The Therapeutic Potential of Botulinum Toxin

ARNOLD WILLIAM KLEIN, MD

Department of Dermatology/Medicine at the David Geffen School of Medicine at UCLA and the American Foundation
for Aids Research, Beverly Hills, California
BACKGROUND. Botulinum toxin type A (BTX-A; commercial
preparation BOTOX) is most well known for its effect on
muscle contraction because of the BTX binding to the
presynaptic nerve terminal, inhibiting the release of acetylcho-
line (ACH). The therapeutic benet of BTX-A, however, can
also be isolated to pain relief alone, suggesting that BTX-A also
works through additional modes of action.
OBJECTIVE. This article provides insight by an experienced
physician into four different case reports. Each case demon-
strates the therapeutic potential of BTX-A and the possibility of
a different mechanism of action for BTX other than the
inhibition of ACH release.
RESULTS. Four patients, each with different symptoms such as
relapsingremitting multiple sclerosis, postherpetic neuralgia,
peripheral neuropathy, and severe tingling caused by herniation
of cervical vertebrae at the level of C8, were treated with
BOTOX, and their symptoms were alleviated.
CONCLUSIONS. The BTX-A mechanism providing pain relief is
hypothesized to be something other than muscle relaxation by
inhibiting the release of ACH at the neuromuscular juncture,
such as inhibition of the release of substance P or the blocking
of autonomic pathways, etc. This article is intended to continue
to keep physicians using this substance for dermatologic
indications aware of the potential unsuspected effects.
DR. KLEIN IS A RETAINED CONSULTANT AND INVESTIGATOR FOR BOTH ALLERGAN AND
ELAN PHARMACEUTICALS.
BOTULINUM TOXIN type A (BTX-A; commercial
preparation BOTOX; Allergan Corporation, Irvine,
CA) has received Food and Drug Administration
approval for the treatment of strabismus, blepharos-
pasm, VII nerve disorders, and most recently to
decrease the severity of abnormal head position and
neck pain associated with cervical dystonia. Botox
Cosmetic is identical to the product BOTOX and has
recently received Food and Drug Administration
approval for the treatment of the glabellar frown.
When injected directly into contracting muscles, BTX-
A exerts its effect by binding to the presynaptic nerve
terminal, becoming internalized, and interfering with
exocytosis of the neurotransmitter acetylcholine
(ACH) at the neuromuscular juncture with resultant
inhibition of muscle contraction. Beyond these indica-
tions, there are approximately 100 published uses of
BTX-A, ranging from facial aesthetic applications to
the management of hyperhidrosis.
Apart from its effect on muscle contraction and the
eccrine glands, the therapeutic benet of BTX-A can
also be isolated to pain relief alone. Several publica-
tions have documented the efcacy and safety of BTX-
A in pain syndromes, including tension-type head-
ache,
15
migraine,
610
chronic low back pain,
11
and
myofascial pain.
12,13
Indeed, a large body of data has
documented the efcacy of BTX-A in the management
of both neurologic disease as well as pain syndromes.
In the eld of dermatology, BTX-A has long been used
as an incomparable tool for aesthetic enhancement and
the treatment of hyperhidrosis. Recently, Swartling et
al.
14
reported the response of dyshidrotic eczema to
BTX-A. The authors suggested that this was due to
inhibition of eccrine sweating. Because it has long been
known that dyshidrotic eczema is not due to hyperhi-
drosis, another mechanism of action of BTX-A must
be responsible for this response. On the other hand, it
has long been known in the treatment of cervical
dystonia that the period of pain relief often exceeded
the interval of reduced spasticity. What additional
modes of action have been described for BTX-A that
could explain these observations? Having observed the
following cases and their responses to BTX-A, modes
of action in addition to the simple inhibition of ACH
release must be present.
Case Report
Case 1
Patient A is a 45-year-old female who was diagnosed
at the age of 40 years with relapsingremitting
multiple sclerosis. She was not currently undergoing
any therapy for this condition. At the time of her visit
r
2004 by the American Society for Dermatologic Surgery, Inc.

Published by Blackwell Publishing, Inc.
ISSN: 1076-0512/04/$15.00/0

Dermatol Surg 2004;30:452455
Address correspondence and reprint requests to: Arnold William Klein,
MD, 435 North Roxbury Drive, Suite 204, Beverly Hills, CA 90210, or
e-mail: awkleinmd1@aol.com.
for BTX-A treatment of her frown, forehead, and
crows feet lines, she indicated that she had been
experiencing severe dizziness for 4 to 6 months. She
had seen multiple physicians for this vertigo and had
received various therapies with no response. She had
previously received BTX-A for cosmetic enhancement
of her upper face. Her neurologist felt that the
dizziness was secondary to multiple sclerosis but was
not a contraindication to BTX-A injections. She was
given 21 U of BTX-A to her frown, 9 U to her upper
forehead, and 30 U to her crows feet (15 U per side);
at 72 hours after her treatment, she noted complete
relief of dizziness. The patient was treated again 3
months later and thought that the muscle actions had
returned but that the dizziness had not. The patient
has been evaluated over the 6 months since the initial
treatment, and the dizziness has not recurred.
Case 2
Patient B is a 62-year-old male who sought treatment
of his glabellar frown with BTX-A. Medical history
revealed a 17-week history of postherpetic neuralgia,
which was being managed with eutectic mixture or
local anesthetics and acetaminophen with hydroco-
done bitartrate. Also, he was being managed with
atenolol for hypertension. The Herpes Zoster had been
managed with valacyclovir hydrochloride over a 10-
day period, which was started within 48 hours of
onset. The condition involved the right lumbar 2,3
nerves with maximal residual point pain on his right
lateral side. In addressing the frown, he was given 34 U
of BTX-A to the glabellar area. In regards to the post-
herpetic neuralgia, 20 U of BTX-A were injected
intradermally at the point of maximal tenderness on
his right side. Within 7 days, the patient called to say
that his frown had responded well and that he had
complete relief of neuralgia pain, which has not
recurred in 4 months.
Case 3
Patient C is a 39-year-old HIV-positive male who had
been maintained on HAART (highly active anti-
retroviral therapy) for 2 years. In the course of this
treatment, he developed a severely painful peripheral
neuropathy that was unresponsive to gabapentin and
methadone hydrochloride. A complete neurologic
examination and evaluation by a neurologist specializ-
ing in HIV-associated conditions at David Geffen
School of Medicine at UCLA concluded that the pain
was associated with the disease process itself (HIV)
and not secondary to medication. Because of the severe
nature of the pain and the lack of the patients response
to traditional therapy, the patient was queried regard-
ing his willingness to have BTX-A injections amelio-
rate the pain. With the consent of the patient, 21 U of
BTX-A were administered intradermally in the left
foot. The dose and injection sites were 7 U across the
dorsal surface of the toes, 7 U on the medial aspect of
the foot above the sole, and 7 U posterior to the medial
malleolus. The sites injected were those at which the
patient indicated the greatest pain. The patients right
foot served as a control.
Within 72 hours, the patient noted an almost
complete disappearance of pain in his left foot.
Physician assessment conrmed the patients subjective
evaluation. Treatment was then given to the right
(control) foot 7 days later with similar results. The alle-
viation of pain in the patients feet lasted for 6 weeks.
Furthermore, although the pain began to reappear at 6
weeks, it was not as severe as before the BTX-A therapy.
Case 4
Patient D is a 60-year-old dermatologist who had
experienced severe tingling of his fth nger on his left
hand for 2 years. Herniation of cervical vertebrae at
the level of C8 was diagnosed by both his neurologist
and orthopedist. The patient was told that his only
option was surgical intervention. He experienced
severe insomnia secondary to the tingling, and the
tingling did not respond to paraspinal steroids. The
patient was then treated with 5 U of BTX-A to the
central site of tingling (nger pad), and within 24
hours, there was total amelioration of the symptoms.
The patient had a recrudescence of the symptom 6
months later, and this was again successfully treated
with 5 U of BTX-A.
Discussion
The family of botulinum neurotoxins includes seven
distinct subtypes: A, B C, D, E, F, and G. Although
they are all capable of interfering with ACH release,
they vary in their size, biosynthesis, and cellular
mechanism of action. Consequently, they differ in
their clinical usefulness. Type A is the most powerful
of the subtypes and the rst to be developed for clinical
applications. Type A is available in the United States as
BOTOX and BOTOX Cosmetic.
It has been well established that the mechanism of
action of BTX-A provides dose-dependent muscle
relaxation by inhibiting the release of ACH at the
neuromuscular junction.
15
However, recent evidence
suggests that alternative mechanisms of action may
account for the efcacy of BTX-A in various neuro-
logic conditions and pain syndromes.
16
The mechan-
ism providing pain relief is hypothesized by some to be
Dermatol Surg 30:3:March 2004 KLEIN: THERAPEUTIC POTENTIAL OF BTX 453
related not only to ACH inhibition but also to a
blocking action on the parasympathetic nervous
system.
32
In other studies, it has been shown that
BTX-A may inhibit the release of neurotransmitters
and neuropeptides other than ACH,
17,18
including
substance P
24,25
and calcitonin gene-related peptide.
26
Additionally, retrograde uptake of BTX-A into the
central nervous system is believed to inuence the
substance P and enkephalins levels in the spinal cord
and nucleus raphe. This could lead to a blockade of
pain seen in migraine.
33
BTX-A has been shown to
block autonomic pathways,
27
and there is evidence
that BTX has a direct effect on afferent bers, suggest-
ing an inhibition potential of the sensory system.
2830
BTX may reduce various substances that sensitize
nociceptors, and as a result, BTX-A and BTX-B are
now being actively studies in nociceptive and neuro-
pathic pain disorders to better dene their roles as
analgesics.
34
Newer synthetic or altered forms of
BTX are currently being investigated for specic relief
of pain because of their ability to target afferent
nerves.
Additionally, the distinct antinociceptive mechan-
ism of action of BTX-A may be through its effect on
the communication receptors of muscle spindles or
through a direct effect on the central nervous system
when larger doses are used.
31
Further study of the
potential for BTX-A in peripheral neuropathies and
other neurologic conditions is warranted, as well as
other possible dermatologic applications.
3544
Indeed,
all physicians using this substance for dermatologic
indications should be aware of the potential unsus-
pected benecial effects.
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