This paper is divided into two parts; the first part provides a background on botulinum neurotoxin (BoNT) for medical uses as well as a description of how to use it. The second part provides a critical review of the evidence regarding the use of BoNT for pain in the orofacial region. This review was based on published literature gathered from Medline databases. Specifically, the authors looked for papers that were randomized, double-blind, placebo-controlled trials (RBCTs) that were published in peer-reviewed journals. Where these were not widely available, they describe the case report and open-label clinical trials–based evidence.
Regarding the medical use of BoNT, as soon as it became evident that victims of food poisoning experienced motor paralysis as a part of their disease and that the bacterium Clostridium botulinum was responsible, the idea that a toxin that is produced by this bacteria might have medical uses was not far behind. It was in the 1920s that BoNT was purified first . It was not a single toxin that was produced by this anaerobic bacterium; seven serologically distinct forms were discovered (BoNT/A, B, C, D, E, F, G) . From that point to the point at which the United States Food and Drug Association (FDA) approved BoNT/A was 60 plus years . Toxin A was found to be the most potent and longest lasting of these seven toxins, and it has since proven to be a valuable treatment for focal muscle hyperactivity disorders (eg, focal dystonias). BoNT/A was approved for use by the FDA for the temporary treatment of two eye muscle disorders (blepharospasm and strabismus), and for cervical dystonia 1 year later . The injections clearly reduce the severity of motor contraction–induced abnormal head position and accompanying neck pain. Also in 2000, the FDA approved BoNT/B for the treatment of cervical dystonia in patients who developed BoNT/A resistance. Since then, BoNT/A has been approved for the treatment of primary axillary hyperhidrosis (excessive sweating) and for the reduction of deep glabellar lines in the face. Table 1 contains the FDA-approved use specifications for BoNT/A and BoNT/B. BoNT/A is supplied in vials in a lyophilized form, at a dose of 100 units (U) per vial. The typical expiration date is 24 months when stored at −5 to −20°C. Another serotype, BoNT/B, is marketed by Solstice Neurosciences, Inc. (San Diego, California) as Myobloc. Another BoNT/A formulation, Dysport, is marketed outside of the United States by Ipsen Ltd. in Europe. All of these preparations—Botox, Myobloc, and Dysport—differ in formulation and potency; hence, their units are not interchangeable.
| Disease or condition | FDA approval | Age limitation | Dosing recommendations (initially always use lower dose) a |
|---|---|---|---|
| Blepharospasm, strabismus association with dystonia, including benign essential blepharospasm or VII nerve disorders. | 12/29/1989 | Adults (>12 y) | Botox: dose is 1.25–2.5 U (0.05 mL to 0.1 mL at each site) injected into the medial and lateral pretarsal orbicularis oculi of the upper lid and into the lateral pretarsal orbicularis oculi of the lower lid. |
| Cervical dystonia in adults to decrease the severity of abnormal head position and neck pain associated with cervical dystonia. | 12/21/2000 | Adults (>16 y) |
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| Cosmetic use for moderate to severe glabellar lines associated with corrugator or procerus muscle activity. | 4/12/2002 | Adults (≤65 y) | Botox Cosmetic: dose is 0.1 ml IM times 5 sites. This solution is injected into each corrrugator muscle and into the centrally located procerus muscle. |
| Primary axillary hyperhydrosis: Botox is indicated for the treatment of severe primary axillary hyperhidrosis that is inadequately managed with topical agents. | 7/12/2004 | Adults (>18 y) | Botox: dose for primary axillary hyperhidrosis is 50 U intradermal/axilla; divide dose into 10–15 injections of 3–4 U per injection positioned 1–2 cm apart. |
Off-label botulinum neurotoxin use
In addition to the above on-label uses, BoNT/A is used off-label in the orofacial region to help treat primary and secondary masticatory and facial muscle spasm, severe bruxism, facial tics, orofacial dyskinesias, dystonias, and even idiopathic hypertrophy of the masticatory muscles. A recent review of the literature describes the muscle hyperactivity–related indications for BoNT/A in the orofacial muscles . With the exception of hypertrophy, the common link for these conditions is that they are involuntary motor hyperactivity disorders; although their treatment with BoNT is off-label, they are similar in pathophysiology to the condition for which BoNT is approved by the FDA. Even more “off-label” is the suggested use of BoNT for pain disorders without a clear-cut motor hyperactivity basis. These pain disorders include conditions, such as chronic migraine headache, chronic daily headache (CDH), chronic myofascial pain, focal sustained neuropathic pain, and, more recently, episodic trigeminal neuralgia.
Using a drug off-label sometimes generates interest by the medical, legal, and federal regulatory communities. Off-label drug use is not illegal, and the FDA recognizes that the off-label use of drugs often is appropriate and, in time, may represent the standard of practice for a specific condition. The purpose of establishing an approved or labeled use of a drug by the FDA is to protect patients from unsafe or ineffective drugs; however, it is the prerogative of practitioners to use their professional judgment in providing the best treatment possible for their patients. Off-label use of a medication is not a license to use any product off-label without regard for the published scientific evidence of efficacy. The practitioner who elects to use a drug “off-label” bears some inherent liability risk. Legal rulings have suggested that off-label drug use in itself is not sufficient evidence of negligence; however, the practitioner should do so only when one believes that the off-label use is outweighed by the potential benefit to the patient. In such situations, the risks and benefits should be explained to the patient, and a consent form ( Fig. 1 ) should be signed by the patient. The clinician also should be familiar with a reasonable body of scientific evidence that supports the application of the drug (in this case BoNT/A) specifically for the disorder under treatment. It also is important that the patient be informed that the expected therapeutic benefit may only extend weeks to months, and that the treatment will need to be repeated to have an ongoing effect.
Mechanism of action
BoNT inhibits the exocytosis of acetylcholine (ACh) on cholinergic nerve endings of motor nerves . Autonomic nerves also are affected by the inhibition of ACh release at the neural junction in glands and smooth muscle . BoNT achieves this effect by its endopeptidase activity against SNARE proteins, which are 25-kd synaptosomal-associated proteins that are required for the docking of the ACh vesicle to the presynaptic membrane. It was suggested that when BoNT was used for the treatment of neuromuscular disorders—particularly focal dystonias and spastic conditions—patients reported a marked analgesic benefit . Initially, this benefit was believed to be due to the direct muscle relaxation effect of BoNT; however, various observations have suggested that BoNT may exert an independent action on peripheral nociceptors by blocking exocytosis of such neurotransmitters as substance P, glutamate, and calcitonin gene–related peptide (CGRP). In addition, because BoNT does not cross the blood–brain barrier, and because it is inactivated during its retrograde axonal transport, the effect is believed to be in the first-order sensory nerve and not more centrally . The actual experimental evidence that examines this analgesic claim is presented below.
Mechanism of action
BoNT inhibits the exocytosis of acetylcholine (ACh) on cholinergic nerve endings of motor nerves . Autonomic nerves also are affected by the inhibition of ACh release at the neural junction in glands and smooth muscle . BoNT achieves this effect by its endopeptidase activity against SNARE proteins, which are 25-kd synaptosomal-associated proteins that are required for the docking of the ACh vesicle to the presynaptic membrane. It was suggested that when BoNT was used for the treatment of neuromuscular disorders—particularly focal dystonias and spastic conditions—patients reported a marked analgesic benefit . Initially, this benefit was believed to be due to the direct muscle relaxation effect of BoNT; however, various observations have suggested that BoNT may exert an independent action on peripheral nociceptors by blocking exocytosis of such neurotransmitters as substance P, glutamate, and calcitonin gene–related peptide (CGRP). In addition, because BoNT does not cross the blood–brain barrier, and because it is inactivated during its retrograde axonal transport, the effect is believed to be in the first-order sensory nerve and not more centrally . The actual experimental evidence that examines this analgesic claim is presented below.
Training and injection procedures
Training in the use of BoNT/A usually is accomplished by way of short training programs or preceptorships in the office of an experienced caregiver. As with any injected medication, it is imperative that clinicians undergo training that includes knowledge of anatomy, injection techniques, handling of the materials, side effects, and appropriate dosing, because different dosages are used in the different areas of the mouth, face, and neck for different medical conditions. Although the skills to inject BoNT into a muscle are learned easily, some training in this arena is suggested. Essentially, BoNT is injected in the same manner as are local anesthetics, and a 23- to 30-gauge needle is placed into the target muscle. Targeting is confirmed by palpation in larger muscles. When a muscle is difficult to palpate, such as the anterior digastric or lateral pterygoid muscles, confirmation of correct needle position before injection can be confirmed by use of a Teflon-coated monopolar injection needle that also has the ability to record the electromyographic (EMG) signals from the muscle. This technique requires specific training in the use of an EMG machine. The authors wish to emphasize that EMG guidance is not a requirement for injecting most orofacial muscles, because they can be injected safely by using palpation confirmation of location. Depending on the equipment used, the recording is displayed on a screen or turned into the sound pattern. The graphic display or sound increases in amplitude, frequency, or volume when the muscle contracts. To be sure that the practitioner is in the correct muscle, the patient may be asked to make a specific movement or effort to activate the target muscle. One can reduce the risk for BoNT dispersion into unwanted adjacent sites by using superficial injections, having the patient keep activity to minimum, and not massaging the area for 4 hours; this allows the toxin to penetrate mainly the target nerves. Ultrasound, fluoroscopy, or CT also may be used, but is needed rarely for the orofacial muscles.
Injection preparation, dosing, and effect duration
BoNT/A is kept frozen (2–4°C) in a vial until it is ready to use. The drug is put into solution, following manufacturer’s guidelines, by adding normal saline (preservative-free 0.9% saline solution). Once prepared it should be used within 4 hours. The preferred syringe is a calibrated 1.0-mL tuberculin syringe, and the needle selected for injection usually is between 26 and 30 gauge. Skin preparation involves alcohol wipes and dry sterile gauze sponges. Aspiration before injection is recommended. Usually, dosing is established by the diagnosis and reason for use of the toxin, size of the muscle, and medical conditions or medications. Until studies narrow down all specifics, the final dilution and dosage used is left to the clinical experience and discretion of the practitioner. The number of injection sites usually is determined by the size of the muscle. Theoretically, it may be appropriate to inject more sites with smaller doses, and using more injection sites should facilitate a wider distribution of BoNT/A to nerve terminals; however, too many injection sites may cause local injection site pain. The proper targeting of muscles is a crucial factor in achieving efficacy and reducing adverse effects from BoNT/A injections. The therapeutic effects of BoNT/A first appear in 1 to 3 days, peak in 1 to 4 weeks, and decline after 3 to 4 months.
Adverse events and side effects
BoNT is classified as a Category C drug by the FDA, because its reported use in pregnant and lactating women is scant. Approximately 1% of patients who receive BoNT/A injections may experience severe, debilitating headaches that may persist at high intensity for 2 to 4 weeks before fading gradually . Care in choosing the injection site and dose used may limit undesirable muscle weakness. A small group of patients eventually may develop antibodies; this problem generally occurs when patients receive higher doses, especially at more frequent intervals. Therefore, the FDA-approval label recommends injecting no more frequently than once every 3 months and using the lowest effective dose to minimize antibody formation.
Cautions and contraindications
When using BoNT/A, caution must be used when injecting individuals who have peripheral motor neuropathic diseases or neuromuscular junctional disorders. Moreover, drugs that interfere with neuromuscular transmission, such as aminoglycosides, magnesium sulfate, anticholinesterases, succinylcholine chloride, polymyxins, quinidine, and curare-like nondepolarizing blockers, can potentiate the effect of BoNT/A. BoNT/A treatment is contraindicated in the presence of infection, especially at the injection site and in individuals who have known hypersensitivity to any ingredient in the formulation. Formation of neutralizing antibodies to BoNT/A may reduce its effectiveness by inactivating the biologic activity of the toxin and the rate of formation of these neutralizing antibodies in patients who receive BoNT/A treatment; its long-term effects have not been studied well. The reformulated BoNT/A has a lower protein content that may decrease the risk for antibody formation and the development of resistance. Patients who have neuromuscular disorders who receive BoNT/A could have amplified effects of the drug, such as severe dysphagia and respiratory difficulties. Patients who have BoNT/A injections in the cervical region, tongue, or posterior region of the mouth may experience dysphagia. Rare cases of arrhythmia and myocardial infarction have been reported. Some of these patients had pre-existing cardiovascular disease. Caution also should be exercised when injecting patients who have excessive atrophy or weakness in target muscle, ptosis, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin, marked facial asymmetry, and inflammatory skin disorder at the planned injection site. Box 1 contains a preinjection checklist.
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Appropriate emergency drugs, such as epinephrine, should be available when a toxin is to be injected.
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The practitioner should have an established injection protocol that includes the specific locations and appropriate doses for the condition to be treated.
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All injection sites should have been evaluated properly. If the region to be injected has been surgerized previously, potential anatomic variations should be taken into consideration.
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The practitioner must be aware of all medications and supplements that are taken by the patient to minimize any effect on the potency of the BoNT/A.
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The practitioner should be aware of all medical conditions; vital signs, such as blood pressure, should be noted before injecting.
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It is strongly recommended that a consent form be explained to and signed by the patient (see Fig. 1 ).
Botulinum neurotoxin and experimental pain in animals
Regarding the evidence for BoNT as a pain control agent, it is appropriate to look first at how BoNT affects experimental pain in animals. Two animal studies examined how the release of pain-inducing neurotransmitters is suppressed in nociceptive afferents and sensory ganglia neurons by BoNT/A treatment . In another rat model, the effect of BoNT on pain from nerve fibers in the bladder was examined. This was done by filling the bladder with a 0.3% acetic acid solution in BoNT/A-treated rats. Rats who had received BoNT/A previously showed a significantly decreased CGRP release at day 7 after the injection compared with control (non-BoNT/A) rats . These neurochemistry studies are supported by an animal pain behavior study that examined the effect of BoNT on pain involved a subcutaneous injection of formalin into the paw of a rat . This injection is known to cause the release of glutamate from the primary afferent neuron, which induces increased paw-licking behavior in the rat. The investigators reported that preconditioning the animal by giving it a BoNT injection into the paw before the formalin injection reduced paw licking. They suggested that this was evidence of a direct analgesic response from BoNT. Finally, in another pain behavior study, the antinociceptive effect of BoNT/A was examined using a rat model of carrageenan (1%)- and capsaicin (0.1%)-induced paw pain . Mechanical and thermal responses were recorded. The investigators reported on the use of BoNT/A (5 U/kg) that was applied 6 days or 1 day before peripheral carrageenan or capsaicin injections. When used 6 days before injection, enhanced sensitivity to mechanical and thermal stimuli was reduced significantly or abolished. Based on these data, it was suggested that BoNT inhibits trigeminal hyperexcitability by blocking the antidromic flow of substance P and CGRP. This results in a decrease in peripheral sensitization of nociceptive fibers, which indirectly reduces central sensitization. Another pain inhibitory effect of BoNT/A may be by blocking stimulated CGRP release from sensory ganglia neurons .
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