek L. Masden, MD, and
James P. Higgins, MD

Objectives: Botulinum toxin A has conventionally been used in the upper extremity to treat
spasticity resulting from stroke, paraplegia, and dystonia. Recently, it has been used to relieve
symptoms of vasospasm in Raynauds phenomenon. This review summarizes the current literature
on botulinum toxin A in the treatment of Raynauds phenomenon and examines the proposed
mechanisms of action, suggested techniques of administration, and clinical efficacy.
Methods: An Ovid MEDLINE search from 1950 to September 2010 was performed to identify
any reports on the use of Botulinum toxin in the treatment of Raynauds disease or associated
vasoconstrictive disorders. All studies pertaining to Raynauds disease, Raynauds, or vaso-
constriction were queried and meshed with a secondary search of studies pertaining to botox or
botulinum toxin type A. These reports were meshed and subsequently limited to human studies.
All studies that met criteria were included and their outcomes evaluated and summarized.
Results: Since 2004, there have been 5 studies that have evaluated the use of Botulinum Toxin A
for the treatment of Raynauds. In each study, patients received a range of botulinum toxin
injections (10-100 units) in their fingers and hands. The studies have many limitations (lack of
controls, variable severity of disease, variability of dosing) but all report favorable clinical results.
All showed overall improvement in patient pain as well as a reduction in soft tissue ulceration.
Conclusions: Initial reports on the use of botulinum toxin A for Raynauds phenomenon are
promising. Larger controlled trials with improved study design are warranted. A better under-
standing of the mechanism of action, appropriate dose and dose frequency, and the efficacy relative
to other medical and surgical treatments requires investigation.
2012 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41:599 603
Keywords: botox, botulinum toxin A, Raynauds phenomenon, vasospasm

T he use of botulinum toxin A has emerged as a
nonsurgical treatment for vasospastic disease.
Botulinum toxin A has conventionally been em-
ployed in the upper extremity for the treatment of spas-
ticity in the setting of stroke, paraplegia, and dystonia. It
has also been used as a means of protecting flexor tendon
surgical repairs during the tendon healing phase. Else-
where in the body, it has been used for muscular imbal-
ance, including torticollis, blepharospasm, and strabis-
mus.
Vasospastic disease is inappropriate reversible vascu-
lar constriction in the distal extremities in response to a
The Curtis National Hand Center, Baltimore, MD.
The authors have no conflicts of interest to disclose.
Address reprint requests to James P. Higgins, MD, care of Anne Mattson, The
Curtis National Hand Center, Union Memorial Hospital, 3333 North Calvert Street,
#200, Baltimore, MD 21208. E-mail: anne.mattson@medstar.net.
0049-0172/12/$-see front matter 2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.semarthrit.2011.07.006
variety of stimuli, most commonly cold or emotional
stress. Primary vasospastic disease can be termed Ray-
nauds disease or primary Raynauds phenomenon.
Secondary vasospastic disease can be termed Raynauds
syndrome or secondary Raynauds phenomenon.
The clinical constellation of signs and symptoms of
Raynauds phenomenon is well described. Digital pain
is associated with sequential pallor, cyanosis, and ru-
bor, and less commonly, acral ulceration. Following a
precipitating vasoconstricting stimulus, small-caliber
digital arteries undergo an exaggerated response of va-
sospasm. This decreases blood flow and the digits ap-
pear ischemic or white. As the trapped blood becomes
increasingly deoxygenated, the digits will then turn
cyanotic or blue, and finally red following reperfusion
hyperemia.
Treatment modalities are aimed at preventing exag-
gerated vasospasm, encouraging vasodilatory response,
599
600 Botulinum toxin A treatment of Raynauds phenomenon

Table 1 Summary of Available Reports Based on Study Design, Criteria for Botulinum Injection, and Patient Symptom
Demographics
Diagnostic
Study Type Indications Excluded Testing N Symptom Response

Fregene et al Retrospective Failed MM, pain, Previous Ultrasound, 26 Pain: 75% improveda
(2009) chronic ulcers, sympathectomy, angiography Color: 56% improved
gangrene active infection dTCO2: 57%
improveda
Ulcers: 48% healed
Neumeister et Retrospective Ischemic pain, History of botox MRA, 19 Pain: 84% improved
al (2009) decreased allergy angiography Ulcers: 100%
pulses, chronic improved
ulceration Doppler: 48.15%
to 317.39%
Sycha et al Pilot/Prospective Primary or None None 2 Pain: Improved
(2004) secondary RP Stiffness: Improved
Doppler: Treated
fingers improved
58% vs untreated
Van Beek et al Prospective Failed MM, None MRA, 11 Pain: 100% improved
(2007) chronic ulcers angiography Ulcers: 100% small
ulcers healed
Neumeister et Retrospective Failed MM, None MRA, 33 Pain: 85% improved
al (2010) ischemic pain angiography Ulcers: 100%
improved
Doppler: 48.15%
to 317.39%
MM, medical management; dTCO2, digital transcutaneous oxygen saturation.
aReported statistical significance of P 0.05.

and increasing red blood cell deformation to augment METHODS

decreased caliber vessel flow. Parenteral calcium chan-
nel blockers have been validated as a therapeutic option
to reduce the frequency of ischemic attacks. These
agents have served as the most common medical treat-
ment of Raynauds disease and phenomenon. The use
of other classes of medications have been reported in-
cluding angiotensin II inhibitors, selective serotonin
reuptake inhibitors, ACE inhibitors, alpha-blockers,
oral and topical nitrates, intravenous prostacyclin, en-
dothelin receptor blockers, phosphodiesterase inhibi-
tors, as well as a myriad of alternative medicine tech-
niques and devices (1,2).
Botulinum toxin A has received increasing attention
as a means of relieving symptoms of vasospasm in Ray-
nauds phenomenon. Botulinum toxin A is thought to
function by blocking vascular smooth muscle depolar-
ization and vasoconstriction, in addition to blockade of
central nervous stimuli for vasoconstriction.
This study serves to review the available literature on
the treatment of Raynauds phenomenon in the setting
of injectable botulinum toxin A. Suggested techniques
of administration, reported clinical efficacy, and pro-
posed mechanisms of action are discussed.
An Ovid MEDLINE search from 1950 to 2010 was
performed to identify any reports on the use of Botu-
linum toxin in the treatment of Raynauds disease or
associated vasoconstrictive disorders. An initial query
was performed that identified all studies pertaining to
Raynauds disease, Raynauds, or vasoconstric-
tion. This yielded 27,266 results. A secondary search
for all studies pertaining to botox or botulinum
toxin type A was then performed, with a total of 4410
results. These reports were meshed and subsequently
limited to human studies, for 18 and 12 results, respec-
tively. Of the 12 reports, 2 were excluded that did not
evaluate clinical or patient outcomes, 3 were excluded
that did not pertain to Raynauds disease, and another
2 were excluded that primarily evaluated secondary
symptoms of hyperhidrosis or pruritis and were not
specific to Raynauds disease. The remaining 5 articles
were included in our analysis. Additional studies that
were not captured by the initial search were included
following bibliographic searches of the reviewed stud-
ies. Table 1 summarizes the reports based on study
design, criteria for botulinum injection, and patient
symptom demographics.
M.L. Iorio, D.L. Masden, and J.P. Higgins
RESULTS
Clinical Reports
The use of Botulinum toxin A for Raynauds phenome-
non was first reported in 2004. Sycha and coworkers re-
ported a case series of 2 patients with intractable and
severe Raynauds phenomenon. This brief report was
their initial experience with the use of botulinum toxin for
the possible reversal of vasoclusive pain or stiffness. These
patients were noted to be given markedly different doses
of botulinum toxin A and demonstrated relief in 3 days
and 1 week, respectively. Both patients noted symptom-
atic improvement of stiffness and numbness following
injection, as well as an increase in digital perfusion as
identified using laser Doppler interferometry in compar-
ison to digits that had not been treated. This initial report
provided no long-term follow-up (3).
The next clinical report was provided by Vanbeek and
coworkers in 2007. They identified 11 patients with se-
vere Raynauds phenomenon in the setting of connective
tissue disorders. All patients were screened with arterio-
grams preoperatively and noted to have no occlusive dis-
ease proximal to the wrist. Injections were performed
around the digital vessels of the affected fingers only. As a
result of early recurrence in noninjected fingers, they
modified their treatment protocol to inject all fingers,
excluding the thumb, at the time of initial treatment.
Targeted injection sites included the superficial palmar
arch, common digital arteries, and proper digital arteries,
using a total of 100 U per hand. All patients demonstrated
pain relief in 24 to 48 hours. Some of the patients re-
quired repeat injections 3 to 8 months after the initial
injection. At an average follow-up period of 9.6 (6-30)
months, they found that all patients reported a decrease in
frequency and severity of vasospastic episodes. In 9 of the
11 patients, soft tissue ulceration healed without further
intervention. The remaining 2 patients underwent skin
grafting with success. In addition, average pain scores
dropped from 9 to 10 to a level of 0 to 2 (4).
Fregene and coworkers endeavored to identify the patient
subgroups that would most benefit from injection therapy
and to define a uniform pattern for injection technique. Pa-
tients with Raynauds phenomenon refractory to medical
treatment, and without obstructive ischemia, were placed
into 3 categories for injection therapy with botulinum toxin
A based on symptoms. The first group received digit injec-
tions along the digital neurovascular bundles. The second
group was injected in the distal palm within the superficial
palmar arch and web space. The third group was injected in
the proximal hand at the distal volar wrist crease adjacent to
the radial and ulnar arteries (5). Criteria for digital injection
included distal digital ischemia only. If color change, tem-
perature change, or ischemia extended to the base of the
digit, the distal palm was injected. Finally, if more than 1
digit was involved, the proximal hand was injected. A total of
26 patients were treated with a range of 10 to 100 U, with a
significant decrease in pain scores in all groups, and signifi-
601
cant improvement in transcutaneous oxygen saturations and
ulcer healing. However, statistical evaluation was unable to
find a specific injection site as superior.
In 2009, Neumeister and coworkers studied 19 pa-
tients with Raynauds phenomenon. All patients under-
went magnetic resonance angiograms or contrast angiog-
raphy to rule out proximal occlusive disease. Patients were
provided either 50 or 100 units of botulinum toxin A per
hand distributed at the webspaces and distal palm. Sixty-
three percent of the patients required more than 1 injec-
tion; 84% of the patients reported pain reduction. The
majority reported onset of pain relief immediately after
injection. All patients underwent Doppler scanning just be-
fore, and within 30 minutes after, the botulinum toxin A
injections. Doppler scanning demonstrated increased perfu-
sion of the digits in 10 of 14 of the patients. The effects of the
botulinum toxin A appeared to last greater than 12 months.
All of the digital ulcers healed within 60 days. This study
shed more light onto the efficacy of botulinum toxin A in
digital vasospasm and brought into question our under-
standing the mechanism of this action. The author submit-
ted that the immediacy and duration of the action of the
botulinum toxin A suggests that its mechanism of action is
multifactorial and more complex than previously under-
stood (6). In a follow-up study and review of technique,
Neumeister standardized his injection technique and placed
10 units of botulinum toxin A on each neurovascular bundle
at the level of the MCP flexion crease (7). Results were ob-
tained through Doppler perfusion imaging and subjective
reports of pain and wound healing. A total of 33 patients
received treatment. Reduction of pain was reported in 28
patients and tissue perfusion changes measuring between
48.15% and 317.39% using laser Doppler perfusion. As
illustrated in Table 2, this represents the largest study cohort
yet reported and provides a standardized technique for dos-
age and injection site.
DISCUSSION
Raynauds phenomenon involves a mismatch between
constriction and dilation of the small arteries of the upper
extremity. The etiology is multifactorial, including intrin-
sic vascular abnormalities with a resultant failure to ade-
quately vasodilate, and neural abnormalities that may
overpromote vasoconstriction.
Vascular abnormalities include both structural and
functional problems. Small vessel endothelium fails to
appropriately vasodilate through the production of nitric
oxide and prostacyclin. Studies of microvascular circula-
tion have found that when an endothelial-dependent va-
sodilation stimulus, such as acetylcholine chloride, is
given, there may be a decrease in measured microvascular
flow, as compared with endothelial-independent vasodi-
latory stimuli (8,9).
Structural vascular derangements such as endothelial
hyperproliferation may also contribute by decreasing the
absolute caliber of the vessel and causing near total occlu-
602 Botulinum toxin A treatment of Raynauds phenomenon

Table 2 Summary of Reported Injection Techniques, Botulinum Dosages, and Complications

Study Injection Site Volume Injected Patient Complications

Fregene et al (2009) 1. Digital (38%)a
2. Distal palm (83%)a
3. Proximal hand (13%)a
Neumeister et al (2009) A1 pulley/MCPJ level
Sycha et al (2004) Digital (6 sites per finger)
Van Beek et al (2007) 1. Digital (18%)
2. Digital and superficial
arch (82%)
Neumeister et al (2010) MCPJ level
MCPJ, metacarpophalangeal joint.
aCombination of injection sites during treatment.
10 to 100 U (average 77 U) per
treatment
50 to 100 U/hand (all digits)
1 to 10 U/site (affected digits)
100 U/hand (8 to 12 U/site)
100 U/hand (all digits)
Intrinsic weakness: 6 (23%)
Dysesthesia: 1 (4%)
Resolved prior to 5 mo
Intrinsic weakness: 3 (16%)
Resolved prior to 2 mo
None
Intrinsic weakness: 3 (27%)
mild
Intrinsic weakness: 3 (9%)
Resolved prior to 2 mo

sion during vasospasm. These intrinsic and functional
vessel factors seen in Raynauds phenomenon are thought
to be related; damaged endothelium is unable to produce
adequate amounts of nitric oxide or to appropriately re-
spond to signals for vasodilation.
Neural abnormalities may also contribute by affecting
the autoregulation of vascular tone through either an
overproduction of alpha-andrenergic receptors and sub-
sequent vasoconstriction or a decrease in vasodilatory
stimuli. Sensory afferent nerves that regulate blood vessels
produce calcitonin gene-related peptide, a potent vasodi-
lator. In the setting of Raynauds phenomenon, immuno-
histochemical studies have demonstrated a decrease in the
circulating level of calcitonin gene-related peptide, possi-
bly contributing to impaired stimulus for vasodilatation,
and prolonged or exaggerated vasoconstriction. It has
been shown that intravenous administration of the calci-
tonin gene-related peptide may increase vasodilatation
and decease the severity of symptoms in patients with
Raynauds phenomenon (8,10). In addition, neural ab-
normalities may also contribute by causing an upregula-
tion in neurotransmitters and receptors specifically within
the alpha-adrenergic system. This system regulates the
sympathetic tone of the smooth muscle within the tunica
media of the small-caliber arterioles. Of the receptors
studied, the 1 that appears to be the most important for
regulation of digital vessel tone is the 2-adrenoreceptor
(8,11). Studies have implicated this receptor in the regu-
lation of vascular tone, most specifically in response to
cold stimuli, and have found an increased level of reactiv-
ity of this receptor in arterioles of patients with Raynauds
phenomenon-associated disease states, as compared with
unaffected controls (8,12).
Botulinum toxin type A is produced by the bacterium
Clostridium botulinium. It has been specifically refined for
the treatment of muscle spasm in the setting of blepharo-
spasm and strabismus and became first commercially
available as Botox (Allergan, Inc, Irvine, CA). It decreases
muscular tone by blocking neurotransmitter response
across the neuromuscular endplate. This is accomplished
by inhibiting the release of acetylcholine vesicles at the
motor end plate terminals and subsequently inhibiting
smooth muscle vasoconstriction (6,13).
Botulinum toxin type A affects vascular smooth muscle
and therefore vasoconstriction via 2 additional mecha-
nisms. It blocks the transmission of the norepinephrine
vesicle, preventing sympathetic vasoconstriction of the
vascular smooth muscle. Additionally it blocks recruit-
ment of specific 2-adrenoreceptor (alpha 2c), which de-
creases the activity of chronically upregulated C-fiber
nociceptors. This leads to a subsequent reduction in cold-
induced vascular smooth muscle constriction and pain
(6,14,15).
These available studies reviewed report improvement
in symptoms of pain in patients with vascular ischemia by
utilizing botulinum toxin A. The studies thus far have not
included prospective controlled trials. The reports in-
clude patients with a number of different collagen vascu-
lar diseases and the doses provided vary widely in their
concentration, magnitude, and distribution throughout
the hand. Variable treatment protocols and outcome end-
points include subjective pain improvement, wound res-
olution, and an assessment of the color of the digits.
Most problematic with the available literature thus far
is the lack of a standardized injection and study design.
The 2 reports provided by Neumeister address the diffi-
culty in selectively treating individual digits in a disease
that should universally affect the small arterioles of the
extremities. This is done by injecting all digits, along the
level of the superficial palmar arch with a standard tech-
nique and botulinum dose. However, the lack of control
or placebo cohorts limits the value of the studies and
requires further investigation.
Remaining areas of study include the exact mechanism
of action, appropriate dose and dosing frequency, and the
efficacy relative to surgical periarterial sympathectomy or
M.L. Iorio, D.L. Masden, and J.P. Higgins
other medical treatment protocols. Likewise, the indica-
tions need to be further defined. While our conventional
knowledge of the action of botulinum toxin A would lead
us to believe that only true vasospastic disease would dem-
onstrate clinical benefit from botulinum toxin A, it may
be possible that botulinum toxin A will prove useful in
other settings. These could include treatment of down-
stream vasospasm secondary to more proximal large ves-
sel occlusive disease, posttraumatic digital cold intoler-
ance, and adjuvant intraoperative chemical palmar
sympatholysis in the setting of more proximal bypass
grafting.
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