Int. J. Oral Maxillofac. Surg.

2010; 39: 197207

doi:10.1016/j.ijom.2009.10.022, available online at http://www.sciencedirect.com

Invited Review Paper

Therapeutics

Clinical use of botulinum toxins O. W. Majid

Department of Oral and Maxillofacial Surgery,
College of Dentistry, University of Mosul,
Mosul, Iraq

in oral and maxillofacial surgery

O. W. Majid: Clinical use of botulinum toxins in oral and maxillofacial surgery. Int. J.
Oral Maxillofac. Surg. 2010; 39: 197207. # 2009 International Association of Oral
and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Botulinum toxin (BTX) is a bacterial toxin that could be used as a medicine. Clinical
applications of BTX have been expanding over the last 30 years and novel
applications reported. Its mechanism of inhibiting acetylcholine release at
neuromuscular junctions following local injection is unique for the treatment of
facial wrinkles. Other dose-dependent anti-neuroinflammatory effects and vascular
modulating properties have extended its spectrum of applications. Conditions such
as temporomandibular joint disorders, sialorrhea, headache and neuropathic facial
pain, muscle movement disorders, and facial nerve palsy could also be treated with
this drug. Further applications of BTX are likely to be developed. This paper Keywords: botulinum; clinical use.
reviews the established and emerging applications of BTX in the field of oral and
maxillofacial surgery. An overview of the pharmacology, toxicity and preparations Accepted for publication 30 October 2009
of the agent is given. Available online 2 December 2009

Purified botulinum toxin (BTX) was the
first bacterial toxin used as a medicine.
Since its introduction into clinical use,
over 30 years ago, it has become a versa-
tile drug in various fields of medicine. The
clinical applications of BTX have been
expanding and novel applications devel-
oped.
BTX is widely used in cosmetic appli-
cations for the treatment of facial wrinkles
after local injection, but conditions such as
temporomandibular joint disorders, sialor-
rhea, headache and neuropathic facial
pain, muscle movement disorders, and
facial nerve palsy could be treated with
this drug. Many other indications are
under investigation, and further applica-
tions for BTX are likely to be devel-
oped220. In the maxillofacial region,
most studies on the use of BTX are of
low quality (noncomparative, non-rando-
mized trials), but the overall results were
promising.
In this review, established and emerging
applications of BTX in the field of oral and
maxillofacial surgery are discussed.
Emphasis is placed on the mechanism of
action and outcome of treatment in differ-
ent clinical situations. An overview of the
pharmacology, toxicity and different pre-
parations of the agent is given.
History
The idea of a possible therapeutic use for
botulinum toxin (BTX) was first devel-
oped by the German physician and poet
Justinus Kerner (17861862); he called it
sausage poison. In 1870, Muller, another
German physician, coined the name botu-
lism. The Latin form is botulus, which
means sausage66.
In 1897, Emile van Ermengem investi-
gated an epidemic of botulism in Elle-
zelles, Belgium, after the consumption
of raw ham. He isolated the bacteria from
the ham and produced the disease in
laboratory animals by injecting the toxin
produced by the organism41.
BTX was developed as a biological
weapon by many countries in the twenti-
eth century50. Although many countries
stopped research related to biological
weaponry after signing the Biological
and Toxin Weapons Convention, purifica-
tion of BTX for medical use continued222.
A therapeutic use for botulinum toxin
type-A (BTX-A) was first studied in pri-
mates by Scott et al in 1973187. In the late
1970s, the toxin was introduced as a ther-
apeutic agent for the treatment of strabis-
mus186. Since then, its therapeutic
applications have expanded into many

0901-5027/030197 + 11 $36.00/0 # 2009 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
198 Majid
different fields, often with innovative
treatments and surprising results.
BTX was first used for treating facial
wrinkles and aging skin in 1988, but its
widespread cosmetic use did not occur
until the mid-1990s148. There was much
speculation about the storage, dilution,
delivery methods and treatment doses. In
maxillofacial surgical practice, Niamtu
reported on the cosmetic use of BTX for
facial rhytids and dynamic lines in 1999
and 2000147,149. During the mid- and
late-1990s, BTX was used for lateral
canthal lines (crows feet), platysmal
banding, orbicularis oris injection, mass-
eter muscle injection and the treatment
of temporomandibular disorders
(TMDs). Later, there were many
attempts to use BTX for different clin-
ical situations in oral and maxillofacial
surgery.
Bacteriology
Clostridium species bacteria are sporulat-
ing, obligate anaerobic, Gram-positive
bacilli. The spores of C. botulinum are
ubiquitous, distributed widely in soil and
marine sediments worldwide and often
found in the intestinal tract of domestic
grazing animals199,206.
Under appropriate environmental or
laboratory conditions, spores can germi-
nate into vegetative cells that will produce
toxin. C. botulinum grows and produces
neurotoxin in the anaerobic conditions
frequently encountered in the canning or
preservation of foods200,223.
Seven different strains of Clostridium
have been described (designated A, B, C
(1 and 2), D, E, F and G), and each
produces a distinct neurotoxin identified
by the corresponding letter of the bacterial
strain producing it, so, there are 7 distinct
neurotoxins (BTX-A, -B, -C, -D, -E, -F, -
G)100,216. Humans can be affected by the
toxins of 5 strains (A, B, E, F and G) and
are not affected by the toxins of strains C
and D71,100. All 7 toxins may potentially
cause botulism in humans given a high
enough exposure140. All 7 neurotoxins are
structurally similar but immunologically
distinct92. There is some serum cross-
reactivity among the serotypes because
they share some sequence homology with
one another as well as with tetanus
toxin91.
Structure and Toxicity
Toxins produced by clostridial bacteria
are high-molecular-weight protein com-
plexes that include 3 key proteins: a 150-
kDa toxin, a non-toxin hemagglutinin
protein, and a non-toxin non-hemagglu-
tinin protein. The 150-kDa toxin is com-
posed of a 100-kDa heavy chain and a 50-
kDa light chain. Disulfide and noncova-
lent bonds link the heavy and light chains,
and both chains are required for neuro-
toxicity100.
BTX is the most toxic material known.
It is 4 times more lethal in mice than
tetanus toxin, 1  1010 more lethal than
curare, and 100  1010 more lethal than
sodium cyanide33. The estimated human
dose (assuming a weight of 70 kg) of type
A toxin lethal to 50% of an exposed
population (the LD50) is estimated, based
on animal studies, to be approximately
0.090.15 mg by intravenous administra-
tion, 0.70.9 mg by inhalation and 70 mg
by oral administration76,96,180,188. Based
on findings from primate studies, human
LD50 for intramuscular BTX injection is
estimated at 25003000 U for a 70-kg
adult (3540 U/kg).
Mechanism of Action
BTX is a protease that causes temporary
chemical denervation of skeletal muscle
by blocking the Ca+2-mediated release of
acetylcholine from nerve endings of alpha
and gamma motor neurons (myoneural
junction), producing a transient dose-
dependent weakening of the muscle activ-
ity rendering it nonfunctional without sys-
temic effects23. This inhibition of
muscular contraction is believed to be
followed by the sprouting of new axon
terminals, which results in synaptic regen-
eration and the reestablishment of neuro-
muscular transmission15.
The 7 neurotoxins have different spe-
cific toxicities,87,113,151 different durations
of persistence in nerve cells49,74, and dif-
ferent potencies5. All BTX serotypes, ulti-
mately, inhibit acetylcholine release.
The area of flaccidity produced may be
larger than the area of muscle denervated
as a result of postulated paralysis of
gamma motor neurones, so the output of
the muscle spindles is reduced leading to
reduced muscular contraction at adjacent
sites within the injected muscle150. Weak-
ening of surrounding muscles not injected
may also occur because of toxin diffusion.
Animal studies have demonstrated that
BTX-A diffuses across fascial planes to
surrounding muscles193.
Clinical effect occurs within approxi-
mately 37 days (typically seen after 13
days) after administration, followed by 1
2 weeks of maximum effect, which then
levels off to a moderate plateau until full
nerve recovery within 36 months (typi-
cally at approximately 3 months)176.
Preparations
A number of BTX preparations have been
approved in different countries. Currently,
there are 6 different BTXs available on the
market, 5 contain BTX-A (Botox, Dys-
port, Xeomin, Prosigne and PurTox) and
the other contains BTX-B (Myoblocs/
NeuroBlocs). Approval procedures are
complex and vary between preparations
and countries, but, in general, Botox has
garnered the most approvals worldwide,
followed by Dysport220.
Treatment doses of BTX vary depend-
ing on the brand of toxin used. The dose
given for any toxin refers only to that
particular preparation and does not readily
transfer to doses of other products, even if
they are of the same toxin serotype. These
ratios should be applied with extreme
caution because different preparations
may have different efficacy in different
parts of the body77.
BTX-A
Botox (Allergan Inc, USA): BTX-A (ori-
ginally called Oculinum) was first used
in humans in 1968 to treat strabismus187.
In 1991, Allergan Inc. purchased several
batches of this purified BTX-A, and the
agent was given the name Botox216.
Botox is the only available BTX pro-
duct approved for cosmetic use in North
America. It is specifically approved for the
therapeutic treatment of strabismus, ble-
pharospasm, cervical dystonia and axillary
hyperhidrosis. There are reports of Botox
specifically improving patient self-percep-
tion35,37,38,69,90,124,126,127.
Each vial of Botox contains 5 ng (100
U) of air-dried toxin, with 1 unit (U) equal
to the median amount necessary to kill
50% of female Swiss-Webster mice
weighing 1820 g each after intraperito-
neal injection (LD50)135,176,216. Each vial
contains 500 mg of albumin and 900 mg of
sodium chloride135.
Dysport (Ipsen Limited, UK) is
another BTX-A product approved for
cosmetic use, which is marketed and
sold in many European countries as well
as Russia, New Zealand, Mexico, Brazil,
Argentina and Vietnam35. Each vial con-
tains 12.5 ng (500 U) of air-dried toxin,
125 mg of albumin, and 2.5 mg of lac-
tose135. Dysport comes from a different
type A strain of bacteria than Botox and
doses are not equivalent. Direct compar-
isons of Botox and Dysport in animal
studies suggest that the equivalence
doses are 1 U Botox to 2.55 U Dysport,
though in humans, this conversion is
largely an estimate135.

Xeomin (NT-201; Merz Pharmaceuti-
cals GmBH, Germany), packaged as a
freeze-dried powder, is a purified BTX-
A that is free of the accessory complexing
proteins (hemagglutinin and nonhemag-
glutinin) found in the other BTX-A pro-
ducts229. It is reported to be less
immunogenic than other BTX-A pro-
ducts,107 making it useful when large
amounts of toxin are required for extended
periods77. Animal studies support this, but
reliable human immunogenicity data are
not available107.
Many studies have found that Botox
and Xeomin have similar dose-dependent
paralytic effects and minimal diffusion
effects on surrounding musculature53,229.
It has been suggested that conversion of
Botox and Xeomin doses can be per-
formed in a 1:1 ratio allowing exchange
of both BTX drugs in a therapeutic set-
ting.
Prosigne (Lanzhou Biological Products
Institute, China) is a BTX-A that is only
approved in China; it has been available
for clinical use there since October
1993215. Preliminary studies suggest that
Prosigne may have therapeutic actions
comparable with Botox for some thera-
peutic purposes168,215. Trials specifically
examining Prosigne for cosmetic uses are
lacking77.
PurTox (Mentor Corp, Santa Barbara,
CA, USA) is a purified BTX-A that is
undergoing trials to approve its efficacy
in some therapeutic uses77.
BTX-B
BTX-B is available as Myobloc (Solstice
Pharmaceuticals, South San Francisco,
CA, USA) and is marketed as Neurobloc
(Elan Pharmaceuticals, Shannon, County
Clare, Ireland)135. Myobloc has shown
efficacy in clinical trials for the treatment
of various movement disorders since 1995
and was approved by the FDA for the
treatment of cervical dystonia and hemi-
facial spasm in 2001163. Myobloc has not
received cosmetic approval in any coun-
try, but there are reports of its efficacy in
the treatment of lateral canthal, glabellar
and forehead rhytides. It appears to offer
versatility in cosmetic neuroblockade by
exhibiting action in patients resistant to
BTX-A products3,11,119,125,135,163,174176.
Myobloc is preconstituted in vials con-
taining 25 ng (2500 U)/0.5 cc, 50 ng (5000
U)/1.0 cc and 100 ng (10,000 U)/2.0 cc of
product in solution with 0.05% albu-
min135. Treatment of patients with cervi-
cal dystonia with Botox and Myobloc led
to attempts at equivalency doses in many
cosmetic studies (1 U Botox equals
Clinical use of botulinum toxins in oral and maxillofacial surgery
approximately 50100 U Myobloc), but
the optimal ratio has not been estab-
lished77.
Studies comparing the cosmetic effi-
cacies of BTX-A and BTX-B report
that the latter causes more pain during
injection, has shorter action and prob-
ably a less predictable diffusion pat-
tern70,73,125,135,163. BTX-B could be
useful in situations in which rapid onset
is desirable or in which there are
concerns about antibody production to
BTX-A77.
Cosmetic Uses
Intramuscular injection of BTX to reduce
facial wrinkles is the most common cos-
metic procedure performed in many coun-
tries. In conjunction with fillers, BTXs
allow the practitioner to sculpt the face
through alterations in the dynamics of the
facial muscles. The limited on-label uses
of these drugs for hyperkinetic forehead
wrinkles and brow furrows belie its range
of cosmetic applications.
Facial Wrinkles
Glabellar lines, also called frown lines,
occur naturally with facial animation, as a
result of the pulling of the skin by the
underlying musculature, predominantly
the procerus muscle and the corrugator
supercilii. With aging and chronic activity
of the facial muscles, these lines become
more prominent93. The cosmetic potential
of BTX-A was first explored in the mid
1980s in the treatment of hyperfunctional
facial lines. Since then, BTX-A has been
used to temporarily treat glabellar lines
and other hyperfunctional facial lines
such as horizontal forehead lines, lateral
canthal lines crows feet, platysma fully using BTX injection; there were no
bands and perioral lines68,75,147. The evi-
dence for the effect of BTX in the treat-
ment of facial wrinkles is level 2 evidence
(evidence from randomized controlled
trials).
The technique for injecting BTX is
generally simple and most patients toler-
ate injections without anesthesia quite
well, although topical anesthetics are used
by some practitioners. Some have used
acid mantle cream mixed with lidocaine
(4%) and Lidoderm patches (lidocaine
5%)146. Many patients treated with topical
anesthesia elected not to use it for subse-
quent treatments148.
Multiple injection techniques have been
described. Some authors describe a
method based on brow position36. Others
describe a method based on needle angu-
lation and measurement147,149. All injec-
199
tions are now made perpendicular to the
skin surface and are tailored to the specific
anatomy, but they must be 10 mm away
from the bony orbit because the apparent
diffusion of BTA is approximately
10 mm148.
Botox has only been approved offi-
cially for the treatment of glabellar lines,
but other uses have shown the same
degree of improvement for frontalis and
lateral canthal regions. Botox has also
been used for the reduction of platysmal
bands108,134. Several patients with men-
talis wrinkling and lower eyelid orbicu-
laris hypertrophy were treated
successfully with Botox injections72,148.
Other sites treated include the vertical lip
rhytids (lipstick lines) with minimal
improvement and good patient satisfac-
tion but perioral muscular palsy was
reported in some cases148,186. Some have
described an improvement in patients
with excessive gingival exposure. By
weakening the lip elevators, the amount
of movement decreases and the patient
shows less gingiva on smiling34.
Masseteric and temporalis muscle
hypertrophy
Masseteric hypertrophy usually results
from anatomical asymmetry of the jaw,
habitual asymmetric use of the jaw,
clenching during exercise or sleep, exces-
sive chewing of gum or congenital mal-
formations. It may be unilateral or
bilateral. The early results of treatment
with intramasseter injections of BTX have
been encouraging and satisfying to
patients, but the effect has not been well
quantified12,138,144,170.
Temporalis muscle hypertrophy is less
common but has been managed success-
appreciable side effects103.
Therapeutic Uses
BTX has evolved from a poison to a
versatile clinical tool for a growing list
of conditions resulting from muscular
hyperfunction. In the head and neck, this
list includes focal dystonias, vocal tics
and stuttering, cricopharyngeal achalasia,
various manifestations of tremor, hemi-
facial spasm, temporomandibular joint
dysfunction, bruxism, masticatory myal-
gias, sialorrhea, hyperhidrosis and head-
ache80,220. Recently, it has been reported
for clinical use in dental implantology for
the prophylactic reduction of masseter
and temporalis muscle strength after
implantation in immediate load proto-
cols101.
200 Majid
Temporomandibular joint (TMJ)
Many reports on BTX-A treatment for
TMJ disorders have dealt with TMJ and
masticatory muscle pain78,79, reduced jaw
opening capacity10,202, recurrent TMJ dis-
locations143,195,235, and masticatory
hyperactivity225. Most of these studies
were case series (level 4 evidence).
Temporomandibular disorders (TMDs)
are subgroups of musculoskeletal and
rheumatologic disorders, and are consid-
ered the major cause of pain in the orofa-
cial region152. TMDs may be divided into
those related to the muscles acting on the
joint (myofascial) and those related to the
joint itself (arthrogenic). Joint noise, pain
and a restricted range of mandibular
motion are the most frequent symptoms
of TMD58. Directing treatment at the mus-
cular component of TMD, which in some
patients can be identified as non-spastic
clenching or bruxism, could yield impor-
tant therapeutic gains. BTX-A has been
effective in the treatment of some patients
with TMD with high specificity as well as
tolerable side-effects82. Injections are
usually performed under electromyo-
graphic or ultrasonic control12,82.
The source of chronic myofascial pain
is not clear57,227. There is some consensus
that peripheral and central mechanisms
are variably involved in the propagation
of pain in TMD192,208. The injection of
BTX-A into the masseter and temporalis
muscles of patients with TMD reduced
subjective pain and tenderness in some
patients coincident with the objective
and subjective weakening of the mastica-
tory muscles and not before81,83. This
observation was attributed to the pre-
sumed action of BTX on nociceptors201
and the inhibitory effect of specific pro-
tein-receptor binding within the intracel-
lular compartment on the release of
neuropeptides and inflammatory mole-
cules, such as calcitonin gene-related pep-
tide, substance P, and glutamate56.
Most patients with restricted mouth
opening experienced some degree of
improvement in the maximal range of
vertical motion after BTX therapy. Mus-
cular relaxation, reduction of inflamma-
tion in the muscle and the TMJ, and the
guarding response to pain may contribute
to this finding81.
Earlier studies suggest that displace-
ment of the articular disc may be caused,
precipitated or maintained by lateral pter-
ygoid activity or friction between the
articular surfaces of the disc and condyle
causing clicking48,115,128. BTX injection
into the lateral pterygoid muscle has
reduced the clicking associated with
TMD9,26,45,94,95,217. Clicking was perma-
nently eliminated in some cases with a
small but distinctive positional improve-
ment in the disccondyle relationship9.
The term bruxism is derived from the
Greek word brychein, which means to
grind or gnash the teeth141. When severe,
this rhythmic grinding is associated with
headache, masseter hypertrophy, dysar-
thria, TMJ destruction and dental wear165.
Several studies have described the treat-
ment of bruxism with BTX104,212,221.
Some authors have found that BTX-A
injection into the flexor muscles of the
mandible produced subjective and objec-
tive reductions in the power of muscular
voluntary contraction in most subjects81.
There have been no double-blind studies
to assess the effectiveness of BTX therapy
in bruxism.
Arthrocentesis is a less invasive surgical
intervention than open arthrotomy to
relieve the discomfort and dysfunction
associated with chronic cases of internal
derangement of TMJ85. Intramuscular
injection of BTX as an adjunct to arthro-
centesis of the TMJ gave encouraging
results regarding duration of improve-
ment, suggesting that there may be
synergy between the two procedures78.
Dislocation of the TMJ occurs when the
mandibular condyle is displaced anteriorly
beyond the articular eminence. It repre-
sents 3% of all reported dislocated
joints123. There have been several anec-
dotal reports of the use of BTX-A as
treatment for TMJ dislocation45,143, but
a controlled clinical trial is needed to
prove evidence of its efficacy. BTX-A
was first used to treat surgical failures
and then used as initial treatment158.
The muscle selected varies with each case,
but the lateral pterygoid is that most com-
monly reported. Treating only the lateral
pterygoid muscle appears to be sufficient
to prevent temporarily recurrent disloca-
tion of the TMJ158, but, in some reports,
the superficial part of the masseter at the
angle of the mandible was also injected45.
BTX injection is invasive, but it is a
relatively conservative option. It is speci-
fically indicated in patients for whom con-
servative treatment of recurrent dislocation
of the TMJ has failed and for whom surgery
carries major risks. BTX injection therapy
is also an option in patients who suffer
recurrent dislocation of the TMJ as a result
of impaired muscle coordination secondary
to oromandibular dystonia, neuroleptically
induced early and late dyskinesias, epilepsy
and brain-stem syndromes45,158.
BTX treatment of protracted TMJ dis-
location after medical conditions such as
anoxic encephalopathy and stroke or cer-
ebrovascular event has also been
reported,6,45,143,191 which could lead to
an increase in verbalization, mastication
and improved quality of life.
Salivary secretory disorders
Xerostomia is one of the first manifesta-
tions of botulism, which led to investiga-
tions of its application for sialorrhea and
drooling. Topical injection of BTX-A as a
minimally invasive option for the treat-
ment of drooling has been used for many
years in neurological diseases29,86,160. Its
greatest limitation in this indication is its
transient effectiveness (34 months),
requiring multiple and expensive admin-
istrations32. The therapeutic effect is based
on the inhibitory action of the toxin at the
cholinergic receptors of the salivary gland
cells, shown in animal experiments60,63.
An initial animal model showed a signifi-
cant reduction in saliva production with-
out direct toxicity to the acinar cells194.
Only pilot studies with relatively small
groups of patients are available with a
brief follow-up (level 4 evidence),
although here are some studies on sialor-
rhea associated with Parkinsons disease
[level 2 evidence (randomized clinical
trials)]. The outcome of using BTX-A in
the treatment of drooling appears to be
uniformly favorable; the preliminary
results are promising, with rare reports
of serious complications. Up to two-thirds
of patients experienced a marked or mod-
erate improvement in drooling after the
treatment of both parotid glands or parotid
and submandibular glands com-
bined18,106,122,179. Treatment is mostly
focused on the parotid gland and to a lesser
extent on the submandibular gland. The
sublingual gland is seldom injected220.
BTX has found application for sialor-
rhea in Parkinsons disease112,153,155,162,
amyotrophic lateral sclerosis86,189,224,228,
cerebral palsy160,207, and carcinoma of the
upper digestive tract. It has also been used
for accumulated saliva and drooling
caused by swallowing disorders after
tumor operations of the upper aerodiges-
tive tract62 and for diseases of the gland-
ular tissue such as posttraumatic and
iatrogenic salivary sialoceles and
cysts8,30,31,222 or salivary fistulas after sia-
ladenectomy or oropharyngeal cancer sur-
gery130132 where the temporary stopping
of glandular secretory action is needed to
promote healing. It has also been used
successfully to treat auriculotemporal
(Freys) syndrome32,54,111,116,167,190 as it
reduces the skin area affected by gustatory
sweating by inhibiting the sweat glands
abnormally re-innervated by the choliner-

gic pathway55. BTX-A also has advan-
tages in temporarily drooling states
because its effect is only temporary61. In
patients with recurrent and chronic paro-
titis, BTX injection resulted in a reduction
in the number of episodes of parotid swel-
ling32,59. BTX-B has also been successful
in some cases153,162.
With the exception of those with Freys
syndrome who are treated intracuta-
neously, all of the injections are performed
percutaneously, either intraparenchymal
or perilesional. In the case of sialoceles,
the extravasation fluid should be drained
beforehand32. Some authors still use BTX
injections under EMG control131,132 when
treating salivary secretory disorders.
According to others, ultrasonographic-
assisted intraparenchymal infiltration is
preferable and improves efficacy and
safety31,51,129,220. Others have found no
difference in undesired effects associated
with the method of drug application133.
Facial pain (other than myofascial origin)
Chronic facial pain often presents difficult
management problems requiring interdis-
ciplinary consultations and multiple
attempts with different therapies. BTX
injections showed some advantages over
existing therapies regarding safety and
efficacy18. The evidence provided by the
literature in this area lies in level 2 (ran-
domized clinical trials).
Facial pain relief has been reported after
treatment by BTX for other reasons; such
conditions include regional dystonias1,16,
facial wrinkles148, and skull base surgery18.
These observations led to the study of non-
dystonic pain syndromes, such as myofas-
cial pain and tension headache, these pro-
duced beneficial results and were then
studied in larger controlled trials84,171. Sev-
eral studies have been conducted on the use
of BTX-A in pain conditions such as tension
headache, myofascial pain, migraine, tri-
geminal neuralgia, bruxism and hemifacial
contracture after seventh cranial nerve
injury18,84,114,166,183,184,196,198,225,226.
BTX-A was found promising in postopera-
tive wound pain including reconstructive
facial and oral surgery, traditional and
endoscopic sinus surgery, TMJ surgery
and blowout fracture repair17. Chronic
facial pain following post-dental proce-
dures was associated with a poor results17.
Similar benefits have been reported
with the use of BTX-B4. The ultimate
efficacy of BTX in pain is difficult to
assess and the data available do not
permit definitive conclusions. Other stu-
dies did not show a beneficial effect of
BTX-A67,154,181,185,236.
Clinical use of botulinum toxins in oral and maxillofacial surgery
Facial nerve palsy (FNP)
FNP is a disfiguring condition, different
aspects of which have been treated suc-
cessfully using BTX. Most studies were
case series (level 4 evidence).
BTX injection, through an orbital route
or a skin crease, provides a good means of
inducing a protective ptosis by temporarily
sion dystona40,182. Many studies were
paralyzing the levator palpebrae super-
ioris64,177. This intentionally induced ptosis
may be useful in intensive care patients to
prevent desiccation of the cornea89.
Synkinesis is an involuntary uncoordi-
nated muscle movement associated with
voluntary movement of the muscle. It is
secondary to aberrant regeneration164.
BTX-A is commonly used to relieve the
symptoms of synkinesis with marked
improvement19,42.
In patients with facial asymmetry,
chemo-denervation of the normal side
with BTX7,28,43,110,197 has been reported
to be an effective disguising tool. In this
setting, BTX reduces the relative hyper-
kinesis of the contralateral side to the
paralysis, resulting in a more symmetrical
function of the face.
An aberrant connection of the salivary
sceromotor fibres to the fibres of the lacri-
mal gland may develop after a facial palsy,
causing a hyperlacrimation whenever the
patient salivates (crocodile tears). Injec-
tion of BTX into the lacrimal gland is a
successful treatment for hyperlacrimation
in these cases97,142,169.
Other nerve palsies
Trauma is a common cause of acquired
third-nerve palsy in adults and chil-
dren102,218. Such patients are less likely
to recover than those with palsies of other
causes121. There are few reports (level 4
evidence) of BTX injection to the lateral
rectus muscle for treatment of third-nerve
palsy139,173,210. BTX injection decreases
the likelihood of contracture of the lateral
rectus muscle, thereby allowing return of
medial rectus muscle function136.
The abducens nerve can be injured dur-
ing a severe orbital trauma172. In such
cases, BTX injection of the medial rectus
muscle has been studied with variable
improvements99,109,161.
Muscle movement disorders
BTX has been used since 1977 as a ther-
apeutic agent in the treatment of numerous
neuromuscular disorders15. BTX-A injec-
tions are considered a safe and efficient
local treatment for focal dystonia and
muscle spasms105. Other serotypes have
been used with comparable effects44,156.
201
Dystonia refers to the involuntary con-
traction of specific muscles. Numerous
studies document the usefulness of BTX
therapy in the treatment of oromandibular
dystonia14,95,213, cervical dystonia (spas-
modic torticollis)22,27,44,203, hemifacial
spasm26,157,211,232, tardive dyskine-
sia205,219,231, and tardive tongue protru-
double-blind randomized trials (level 2
evidence).
A specific type in this category is hyper-
kinesia of the platysma. In the literature,
data on successful treatment of the pla-
tysma with BTX are nearly always related
to its use for aesthetic indica-
tions13,21,108,134. BTX also provides a
favorable therapeutic option117.
Perioperative use of botulinum toxins
In patients with movement disorders who
require surgery, the presence of postopera-
tive involuntary movements may be detri-
mental to healing. BTX weakens the
muscle and in so doing may improve post-
operative recovery and healing. Wound
healing improves if the muscles involved
are injected with BTX prior to surgery2.
In maxillofacial surgery, patients under-
going eyelid reconstructive surgery had
successful wound healing after adjunct
treatment with BTX2. BTX was better
than placebo in the wound healing of
facial lacerations requiring surgery120.
BTA has been used to immobilize muscles
after jaw fractures (level 4 evidence)137 to
reduce the displacing forces on the frac-
ture ends and obtain good immobilization
especially if rigid internal fixation is not
available or feasible.
BTX has also been beneficial during the
initial osseointegration phase for dental
implants. This indication is mostly experi-
mental, but some authors have found it to
be safe and effective in the prophylactic
reduction of masseter and temporalis mus-
cle strength after implantation in immedi-
ate loading protocols101.
Complications
Botox has a large margin of safety216. The
most important side effects reported for
cosmetic use of BTX include immuno-
genicity, allergy and local complications.
Neutralizing antibodies to BTX-A tox-
ins can lead to loss of treatment effect.
Clinical resistance to BTX-A has been
estimated as high as 7%27, and BTX-B
is being investigated as an alternative
therapeutic agent22,27.
In theory, because human albumin is
used in the preparation of Botox, a patient
202 Majid
could exhibit an allergic reaction,148 but
no case has been reported.
Adverse effects such as pain, oedema,
erythema, ecchymosis and short-term
hypoesthesia may occur after injection
of BTX-A39,148. Other reported adverse
events are headache, blepharoptosis and
perioral muscular palsy148,178,204.
In therapeutic applications, complica-
tions were mostly local and relatively
mild, such as pain, erythema, ecchymosis
of the region injected, dry eyes, mouth
droop, ptosis and lid edema, facial muscle
weakness, asymmetry of facial expression
during dynamic facial movements, xeros-
tomia, transient dysphagia, restricted
mouth opening, nasal regurgitation and
nasal speech, headache, blurred vision,
dizziness, upset stomach, infection, neck
weakness, voice changes, difficulties in
chewing and breathing risk of aspiration,
recurrent jaw dislocation, dysarthria, sali-
vary duct calculi and local injuries of the
carotid arteries or branches of the facial
nerve14,18,2426,44,45,61,65,79,94,98,129,153,155,
157,159,162,207,214,228,232
. management of hyperfunctional facial
Systemic side effects are rarely
reported, generally not dose related, and
can include transient weakness, fatigue,
nausea and pruritis14. Flu-like syndromes
have been reported, but they are generally
of brief duration12.
Some adverse effects such as xerosto-
mia and dysphagia are more frequently
seen after treatment with BTX-B than
BTX-A22,27,52,118.
Contraindications
Contraindications to BTX-A are generally
few. In many studies, no complaints were
received about systemic problems asso-
ciated with cosmetic injection. Allergan
lists Botox contraindications as pregnancy
and breastfeeding, disorders of the neuro-
muscular junction (myasthenia gravis,
amyotrophic lateralizing sclerosis, myo-
pathies) and theoretical drug interactions
(aminoglycoside antibiotics, quinidine,
calcium channel blockers, magnesium sul-
fate, succinylcholine, and polymyxin)20.
Other reported contraindications are
EatonLambert syndrome and hypersen-
sitivity to BTX or one of its ingredients100.
Potential Therapeutic Uses
Topical Formulations
Because intradermal BTX injection has
been successful in treating focal hyperhi-
drosis of the palms, soles, axillae and facial
areas47,145,209, investigators have consid-
ered the potential for a topical formulation.
Topical BTX has been used for axillary
hyperhidrosis with promising results88.
Keloid and Hypertrophic Scar
Clinical observations indicate that BTX-A
can improve the appearance of hyper-
trophic scar and inhibit its growth46,120,234.
Evidence supporting this potential use
arise from BTXs ability to prevent exces-
sive muscle contraction of the skin near
keloid tissue33, and its reported influence
on cellular apoptosis and cellular prolif-
eration230,233.
Funding
None.
Competing interests
None declared.
Ethical approval
Not required.
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Address:
O.W. Majid
Department of Oral and Maxillofacial Surgery
College of Dentistry
University of Mosul
Mosul, Iraq
E-mail: omerw_majid@yahoo.co.uk