Injectables and Resurfacing Techniques: Botulinum toxin (BoNT-A)

Pharmacology and Pharmacokinetics

Clostridium botulinum is a Gram-positive, anaerobic bacterium that is known to produce seven serologically distinct types of toxin, designated A through G, of which type A is the most potent. Botulinum toxin types A and B are used medically and are available in the US. The type A toxin is a fully sequenced, 1296 amino acid polypeptide protein consisting of a 100-kDa heavy chain joined by a disulfide bond to a 50-kDa light chain.

In the normally functioning neuromuscular junction, the propagation of an action potential at the presynaptic neuron terminal opens voltage-dependent calcium channels. The influx of extracellular calcium ions causes vesicles containing acetylcholine to dock and fuse to the presynaptic neuron's cell membrane through the action of a 25-kDa soluble N -ethylmaleimide-sensitive factor attachment protein (SNAP-25). The released acetylcholine crosses the synaptic cleft, where it binds with nicotinic receptors at the motor endplate, opens sodium–potassium ion channels, depolarizes the motor endplate, and initiates the sequence of events that leads to contraction of the muscle fiber.

Following the administration of botulinum toxin, the heavy chain binds to the axon terminal, which enables the toxin to enter the neuron via endocytosis. In the cytoplasm, the proteolytic light chain degrades SNAP-25, thereby preventing fusion of the acetylcholine-containing vesicle with the cell membrane, preventing release of acetylcholine. Within a few days, the affected nerve is incapable of releasing acetylcholine, resulting in flaccid paralysis of the muscle fiber it innervates. Type-B botulinum toxin also causes flaccid paralysis but does so by inhibiting synaptobrevin, a vesicle-associated membrane protein similar to SNAP-25. Unless specified, the remainder of this chapter concerns botulinum toxin type A.

Recovery begins to occur after several weeks, although the mechanism for this is not completely understood. Initially, small neuritic processes grow out of the affected neurons and establish new functional synapses, which are capable of acetylcholine release; however, these neuritic networks shrink and disappear as the original neurons regain function. The initial clinical response to botulinum toxin is usually readily apparent for 3–4 months, although 6–7 months are often required for the effects to completely disappear. BoNT-A begins to display an increased duration of action in most patients when they undergo treatment on a regular basis. When used cosmetically, the duration of action of BoNT-B is significantly less than that of type A, with an effective initial response of 2–3 months.

Cosmetic Indications

Botox Cosmetic is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients. It is also indicated for the temporary improvement in the appearance of moderate to severe lateral canthal lines associated with orbicularis oculi activity in adult patients.

Dysport is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with procerus and corrugator muscle activity in adult patients <65 years of age.

Xeomin is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients.

Although the approved use of BoNT-A formulations for cosmetic use is limited to glabellar rhytids and lateral canthal lines, it is extensively used off label, and the author has used it to treat every muscle in the face since 1991.

BoNT-B plays a relatively minor role for cosmetic applications. It has a faster onset of action than BoNT-A, which can be beneficial, but its cosmetic usefulness is limited by greater pain on injection due to its low pH and a shorter duration of action. In isolated instances, it may be considered if a patient fails to respond to BoNT-A. It may also be useful for full-face laser resurfacing and lower-face scar revision, as the shorter duration of action will keep the treated area relatively motionless during the early healing phase while avoiding prolonged, unattractive facial weakness.

The use of BoNT-A and BoNT-B for neurological purposes has become extensive. Its approved use for the treatment of cervical dystonia has grown to include limb spasticity and dystonias, hypersecretory syndromes such as sialorrhea, headache, low back pain, and writer's cramp.

Warnings and Contraindications

The use of products containing botulinum toxin is contraindicated in the presence of infection at the proposed injection site and in individuals with known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation. The use of BoNT-A is contraindicated in patients with disorders of neuromuscular transmission, such as myasthenia gravis or Lambert–Eaton myasthenic syndrome. Dysport contains a small amount of lactose and may contain trace amounts of cow's milk protein. Dysport should not be use in patients with a known allergy to cow's milk protein.

BoNT-A products should be used with caution in patients currently taking drugs known to affect neuromuscular transmission such as neuromuscular blockers, lincosamides, aminoglycosides, polymyxins, quinidine, magnesium sulfate, anticholinesterases, or succinylcholine chloride as they may potentiate the effects of BoNT-A. The safety of administering botulinum toxin to pregnant women has not been established, and its use in this population should be avoided.

Adverse Effects

In the United States, due to reports received by the Food and Drug Administration regarding serious systemic adverse reactions including respiratory compromise and death following the use of botulinum toxins types A and B for both approved and unapproved uses, the labeling of all botulinum toxin-containing products are required to containing the following boxed warning:

Postmarketing reports indicate that the effects of all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses.

Adverse events reported by the manufacturers of BoNT-A and BoNT-B products include nasopharyngitis, headache, injection site pain, bleeding, bruising, edema, erythema, infection, inflammation, sinusitis, ecchymosis and nausea. Weakness of adjacent muscles may also occur due to spread of toxin resulting in undesired effects. These types of adverse events are described in greater detail below. To minimize bruising, patients should avoid the use of aspirin and non-steroidal anti-inflammatory medications for 2 weeks prior to treatment.

Patients have uncommonly developed neutralizing antibodies for BoNT-A following cosmetic use. These events are more often associated with the use of high doses for neurologic purposes, although this has been reported following cosmetic use resulting in treatment failure.

Dosing

The manufacturer of each BoNT-A product provides recommended dosing for their product, which is limited to the indicated uses. However, the facial musculature of patients is highly variable and precludes the use of standardized dosing for different aesthetic procedures. Gender also presents an obvious difference, as men typically (but not always) have larger muscles requiring higher BoNT-A doses compared to women.

Using Botox for the treatment of glabellar lines as an example, the manufacturer recommends injecting 8 U in each corrugator muscle and 4 U in the procerus muscle for a total dose of 20 U; however, many practitioners inject an average of 25 U per glabella, while some advocate doses as high as 80 U and upper face doses of nearly 100 U. A median dose of 15 U is used by the author with a dose range of 5–22.5 U. Consequently, each clinician must gain familiarity with these products through experience and establish their own optimum BoNT-A dosing techniques.

These principles were demonstrated during a recent clinical study. Patients were stratified by demographics and randomized to receive a single treatment with different doses of BoNT-A (Dysport) or placebo. Based on procerus/corrugator muscle mass, women received doses of 50, 60, or 70 U, while men were treated with 60, 70, or 80 U. Using this variable dosing technique, 85% of BoNT-A-treated patients were rated as treatment responders by a blinded evaluator after 30 days compared with 3% of placebo-treated patients (p < 0.001). Compared with patients in other studies who received 50 U to the glabella (the approved, on-label dose), variably dosed patients tended to have improved efficacy and quicker onset without increased adverse events.

BoNT-A products are not bioequivalent and cannot be used interchangeably because of differences in unit potency and fundamental differences in how these units are measured. A randomized, double-blind study comparing onabotulinumtoxinA and incobotulinumtoxinA was performed at a dose of 24 units per glabella and revealed incobotulinumtoxinA to be non-inferior to onabotulinumtoxinA. I believe it is fair to say that onabotulinumtoxinA and incobotulinumtoxinA have similar dosing regimens while the units of abobotulinumtoxinA are quite different.

The indicated dilution volume for the 100-unit vial of Botox Cosmetic is 2.5 mL and for the 300-unit vial of Dysport is either 2.5 mL or 1.5 mL, both with non-preserved normal saline. In actual practice, a wide range of volumes are used from 1.0 mL to 6.0 mL. Most practitioners use preserved saline (off label) for its weak anesthetic effect (benzyl alcohol is the preservative) and as a preservative if the vial is stored for a few days between uses. A recent poll of a consensus group of experts revealed that nearly all used each vial on more than one patient (also not according to the label). Smaller volumes allow for more concentrated dosing with less pain (based on volume of injection) per dosage point. Larger volumes allow for more injection points per dosage and thus, perhaps, more control. I have used 4.0 mL of non-preserved saline for both onabotulinumtoxinA and incobotulinumtoxinA 100-unit vial since 1991 and 2011 and 3.0 mL of non-preserved saline for Dysport since its introduction.