The Saudi Dental Journal (2016) xxx, xxx–xxx

King Saud University

The Saudi Dental Journal

www.ksu.edu.sa
www.sciencedirect.com

REVIEW ARTICLE

Toxin yet not toxic: Botulinum toxin in dentistry

Archana M.S. *

Department of Oral Medicine and Radiology, Goa Dental College and Hospital, Goa, India

Received 4 April 2014; revised 11 March 2015; accepted 23 August 2015

KEYWORDS Abstract Paracelsus contrasted poisons from nonpoisons, stating that ‘‘All things are poisons, and
Acetylcholine; there is nothing that is harmless; the dose alone decides that something is a poison”. Living organ-
Neurotoxin; isms, such as plants, animals, and microorganisms, constitute a huge source of pharmaceutically
Neurotransmitters; useful medicines and toxins. Depending on their source, toxins can be categorized as phytotoxins,
Oro-facial disorders mycotoxins, or zootoxins, which include venoms and bacterial toxins. Any toxin can be harmful or
beneficial. Within the last 100 years, the perception of botulinum neurotoxin (BTX) has evolved
from that of a poison to a versatile clinical agent with various uses. BTX plays a key role in the
management of many orofacial and dental disorders. Its indications are rapidly expanding, with
ongoing trials for further applications. However, despite its clinical use, what BTX specifically does
in each condition is still not clear. The main aim of this review is to describe some of the unclear
aspects of this potentially useful agent, with a focus on the current research in dentistry.
Ó 2015 The Author. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Sites and modes of action of BTX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Forms of BTX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. Injection procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Adverse effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Abbreviations: BTX, botulinum neurotoxin; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNAP-25,
synaptosomal-associated protein; MPDS, myofacial pain dysfunction syndrome; EMG, electromyography; TGF-b1, transforming growth factor
b-1
* Address: Goa Dental College and Hospital, Bambolim, Goa 403202, India. Tel.: +91 0832 22459815, mobile: +91 09845407358, +91
09503947766.
E-mail address: archanam_s@yahoo.com
Peer review under responsibility of King Saud University.

Production and hosting by Elsevier

http://dx.doi.org/10.1016/j.sdentj.2015.08.002
1013-9052 Ó 2015 The Author. Production and hosting by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Archana, M.S. Toxin yet not toxic: Botulinum toxin in dentistry. The Saudi Dental Journal (2016), http://dx.doi.org/10.1016/j.
sdentj.2015.08.002
2 M.S. Archana

4. Applications in dentistry (Table 4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4.1. Pain disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.1. Trigeminal and postherpetic neuralgia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.2. Headache and migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.3. Myofacial pain dysfunction syndrome (MPDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Disorders of the salivary glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Masseter muscle hypertrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. Temporomandibular disorders (TMDs). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4.1. TMJ dislocation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4.2. Bruxism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4.3. Oromandibular dystonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5. Trismus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.6. Gummy smile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.7. Facial nerve palsy/paresis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.8. Cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.9. Carrier for oral vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.10. Oral cavity reconstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.11. Dental implants, and jaw and oral surgery procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.12. Wound healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.13. Hypertrophic scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Contraindications for BTX use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction 2.1. Forms of BTX

Botulinum neurotoxin (BTX) is a neurotoxic protein produced Commercially available various forms of BTX are summarized
by the Gram-positive, rod-shaped, spore-forming, and strictly in Table 2 (Rao et al., 2011). Forms of BTX range in weight
anaerobic bacterium Clostridium botulinum and, rarely, by
Clostridium butyricum and Clostridium baratii, commonly
Table 1 Action of botulinum toxin.
found on plants and in soil, water, and animal intestinal tracts.
Although once considered lethal, BTX is now used as a thera- Absorption via the GI tract or through tissue
peutic drug. BTX exhibits transient, nondestructive, dose-
dependent, and localized actions, with minimal systemic side
effects (Marchese et al., 2008), underlying its wide use in vari- Reaches the lymphatic channels and the blood stream
ous orofacial and dental disorders. The exact mechanism of
action, dosage, and delivery procedure of BTX are very impor-
Circulates in the blood until it reaches cholinergic synapses
tant. In addition to conditions for which BTX is currently used
as a therapeutic agent, evidence supports the expansion of its
indications in dentistry. The purpose of this review is to pro- Binds with the help of binding domain
vide insights into the current indications of BTX, highlight
its expanding use, and review recent advances in the use of
BTX in dentistry. Cholinergic neuronal cell membrane at nerve terminal

2. Sites and modes of action of BTX

Enters neuron by endocytosis
Modes of action of BTX are summarized in Table 1 light chain of the toxin
(Muthane and Panikar, 2003). BTX induces muscle weak-
ness by inhibiting transmission of alpha motorneurons at Crosses the membrane of the endocytic vesicle
the neuromuscular junction. Release of acetylcholine (ACh)
is mediated by the assembly of synaptic fusion com-
Enters cytoplasm of the pre synaptic terminal
plexes—a set of soluble N-ethylmaleimide-sensitive factor
attachment protein receptor (SNARE) proteins, including cleaves to sites on SNARE proteins
synaptobrevin, synaptosomal-associated protein (SNAP), Prevents assembly of synaptic fusion complex
and syntaxin. Seven BTX serotypes have been identified.
BTX types B, D, F, and G cleave synaptobrevin; types A,
C, and E cleave SNAP-25; and type C cleaves syntaxin Blocks docking, fusion and acetylcholine release
(Kant et al., 2009; Davis, 1993).

Please cite this article in press as: Archana, M.S. Toxin yet not toxic: Botulinum toxin in dentistry. The Saudi Dental Journal (2016), http://dx.doi.org/10.1016/j.
sdentj.2015.08.002
Expanding uses in Dentistry 3

Table 2 Forms of botulinum toxin. Table 4 Current and expanding applications in oro-facial
disorders.
Type A – BOTOX
DYSPORT 1. Oro-facial pain conditions like trigeminal neuralgia, post-
XEOMIN herpetic neuralgia, migraine, headache and myofacial pain
Type B – MYOBLOC dysfunction
NEUROBLOC 2. Salivary gland disorders like sialorrhea, sialocele, Frey’s
syndrome etc.
3. Hypertrophy of masseter muscle
4. TMJ disorders like dislocation, bruxism, and oro-
from 300 to 900 kD, with the pure toxin, including both light mandibular dystonia and arthritis
and heavy chains, typically weighing about 150 kD (Muthane 5. Trismus
and Panikar, 2003). Crude toxin is purified and diluted with 6. Gummy smile
human serum albumin. Each vial of 100 units (U) is reconsti- 7. Disorders of the facial nerve i.e. Facial nerve palsy/paresis
tuted with preservative-free normal saline (1–5 ml) immedi- 8. Cancer therapy
ately before use. BTX begins to act within 24–48 h of 9. Botulinum toxin as a carrier for oral vaccines
administration, peaking at 2–3 weeks and maintaining its effi- 10. Preparation of oral cavity for microsurgical
reconstruction
cacy for about 3–4 months (Muthane and Panikar, 2003). Sec-
11. During dental implant, jaw and periodontal surgeries.
ondary nonresponsiveness could be encountered due to the 12. In wound healing
production of neutralizing antibodies. To overcome this effect, 13. Treatment of hypertrophic scars
newer toxins with higher activity levels are being engineered.
Antibody production could be prevented by avoiding repeated
injections and keeping the dose as low as possible (Nigam and
Nigam, 2010).
effects of BTX arise from the direct and indirect (retrograde
2.2. Injection procedure transport) effects of the toxin on peripheral nociceptive
neurons.
The BTX dose should be tailored to the severity of the condi-
tion. Toxin is injected with a 1- to 1.5-inch, 25- to 30-gauge 4.1.1. Trigeminal and postherpetic neuralgia
needle, with electromyography (EMG) monitoring. Subse- When used to treat intractable and idiopathic neuralgia, BTX
quent injections can be given according to the response after type A acts by inhibiting the exocytosis of ACh and other neu-
3 months. rotransmitters. This action could be analgesic if it prevents the
release of neuropeptides from nociceptive nerve endings. BTX
3. Adverse effects type A inhibits the release of norepinephrine and ATP from
postganglionic sympathetic nerve endings, providing an anal-
gesic effect and reducing central and peripheral sensitization.
Side effects of BTX use (Table 3) are generally transient, but
The appropriate dose of BTX for treating trigeminal neuralgia
could last up to several months after administration.
is 20–50 U, injected at the trigger zone or into the masseter
muscle (Zuniga et al., 2008).
4. Applications in dentistry (Table 4) Recently, BTX type A has been used as an alternative treat-
ment modality for refractory cases of postherpetic neuralgia
4.1. Pain disorders (Emad et al., 2011). When provided intradermally at 15 U,
BTX inhibits the release of formalin-induced glutamate, sub-
stance P, and calcitonin gene-related polypeptide (CGRP),
BTX type A inhibits the calcium-dependent release of sub-
with direct effects on sensory neurons and indirect effects on
stance P in the embryonic dorsal root ganglia, producing an
the central nervous system (CNS). Pain decreases to mild
analgesic effect through peripheral inhibition of C and A delta
and tolerable levels within the first week of administration.
fibers (Purkiss et al., 2000). Peripheral and central analgesic
4.1.2. Headache and migraine
Table 3 Side effects of botulinum toxin use. Headache may be due to abnormal excitation of the peripheral
Systemic side effects include anxiety, dizziness, drowsiness,
nociceptive afferent fibers, leading to central sensitization and
headache, dry mouth and eyes, pharyngitis, dysphagia, facial an increase in pericranial muscle hardness and tenderness.
pain, flu-like symptoms, inability to focus eyes, drooping eyelid Headache may also be due to enhanced responsiveness of the
or eyebrow, double/blurred vision, sensitivity to light indigestion, trigeminal nucleus caudalis neurons, leading to the generation
nausea, sweating, fever, chills, allergic reaction like rash, itching, of pain signals that decrease pain modulation involving sero-
dyspnoea, tightness of chest, edema of face, hoarseness of voice, tonin and norepinephrine. Migraine is a neurovascular pain
respiratory infection, anaphylaxis, urticaria, erythema syndrome associated with sterile inflammation and vasodilata-
multiforme, pruritus, loss of bladder control, loss of strength, tion, which activate the trigeminal afferents on the vessel wall
paralysis, seizures etc. and cause pain. In cluster headache, the ophthalmic branch of
Locally, at the injection site side effects include pain, redness,
the trigeminal nerve relays a pain signal, leading to the release
tingling, bruising, swelling or tenderness, stiff or weak muscles at
or near the site, bleeding etc.
of substance P and CGRP, vasodilatation of the dural blood
vessels, and neurogenic inflammation.

Please cite this article in press as: Archana, M.S. Toxin yet not toxic: Botulinum toxin in dentistry. The Saudi Dental Journal (2016), http://dx.doi.org/10.1016/j.
sdentj.2015.08.002
4 M.S. Archana

Four modes of action for BTX in migraine and headache 4.2. Disorders of the salivary glands
have been proposed. (1) BTX may decrease muscle contractil-
ity by preventing ACh release from the presynaptic terminal. BTX has been used in the treatment of disorders of the salivary
However, this theory does not explain why pain relief with glands, such as sialorrhea, sialocele, and Frey’s syndrome.
BTX often occurs before muscle relaxation (Gobel et al., When used in the treatment of hypersalivation (sialorrhea),
2001). (2) BTX may inhibit the extrafusal muscle fibers and BTX acts on the cholinergic nerve endings, causing proteolysis
normalize excessive levels of muscle spindle activity (Rosales of SNAP-25, chemical denervation, and loss of neuronal activ-
et al., 1996; Gobel et al., 2001). Excessive release of ACh at ity. BTX is injected intraglandularly, mainly to the parotid
the neuromuscular junction leads to abnormally high levels gland, at a dose that depends on the condition. Common dose
of end-plate activity, resulting in extrafusal muscle contrac- ranges are 10–100 U of Botox or 20–300 U of Dysport (Fuster
tion. BTX inhibits transmission of neurotransmitters at the Torres et al., 2007). Sialocele is an accumulation of saliva sur-
gamma motorneurons in the muscle spindle and decreases rounded by a tissue reaction, which develops as a postopera-
muscle activity. (3) BTX may enter the CNS, modulating pain tive complication after parotidectomy. When used for this
by inhibiting the release of substance P from the trigeminal condition, BTX type A acts by blocking ACh release from
nerve endings and activating the expression of substance P in the secretomotor parasympathetic autonomic nerve. Doses of
the raphe nuclei. The BTX-mediated inhibition of SNAP-25 50–70 U are given percutaneously in the parotid region
blocks neurotransmitter exocytosis, leading to a decreased (Chow and Kwok, 2003). Another common complication of
pain through the colocalization of vasoactive intestinal peptide parotidectomy, Frey’s syndrome is characterized by facial
and neuropeptide Y with ACh in the parasympathetic neurons. hyperhidrosis in the preauricular region initiated by a gusta-
Further contributing to the analgesic effect is the decompres- tory stimulus. The mode of action of BTX type A in Frey’s
sion of afferent nociceptive neurons, which leads to a decrease syndrome involves inhibition of ACh release at the nerve end-
in excitatory metabolite levels secondary to muscle relaxation ings and in the muscles, and blockade of the motor end plates.
(Weigand and Wellhoner, 1977). (4) BTX may reduce At the autonomic level, sweat secretion is blocked in glands
parasympathetic outflow, leading to analgesia. For this reason, that depend on ACh release for their activation. BTX is typi-
BTX use is indicated in cases of chronic headache (Goadsby cally administered at 30 U, and its efficacy lasts 6–15 months.
and Edvinsson, 1994). Repeated administration decreases the symptom severity,
Methods of BTX administration currently used include a reduces the extent of the affected area, and increases the time
fixed-site approach, following the pain, direct injection into to relapse (Diaz et al., 2008).
the tender muscles, and a combination of these methods. Gla-
bellar injections can provide complete relief. Other injection
4.3. Masseter muscle hypertrophy
sites include the suboccipital region, where higher or lower
doses are necessary for the posterior or anterior (e.g., frontal
and temporal) regions, respectively. Doses of BTX used for Injection of BTX type A is a minimally invasive treatment
headache and migraine range from 10 to 150 U, with clinical modality for massetric hypertrophy, defined as the asymp-
improvement within the first 2 weeks of injection, maximum tomatic enlargement of one or both masseter muscles. The
benefit at about 6 weeks, and efficaciousness for 3 months. masseter muscle is injected with 100 U of BTX type A in
For cluster headache, commons doses are 24–150 U of BTX 2 ml of sterile saline. The only limitation of this therapy is
type A or the equivalent BTX type B (1200 U) (Winner, 2003). recurrence after 6 months, when the procedure must be
repeated (Bas et al., 2010).
4.1.3. Myofacial pain dysfunction syndrome (MPDS)
A complex pain syndrome with an unclear etiology, MPDS is 4.4. Temporomandibular disorders (TMDs)
associated with pain and tenderness of the muscles, especially
those involved in mastication, and with trigger points/bands. TMDs are a group of nonodontogenic facial pain disorders
Injection of 50 U of BTX type A is a simple and effective associated with the temporomandibular joint (TMJ) or associ-
means to reduce the muscle hyperactivity of MPDS, by block- ated muscles.
ing ACh release from the neuromuscular junction (Nixford
et al., 2002). Although this mechanism of BTX has been stud-
ied extensively, the results have been inconclusive owing to the 4.4.1. TMJ dislocation
unclear etiology. For example, EMG studies of MPDS Dislocation of the TMJ is caused by excessive forward move-
patients have not consistently shown muscle hyperactivity. ment of the condyle beyond the articular eminence, with com-
Other studies reported myositis as the underlying cause of pain plete separation of the articular surfaces and positional
in MPDS; however, myositis cannot be treated by BTX as the fixation. By inhibiting ACh release at the neuromuscular junc-
toxin does not have anti-inflammatory activity. Furthermore, tion and weakening the lateral pterygoid muscles via chemod-
the presence of trigger points in MPDS has not been con- enervation, BTX type A causes an imbalance between the
firmed. Overall, insufficient prospective randomized controlled muscles used for opening and closing the jaw. These effects
studies have been performed to prove the effectiveness of BTX of BTX limit mouth opening and help to prevent dislocation
use in MPDS. Until recently, BTX has only been used as a (Fu et al., 2010), with effects lasting 2–4 months. The BTX
temporary therapy to alleviate pain and dysfunction in the dis- dose for this purpose is 25–50 U, injected percutaneously into
order (Fallah and Currimbhoy, 2012; Laskin, 2012). each lateral pterygoid muscle.

Please cite this article in press as: Archana, M.S. Toxin yet not toxic: Botulinum toxin in dentistry. The Saudi Dental Journal (2016), http://dx.doi.org/10.1016/j.
sdentj.2015.08.002
Expanding uses in Dentistry 5

4.4.2. Bruxism 4.7. Facial nerve palsy/paresis

Observed in individuals while awake or asleep, bruxism is an
involuntary disorder manifested by jaw clenching, tooth Facial palsy refers to both incomplete loss (paresis) and com-
gnashing, and grinding. For bruxism treatment, BTX type A plete loss (paralysis) of facial nerve function. Unilateral palsy
is injected into the masseter muscle at 60 U per side. A dose affects the balance between the right and left sides of the face,
range of 25–100 U elicits a good response for up to 3–4 months causing asymmetry. Injection of BTX type A into the con-
(Tan and Jankovic, 2000). tralateral lower facial muscles weakens these muscles and
restores facial symmetry. BTX acts at the neuromuscular junc-
4.4.3. Oromandibular dystonia tion by inhibiting the release of ACh and preventing muscle
These involuntary spasms of the masticatory, lingual, and pha- contraction. A dose of 10–80 U of BTX in saline is given intra-
ryngeal muscles result in distortions of the oral position and muscularly, with the precise dose being tailored to each patient
function. Modes of action of BTX type A in oromandibular and monitored by EMG. On average, the effect begins within
dystonia include local chemodenervation of the motor end 6 days and lasts 7–24 weeks. BTX can be re-administered,
plates and central intracortical inhibition, which normalizes depending on the response. A minor and self-limiting side
the distorted primary motor cortex projection. Which muscle effect of the treatment is drooling of saliva (Sadiq et al., 2012).
is injected depends on the form of dystonia, with the bilateral
masseter muscles being injected for jaw-closure dystonia, lat- 4.8. Cancer therapy
eral pterygoids with the anterior belly of the omohyoid muscle
for jaw-opening dystonia, and tongue muscles for lingual dys- Adjunctive treatment with BTX type A can be used to poten-
tonia. The recommended dose of BTX is 30 U per side (Tintner tiate the tumor response to chemo- or radiotherapy, by open-
and Jankovic, 2002). ing the vascular bed. Local administration of the toxin
promotes tumor perfusion and oxygenation, and modulates
4.4.4. Arthritis. This inflammatory joint disease manifests as the vasoreactivity of vessels. BTX potentiates with the release
joint pain and dysfunction, with joint contractures and muscle of noradrenalin, a vasomodulator that maintains sympathetic
atrophy in advanced stages. The pain in chronic arthritis is vascular tone through activation of the vascular smooth mus-
amplified by neuropeptide release in the periphery. BTX type cle adrenoceptors, in arterioles co-opted by the surrounding
B inhibits neuropeptide release, thereby altering the nociceptor tumor. Greatest effects are seen when BTX is injected 3 days
function and reducing pain and neurogenic inflammation. before beginning anticancer treatment (Ansiaux et al., 2006).
BTX also causes chemodenervation of the articular pain fibers
(Anderson et al., 2010). 4.9. Carrier for oral vaccines

4.5. Trismus Recently, molecular biological techniques have been used to

generate an expression product of BTX type A. While losing
Trismus is defined as a motor disturbance of the trigeminal its neurotoxic effect, the expression product retains the abilities
nerve, especially spasm of the masticatory muscles, with diffi- to escape the gut, reach the general circulation, and evoke an
culty in opening the mouth. In this disorder, BTX type A acts immune response. After the toxin is ingested, it traverses a por-
at the synaptic terminal of the cholinergic lower motorneuron tion of the gastrointestinal system and is transcytosed from the
and causes flaccid paralysis due to blockade of neuroexocytosis gut lumen to the general circulation. Circulating toxin binds to
at the lower motorneuron terminal presynaptically (Andrade peripheral cholinergic nerve endings, is endocytosed, and acts
and Brucki, 1994). The recommended dose of BTX for trismus as a metalloendoprotease to cleave essential polypeptides for
is 25 U injected into each masseter muscle and 10 U into the exocytosis. The most important mechanism for the toxin to
temporalis muscle. penetrate the gut cells is its specific binding to receptors on
the mucosal side of polarized gut cells. Bound toxin is actively
4.6. Gummy smile transported across cells and delivered intact and unmodified
on the serosal side of the monolayer (Simpson et al., 1999).
Gummy smile is defined as the display of excessive gingival tis-
sue in the maxilla upon smiling, caused by hyperfunctional 4.10. Oral cavity reconstruction
muscles of the upper lip. Treatment with BTX type A provides
effective, minimally invasive, and temporary improvement (for In spite of good postoperative care, most oral cancer patients
3–6 months) of gummy smile (Polo, 2005). BTX acts by cleav- who are treated by tumor excision, neck dissection, and recon-
ing SNAP-25, which blocks ACh release from motorneurons struction will encounter complications, including infections,
and enables repolarization of the postsynaptic terminal, result- wound dehiscence, and fistula formation. These complications
ing in partial chemodenervation and blockade of muscular are caused by saliva stagnation due to reduced saliva clear-
contraction. Muscles are injected close to the nasalis or orbic- ance, limited capacity to swallow, and increased saliva produc-
ularis oculi, with some muscle fibers intermeshing the levator tion. Infiltration of BTX type A into the major salivary gland
labii superioris, levator labii superioris alaeque nasi, levator 4 days before surgery can help overcome these complications.
anguli oris, and zygomaticus major and minor. The ideal dose Before injection, sialometry and sialography are performed,
of BTX is about 2.5 U per side at the levator labii superiori and gland markings are made. Then, 3–4 injections are given
and zygomaticus sites, and 1.25 U per side at the orbicularis to each gland, with a total dose of 80–100 U of BTX. The peak
oculi sites. effect is seen on days 5–8 after injection. Treatment results in a

Please cite this article in press as: Archana, M.S. Toxin yet not toxic: Botulinum toxin in dentistry. The Saudi Dental Journal (2016), http://dx.doi.org/10.1016/j.
sdentj.2015.08.002
6 M.S. Archana

50–70% reduction of salivary secretion (Corradino et al., 4.13. Hypertrophic scars

2012).
Increased deposition of collagen fibers and extracellular matrix
4.11. Dental implants, and jaw and oral surgery procedures can lead to hypertrophic scars. BTX type A influences the
fibroblast cell cycle, causing decreased proliferation and
Failure of implant placement is mainly due to the lack of oss- increased apoptosis. These effects, in turn, lead to decreased
eous integration, which could be due to excessive functional expression of TGF-b1 protein. Injection with BTX type A
forces in patients with parafunctional habits. Treatment of decreases tension at the healing site to prevent scar formation.
maxillofacial (e.g., zygomatic and condylar) fractures requires Studies of BTX use for hypertrophic scars have only been per-
multiple fixation sites and hardware to overcome the forces of formed in vitro, but the results are encouraging for further
masticatory musculature that prevent callus formation. Pro- in vivo studies to elucidate the mechanism and standardized
phylactic injection of 100 U of BTX type A into the masseter procedure for BTX use in this context (Xiao and Qu, 2012).
muscle bilaterally 12–48 h before surgery could be beneficial
in reducing these forces. In periodontal surgeries, BTX injec- 5. Contraindications for BTX use
tion can reduce periodontal trauma due to excessive muscular
function (Rao et al., 2011).
Contraindications and precautions for BTX use in dentistry
are summarized in Table 5 (Muthane and Panikar, 2003).
4.12. Wound healing
6. Conclusions
Healing of traumatic, surgical, or other wounds (e.g., fissures
and ulcers) involves multiple processes (e.g., hemostasis,
As a group, the BTXs are the most potent of known neurotox-
inflammation, tissue proliferation, and remodeling), disruption
ins. BTXs are clinically useful in the management of various
of which can lead to a chronic wound. Increases in metabolic
dental and orofacial disorders involving the muscles and
activity and inflammation during the healing process induce
glands. BTX can be used as a helpful and minimally invasive
muscle contraction around the wound edges. Recently, exper-
treatment option to improve the quality of life of patients.
imental treatment with BTX type A has been attempted for
As a versatile treatment option with a rapidly expanding list
wound healing, based on the ability of BTX to eliminate
of uses, this toxin offers a reversible alternative to numerous
dynamic tension on and around healing tissues. This chemoim-
aggressive procedures.
mobilization can potentially improve healing and minimize
scarring for optimal esthetics (Lebeda et al., 2012).
Cleft lip and palate repair is generally associated with dis- Conflict of interest
torted facial growth and retarded development of the mid-
facial region. Causes of these effects have been attributed to There is no actual or potential conflict of interest
a tense cheiloplasty and excessive lifting of the soft tissue,
which causes tension on the healing wound. Intraoperative References
injection of BTX type A into the medial and lateral portions
of the orbicularis oris muscle has been shown to decrease mus- Anderson, S., Krug, H., Dorman, C., McGarraugh, P., Frizelle, S.,
cle activity, thereby decreasing tension at the surgical wound Mahowald, M., 2010. Analgesic effects of intra-articular botulinum
and resulting in better healing. There has been an encouraging toxin Type B in a murine model of chronic degenerative knee
trend in support of using BTX in wound-healing paradigms, arthritis pain. J. Pain Res. 3, 161–168.
although additional studies are necessary to determine a stan- Andrade, L.A., Brucki, S.M., 1994. Botulinum toxin A for trismus in
cephalic tetanus. Arq. Neuropsiquiatr. 52 (3), 410–413.
dardized approach (Galárraga, 2009).
Ansiaux, R., Baudelet, C., Cron, G.O., Segers, J., Dessy, C.,
Martinive, P., De, Wever J., Verrax, J., Wauthier, V., Beghein,
N., Grégoire, V., Buc Calderon, P., Feron, O., Gallez, B., 2006.
Botulinum toxin potentiates cancer radiotherapy and chemother-
apy. Clin. Cancer Res. 12 (4), 1276–1283.
Table 5 Contraindications/precautions for use of botulinum
Bas, B., Ozan, B., Muglali, M., Celebi, N., 2010. Treatment of
toxin. masseteric hypertrophy with botulinum toxin: a report of two
1. Pregnant women and nursing mothers (not yet completely cases. Med. Oral Patol. Oral Cir. Bucal 15 (4), 649–652.
proved) Chow, T.L., Kwok, S.P., 2003. Use of botulinum toxin type A in a case
2. Use in children – could affect the nerve growth (not yet com- of persistent parotid sialocele. Hong Kong Med. J. 9 (4), 293–294.
pletely proved) Corradino, B., Di Lorenzo, S., Moschella, F., 2012. Botulinum toxin A
3. Neuromuscular disorders e.g. Myasthenia Gravis for oral cavity cancer patients: in microsurgical patients BTX
4. Patients with impaired hemostasis injections in major salivary glands temporarily reduce salivary
5. Cardiovascular disorders production and the risk of local complications related to saliva
6. Pre-existing infection at the injection site stagnation. Toxins 4 (11), 956–961.
7. Skin infections e.g. Eczeme, psoriasis Davis, L.E., 1993. Botulinum toxin. From poison to medicine. West. J.
8. Individuals on aminoglycoside antibiotics, quinine, chloro- Med. 158 (1), 25–29.
quine, calcium channel blockers, aspirin Diaz, M.P., Castillo, R.B., Plata, M.M., Gı́as, L.N., Nieto, C.M., Lee,
9. Emotionally disturbed individuals especially after the age of G.Y., Guerra, M.M., 2008. Clinical results in the management of
65 years Frey’s Syndrome with injections of Botulinum Toxin. Med. Oral
Patol. Cir. Bucal 13 (4), 248–252.

Please cite this article in press as: Archana, M.S. Toxin yet not toxic: Botulinum toxin in dentistry. The Saudi Dental Journal (2016), http://dx.doi.org/10.1016/j.
sdentj.2015.08.002
Expanding uses in Dentistry 7

Emad, M.R., Emad, M., Taheri, P., 2011. The efficacy of intradermal Nixford, D.R., Heo, G., Major, P.W., 2002. Randomized controlled
injection of botulinum toxin in patients with post-herpetic neural- trial of botulinum toxin A for chronic myogenous facial pain. Pain
gia. Iran Red. Crescent Med. J. 13 (5), 323–327. 99 (3), 465–473.
Fallah, H.M., Currimbhoy, S., 2012. Uses of botulinum toxin a for Polo, M., 2005. Botulinum toxin type A in the treatment of excessive
treatment of myofacial pain and dysfunction. J. Oral Maxillofac. gingival display. Am. J. Orthod. Dentofacial Orthop. 127 (2), 214–
Surg. 70 (5), 1243–1245. 218.
Fu, K.Y., Chen, H.M., Sun, Z.P., Zhang, Z.K., Ma, X.C., 2010. Long- Purkiss, J., Welch, M., Doward, S., Foster, K., 2000. Capsaicin-
term efficacy of botulinum toxin type A for the treatment of stimulated release of substance P from cultured dorsal root
habitual dislocation of the temporomandibular joint. Br. J. Oral ganglion neurons: involvement of two distinct mechanisms.
Maxillofac. Surg. 48 (4), 281–284. Biochem. Pharmacol. 59 (11), 1403–1406.
Fuster Torres, M.A., Berrini Aytes, L., Gay Escoda, C., 2007. Salivary Rao, L.B., Sangur, R., Pradeep, S., 2011. Application of Botulinum
gland application of botulinum toxin for the treatment of sialor- toxin type A: an arsenal in dentistry. Indian J. Dent. Res. 22 (3),
rhea. Med. Oral Pathol. Oral Cir. Bucal 12 (7), 511–517. 440–445.
Galárraga, I.M., 2009. Use of botulinum toxin in cheiloplasty: a new Rosales, R.L., Arimura, K., Takenaga, S., Osame, M., 1996. Extra-
method to decrease tension. Can. J. Plast. Surg. 17 (3), e1–e2. fusal and intrafusal muscle effects in experimental toxin A
Goadsby, P.J., Edvinsson, L., 1994. Human in vivo evidence for injection. Muscle Nerve 19 (4), 488–496.
trigeminovascular activation in cluster headache: neuropeptide Sadiq, S.A., Khwaja, S., Saeed, S.R., 2012. Botulinum toxin to
changes and effects of acute attacks therapies. Brain 117 (3), 427– improve lower facial symmetry in facial nerve palsy. Eye 26 (11),
434. 1431–1436.
Gobel, H., Heinze, A., Heinze-Kuhn, K., Austermann, K., 2001. Simpson, L.L., Maksymowych, A.B., Kiyatkin, N., 1999. Botulinum
Botulinum toxin A in the treatment of headache syndromes and toxin as a carrier for oral vaccines. Cell. Mol. Life Sci. 56 (1–2), 47–
pericranial pain syndromes. Pain 91 (3), 195–199. 61.
Kant, V., Koshal, R., Verma, P.K., Pankaj, N.K., 2009. Therapeutic Tan, E.K., Jankovic, J., 2000. Treating severe bruxism with botulinum
and cosmetic uses of botulinum toxin. Vet. J. 4 (1) (Article 32). toxin. J. Am. Dent. Assoc. 131 (2), 211–216.
Laskin, D.M., 2012. Botulinum toxin A in the treatment of myofacial Tintner, R., Jankovic, J., 2002. Botulinum Toxin Type A in the
pain and dysfunction: the case against its use. J. Oral Maxillofac. Management of Oromandibular Dystonia and Bruxism. Scientific
Surg. 70 (5), 1240–1242. and Therapeutic Aspects of Botulinum Toxin. Lippincott Williams
Lebeda, F.J., Dembek, Z.F., Adler, M., 2012. Kinetic and reaction & Wilkins, Philadelphia PA, pp. 343–350.
pathway analysis in the application of botulinum toxin A for Weigand, H., Wellhoner, H.H., 1977. The action of Botulinum A
wound healing. J. Toxicol. (Article ID 159726) neurotoxin on the inhibition by antidromic stimulation of lumbar
Marchese, M.R., Almadori, G., Giorgio, A., Palmdetti, G., 2008. Post- monosynaptic reflex. Arch. Pharmacol. 298 (3), 235–238.
surgical role of botulinum toxin-A injection in patients with head Winner, P., 2003. Botulinum toxins in the treatment of migraine and
and neck cancer: personal experience. Acta Otorhinolaryngol. Ital. tension-type headaches. Phys. Med. Rehabil. Clin. N. Am. 14 (4),
28 (1), 13–16. 885–899.
Muthane, U.B., Panikar, J.N., 2003. Botulinum toxins: pharmacology Xiao, Z., Qu, G., 2012. Effects of botulinum toxin type A on collagen
and its current therapeutic evidence for use. Neurol. India 51, 455– deposition in hypertrophic scars. Molecules 17 (2), 2169–2177.
460. Zuniga, C., Diaz, S., Piedimonte, F., Micheli, F., 2008. Beneficial
Nigam, P.K., Nigam, A., 2010. Botulinum toxin. Indian J. Dermatol. effects of botulinum toxin type A in trigeminal neuralgia. Arq.
55 (1), 8–14. Neuropsiquiatr. 66 (3A), 500–503.

Please cite this article in press as: Archana, M.S. Toxin yet not toxic: Botulinum toxin in dentistry. The Saudi Dental Journal (2016), http://dx.doi.org/10.1016/j.
sdentj.2015.08.002