INDICATIONS
Botulinum toxin (BTX) is a natural endotoxin produced by the bacteria Clostridium botulinum . The variant known as C. botulinum toxin A (BTX-A), discovered in 1946, has gained popularity over the last two decades as a method for addressing signs of aging, especially dynamic facial wrinkles. BTX affects acetylcholine (ACh), a neurotransmitter associated with muscle movement, leading to temporary flaccid paralysis of striated muscles. Initially used for strabismus in monkeys in the 1970s, ophthalmologists later employed it for various eye-related conditions. In the 1990s, the first publication on BTX’s cosmetic use emerged. Its applications have since expanded to include preventing and treating dynamic wrinkles, alleviating excessive sweating, correcting neck platysma banding, and treating signs of lower face aging.
There are seven serotypes of BTX labeled A to G, with A being the most potent and the first to be introduced for medical use in the United States. Serotype A operates by cleaving the SNAP-25 (synaptosome-associated protein of 25 kDa) protein, a component of the SNARE (soluble N -ethylmaleimide–sensitive factor attachment protein receptor) complex. Commercially available formulations of BTX derived from serotype A include onabotulinumtoxinA (BOTOX, BOTOX Cosmetic), abobotulinumtoxinA (Dysport), incobotulinumtoxinA (Xeomin), prabotulinumtoxinA (Jeuveau), and daxibotulinumtoxinA (Daxxify, formerly known as DAXI) and LetibotulinumtoxinA (Letybo). RimabotulinumtoxinB (Myobloc, NeuroBloc), derived from serotype B, is not approved for cosmetic use but has been studied for the treatment of facial lines. Physicians and patients select from the diverse range of commercially available BTX formulations by considering key factors that include the speed at which the treatment takes effect, the longevity of its benefits, and the unique responses of individual patients, ensuring a personalized approach to treatment.
BTX is most effective for dynamic lines, and consistent prolonged use may help reduce static lines as well. The distinct muscle groups in the upper face can be selectively treated by skilled injectors, while the less discrete muscle groups in the lower face pose a greater challenge. The following section will explore the injection technique, focusing on approved muscle groups (glabella, forehead region, crow’s feet, and nasalis), and advanced applications such as brow lift, nasal tip ptosis, lower face enhancements, and neck treatments.
TECHNIQUE
Aseptic technique is required when performing BTX injections to prevent infection. Injection sites should be cleaned with an antiseptic solution such as isopropyl alcohol, povidone-iodine, hypochlorous acid, or chlorhexidine gluconate prior to treatment. Patients are typically positioned sitting upright at approximately a 90-degree angle. Injection should be avoided if there is an active infection.
Glabella
Glabellar lines arise due to activity of the procerus and corrugator supercilii muscles. A five-point injection technique is commonly used to administer BTX in this area. However, it is important to consider individual variations and variations of movement and laxity on left versus right. The standard recommended dosing is 4 units of onabotulinumtoxinA into each point, 8 units in each corrugator muscle, and 4 units into the procerus muscle, for a total of 20 units. When injecting the procerus muscle, it is important to avoid touching the periosteum with the needle tip to reduce the risk of postinjection headaches. The injections of the procerus and medial corrugators are deep, as these are deep muscles, while the corrugator becomes more superficial laterally, so when injecting the lateral corrugators, it is important to lift up the brow and inject superficially. Effective glabellar treatment reduces the action of the depressor muscles in the region and can inhibit frowning and thereby promote a relaxed and less angry facial expression. Additionally, sustained muscle relaxation in this area may help prevent or diminish the formation of wrinkles in the brow region over time.
Forehead
In 2017, the FDA approved the application of BTX for treating horizontal forehead lines from the hyperdynamic frontalis muscle. The on-label recommendation to treat forehead wrinkles is 4 units of onabotulinumtoxinA evenly across the forehead for a total of 20 units. The number of injection points will vary according to the location and severity of forehead lines, but injecting the forehead requires an artistic and scientific approach, influencing eyebrow shape significantly. Therefore, the standard dosing and injection pattern is rarely appropriate. Before administering forehead injections, the physician should consider whether they aim to enhance the eyebrow arch or create a more horizontal shape, as well as individual variations of forehead and lid movement and laxity. It is imperative to avoid a standardized approach and tailor forehead injections based on the individual patient’s forehead size and shape. Additionally, the position of the eyebrow over the superior orbital rim must be considered. In some instances, low brows may further descend after BTX injections into the forehead. Therefore, in specific patients, forehead injections should be avoided or strategically placed in higher forehead regions. Careful attention should be paid to avoid the area within 1 cm of the eyebrows to minimize the risk of brow ptosis.
Lateral Canthal Lines (Crow’s Feet)
In 2013, the FDA granted approval for the use of BTX to treat lateral canthal lines. BTX should be injected 1 to 2 cm temporal to the lateral canthus, followed by injections 1 cm above and 1 cm below the initial injection. It is crucial to refrain from injecting medially to the midpupillary line to prevent ectropion, especially when not addressing medial wrinkles.
Nasalis
Using BTX for nasalis treatment is considered off-label. Some patients may display fanning wrinkles at the radix of the nose and medial wrinkling around the eyes, typically originating from the upper nasalis muscle along the bony dorsum of the nose. To address these lines, inject 2 to 4 units of onabotulinumtoxinA equivalent units into each side of the nasalis muscle, precisely within the muscle belly below the angular vein.
Brow Lift
BTX can be used to raise the eyebrows, resulting in a more youthful appearance known as a chemical brow lift. Injections can be administered to the glabellar area, as outlined previously. After injecting 4 units of onabotulinumtoxinA equivalent into the procerus muscle, massage the nasal bridge to ensure the toxin reaches the depressor supercilii portion of the corrugator muscle. Besides glabellar injections, an alternative method involves injecting into the lateral aspect of the eyebrow. Administering around 2 units into the lateral brow depressor muscles can elevate the lateral aspect of the brow.
Nasal Tip Ptosis Correction
BTX is used off-label to correct nasal tip ptosis. There is no universally prescribed method for this procedure. In a general sense, one commonly used technique is the injection of about 2 to 3 units of onabotulinumtoxinA into the base of the columella. The results can vary based on the distance between the top of the columella and the upper lip, or the length of the upper lip.
Gingival (Gummy) Smile
The muscle that retracts the upper lip is known as the levator labii superioris alaeque nasi. This muscle can be overly active, resulting in excessive retraction of the upper lip and the display of the upper gum and incisors, also known as a “gummy smile.” To address this issue, inject 1 to 2 units of onabotulinumtoxinA into the muscle on each side of the bony nasal prominence. This helps relax the muscle, causing the lip to descend and preventing the excessive exposure of the upper gum and incisors. There is also a second type of gummy smile where the upper lip curls under. To correct this, a total of 4 units is injected in 1-unit aliquots along the vermilion border, being careful to stay 1 cm lateral of the lip center to avoid flattening of the upper lip.
Masseter Hypertrophy
Masseter hypertrophy is a clinical condition characterized by the unilateral or bilateral enlargement of the masseter muscle near the angle of the mandible. This enlargement is often associated with bruxism, temporomandibular disorders, and facial asymmetry. While surgical intervention was historically used to address this condition, the advent of BTX introduced a less invasive alternative. The quantity of BTX administered depends on the severity of masseter hypertrophy. Typically, a range of 10 to 30 units of onabotulinumtoxinA per side is injected at a total of 3 to 6 points of the masseter complex. It is important to avoid inadvertent injection of the risorius muscle to avoid affecting the smile.
Platysmal Bands
Another off-label application of BTX involves addressing vertical platysmal bands in the neck. Brandt et al. were the pioneers in introducing the use of BTX for neck aging. Individuals with substantial sun exposure often exhibit more pronounced signs of aging in the neck region. The aging process, compounded by sun exposure, leads to the anterior separation of the platysma, resulting in the formation of vertical bands that can be targeted with BTX. When noticeable platysmal bands are identified, the needle can be vertically inserted into the muscle band. Approximately 2 to 4 units of onabotulinumtoxinA can be injected, spaced about 3 to 4 cm apart along the bands, with a recommended maximum dose range of 20 to 50 units, depending on the age and platysmal band strength. It is important to avoid deep injections, as this could increase the risk of side effects such as dysphagia and dysphonia.
Hyperhidrosis
Hyperhidrosis is a medical condition characterized by excessive sweating, significantly impacting the quality of life for affected individuals. The eccrine glands, innervated by the sympathetic nervous system, are stimulated by the neurotransmitter acetylcholine (ACh) to produce sweat. BTX works by inhibiting ACh secretion and, consequently, reducing sweating. Common areas affected by hyperhidrosis include the axilla, hands, and feet. To identify the areas requiring treatment, a starch-iodine test can be performed. Iodine solution followed by starch solution is applied to the target area, with the appearance of dark purple indicating sweat production.
Typically, 50 to 100 units of Botox are injected into each axilla. OnabotulinumtoxinA can be diluted with 4 mL of normal saline, resulting in 2.5 units per 0.1 mL or a total of 25 units per 1 mL syringe. This dilution usually translates to approximately 20 injection points in each axilla, spaced approximately 1 cm apart.
OUTCOMES
BTX is an effective and overall safe method for reducing the appearance of facial lines. In 1992, Carruthers and Carruthers first reported on the effectiveness of BTX for glabellar rhytids. Among 18 patients treated with C. botulinum -A exotoxin, 16 noted improvement in their glabellar frown lines, with effects lasting 3 to 11 months. Complications were minimal and included transient eyebrow or eyelid ptosis, numbness, swelling, and headache.
Many large, randomized controlled trials have similarly demonstrated the efficacy of BTX for the treatment of dynamic glabellar rhytids. OnabotulinumtoxinA was superior to placebo at all studied time points for the treatment of moderate-to-severe glabellar lines and crow’s feet. Treatment effects were dose dependent, with higher doses leading to greater magnitude and duration of effect. Clinical response was sustained for 4 months in more than 50% of patients. ,
AbobotulinumtoxinA was shown to be superior to placebo and noninferior to onabotulinumtoxinA for the treatment of moderate-to-severe glabellar lines. Median duration of treatment effects was 4 months, though effects lasted up to 6 months in approximately 17% of patients. , , , IncobotulinumtoxinA, rimabotulinumtoxinB, and prabotulinumtoxin were also superior to placebo for treatment of glabellar rhytids. ,
DaxibotulinumtoxinA, was FDA-approved in 2022 for the treatment of moderate-to-severe glabellar lines. In the SAKURA 1 and SAKURA 2 trials, treatment with 40 units of daxibotulinumtoxinA led to significant reduction in glabellar lines compared to placebo. Median duration of treatment effects was 24 weeks, indicating a more prolonged treatment effect compared to other formulations. LetibotulinumtoxinA (LETYBO) is the most recently approved formulation of botulinum toxin A. Multiple randomized controlled trials have demonstrated its efficacy in reducing glabellar and crow’s feet lines [PMID: 35092418, 33721365, 38470985]. Side effects were comparable to other botulinum formulations.
Improvement in facial rhytids was consistently observed by both study investigators and subjects. Median time to onset was one to three days, with peak effects seen 1 to 4 weeks after treatment. The effects of BTX are transient, with clinically evident recovery of muscular function approximately three months after treatment. The duration of response, however, may vary based on injection site, dose, and formulation of BTX used. Though BTX has clinically been shown to reduce rhytids in various anatomic locations, large studies evaluating these outcomes are limited.
BTX is also an effective treatment for focal hyperhidrosis, significantly reducing sweat production and improving quality of life, as demonstrated in various studies. It is a second-line treatment option for patients with severe axillary hyperhidrosis inadequately controlled with topical antiperspirants. Treatment response is typically evident within two to four days and lasts for 3 to 9 months. For optimal results, the treatment should be repeated every 4 to 6 months. Notably, treatment duration may increase with subsequent injections, possibly due to increasing time needed for regrowth of axon terminals. Most studies evaluated onabotulinumtoxinA or abobotulinumtoxinA for the treatment of hyperhidrosis, but other formulations may also be effective. Only onabotulinumtoxinA is FDA approved for the treatment of axillary hyperhidrosis, with typical dosing of 50 units per axilla. Although 200 units of abobotulinumtoxinA led to significantly greater sweat reduction than 100 units, the clinical relevance remains unclear, and the duration of treatment is likely unaffected. ,
COMPLICATIONS
Complications arising from BTX for cosmetic use are generally brief and reversible within weeks to months. A common adverse effect is bruising at the injection sites, which can be minimized by avoiding aspirin, NSAIDs, green tea, vitamin E, and other anticoagulants for 10 days prior to treatment. Other reported side effects include headaches, swelling, and pain. Anecdotal evidence suggests that preinjection application of ice packs may alleviate pain and reduce bruising. The use of preserved saline and topical anesthetics can minimize pain with injections. Furthermore, a small-volume syringe and needle should always be used. In one study, patients reported significantly less pain with a 32-gauge needle compared to a 30-gauge needle. Some studies propose a link between the use of larger BTX doses for neurological purposes and postinjection flu-like symptoms and dry mouth.
In the upper face, the most serious side effects of BTX treatment include asymmetry, ptosis, and, rarely, diplopia or ectropion. Skillful injection technique and precise toxin placement significantly reduce the occurrence of these temporary side effects. Anecdotal observations indicate a decrease in ptosis induction from approximately 4% in inexperienced physicians using BTX injections in the upper face to 0.5% with practice.
Complications from platysma injections may involve bruising, drooling, corner-of-the-mouth downturn, neck muscle weakness, and dysphagia. Injections in this area can result in lip or mouth asymmetry.
BTX injections for hyperhidrosis of the palms and soles may cause temporary muscle weakness, necessitating caution when treating individuals requiring a strong grip (e.g., tennis players) or manual dexterity (e.g., piano players).
BTX has been linked to unmasking underlying myasthenia gravis in one patient, making its use contraindicated in those with myasthenia gravis, systemic lupus, and other autoimmune disorders with a preexisting neuromuscular condition.
Postmarketing reports suggest the potential spread of BTX products beyond the injection site, leading to symptoms such as asthenia, generalized muscle weakness, diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. However, side effects with BTX for cosmetic use are generally rare and minimal, and BTX is considered a safe and effective tool for facial rejuvenation.
Binding or neutralizing antibody formation can occur in patients treated with botulinum toxin. Reassuringly, this phenomenon occurs in less than 1% of patients and rarely leads to loss of treatment efficacy. IncobotulinumtoxinA, a formulation free of complexing proteins, is a suitable option for patients in whom botulinum immunoresistance is suspected.
OTHER CONSIDERATIONS
Reconstitution
BTX requires reconstitution with sterile saline prior to use. For a 100-unit vial of onabotulinumtoxinA, incobotulinumtoxinA, LetibotulinumtoxinA or prabotulinumtoxinA, dilution with 2.5 mL of sterile 0.9% sodium chloride is recommended. A dilution volume of 2.5 mL is also recommended for a 300-unit vial of abobotulinumtoxinA. A 100-unit vial of Daxxify should be reconstituted with 1.2 mL of sterile saline. Dilution volumes vary in clinical practice, as lower volumes may be preferred to minimize diffusion and provide more precise delivery of toxin. Higher dilution volumes may be preferred for larger treatment areas.
Once reconstituted, BTX can be stored for future use. Product labels state that BTX should be stored in a refrigerator (2° to 8°C) and used within 24 hours. In clinical practice, however, BTX is routinely stored for greater than 1 week and used safely for other patients. Studies have shown that BTX remains effective for at least 6 weeks after reconstitution.
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