Overview of botulinum toxin for cosmetic indications

INTRODUCTION — Botulinum toxin is an injectable neuromodulator derived from neurotoxins produced by Clostridium botulinum, the bacterium responsible for botulism. Through the inhibition of neurotransmission between peripheral nerve endings and muscle fibers, botulinum toxin weakens or paralyzes skeletal muscle. Initially used for medical indications, botulinum toxin injection has now become one of the most requested procedures in facial rejuvenation.

When used appropriately, botulinum toxin injection is an overwhelmingly safe method for improving cosmetic defects that are caused by or exacerbated by muscle contraction, such as prominent glabellar rhytides. The effects of botulinum toxin are transient; muscular function typically returns to baseline within a few months.

The mechanism of action, formulations, clinical use, and safety of botulinum toxin injections for cosmetic indications will be reviewed here. The use of botulinum toxin for specific cosmetic or medical indications is discussed elsewhere. (See "Botulinum toxin for cosmetic indications: Treatment of specific sites" and "Treatment of dystonia in children and adults", section on 'Botulinum toxin injections' and "Treatment of myoclonus", section on 'Segmental or peripheral myoclonus'.)

DISCOVERY AND DEVELOPMENT — The clinical relevance of C. botulinum, a gram-positive bacillus, was first recognized in 1897, when the toxin produced by the organism was identified as the etiologic agent of botulism [1,2]. Since then, seven serotypes of botulinum toxin (A, B, C1, D, E, F, and G) produced by different strains of the bacterium have been identified. The pharmacologic properties of the serotypes differ, and only serotypes A and B are available for clinical use [3-5]. Botulinum toxin type A is the most common form of botulinum toxin used in aesthetic clinical practice.

The clinical utility of botulinum toxin initially became evident in the treatment of strabismus [6]. Subsequently, botulinum toxin has been utilized for a variety of other medical conditions characterized by muscular hyperactivity, including blepharospasm [7], hemifacial spasm [8,9], and cervical dystonia [10]. (See "Treatment of dystonia in children and adults", section on 'Focal dystonia' and "Treatment of myoclonus", section on 'Segmental or peripheral myoclonus'.)

In 1992, we published the first report of the use of botulinum toxin for a cosmetic indication. This report documented the benefit of botulinum toxin type A for the treatment of glabellar frown lines [11]. Botulinum toxin is now utilized for multiple cosmetic concerns that can be improved with local muscle relaxation, such as other dynamic rhytides on the upper face and skin lines located on the lower face and neck [12-18].

MECHANISM OF ACTION — The clinical utility of botulinum toxin stems from the ability of the toxin to prevent muscular contraction through inhibiting the release of acetylcholine from peripheral nerve cells into neuromuscular junctions [19]. Botulinum toxins are peptides that are composed of one heavy chain and one light chain. After the heavy chain of the injected toxin binds to receptors on the terminal ends of nerve cells, the peptide enters the cytoplasm through endocytosis. Once in the cytoplasm, the light chain cleaves components of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor), a complex of proteins necessary for the exocytosis of acetylcholine. The sites of cleavage within the SNARE protein complex differ among the serotypes; while botulinum toxin types A, C1, and E cleave SNAP-25 (synaptosome-associated protein of 25 kd), serotypes B, D, F, and G cleave VAMP (vesicle-associated membrane protein). VAMP is also known as synaptobrevin.

As a result of this cleavage, acetylcholine remains in the neuron, where it is unable to bind to receptors on muscle fibers and stimulate muscle contraction (chemodenervation). The inhibitory effect of botulinum toxin is temporary; recovery of muscular function often becomes clinically evident approximately three months after treatment as the neuromuscular junction begins to recover. The development of new collateral nerve ends may be partially responsible for recovery; however, these terminal buds appear to be transient, and recovery of the original nerve terminal eventually occurs [20].

FORMULATIONS — Two serotypes of botulinum toxin have been formulated for clinical use, including botulinum toxin type A (the most common serotype used for cosmetic applications) and botulinum toxin type B. In order to prevent confusion between products, in 2009, the US Food and Drug Administration (FDA) recommended the use of specific names, rather than serotypes, to refer to the available formulations of botulinum toxin [21]. Commercially available formulations of botulinum toxin type A in North America include onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and prabotulinumtoxinA [19]. Commercial availability of daxibotulinumtoxinA is pending. RimabotulinumtoxinB is the established name for botulinum toxin type B.

OnabotulinumtoxinA — Of the formulations of botulinum toxin type A that are available or in development, onabotulinumtoxinA (Botox, Botox Cosmetic, Vistabel, Vistabex) has been studied most extensively. OnabotulinumtoxinA is supplied as a preservative-free, vacuum-dried powder that contains the C. botulinum type A neurotoxin complex (50 or 100 units per vial) plus human albumin and sodium chloride. The FDA has approved onabotulinumtoxinA for the treatment of glabellar rhytides, lateral canthal lines (crow's feet), and forehead lines, but the toxin also is widely used for the treatment of other skin lines and for facial contouring [22].

AbobotulinumtoxinA — Initially marketed in Europe, abobotulinumtoxinA (Dysport) is another formulation of botulinum toxin type A utilized for cosmetic therapy. AbobotulinumtoxinA is supplied in vials that contain 300 or 500 units of lyophilized abobotulinumtoxinA plus serum albumin and lactose. AbobotulinumtoxinA became commercially available in North America in 2009 and has FDA approval for the treatment of glabellar lines.

IncobotulinumtoxinA — IncobotulinumtoxinA (Xeomin or Bocouture), a newer formulation of botulinum toxin type A, is approved for medical use and for injection of glabellar lines in multiple countries, including the United States. IncobotulinumtoxinA is supplied as a lyophilized powder that contains botulinum toxin A (50 or 100 units), human albumin, and sucrose. IncobotulinumtoxinA is free of complexing proteins, which some authors believe may result in a reduced risk of sensitization and antibody formation against the toxin [23,24]. (See 'Immunogenicity' below.)

PrabotulinumtoxinA — In 2019, the FDA approved prabotulinumtoxinA-xvfs (Jeuveau) for the treatment of moderate to severe glabellar lines in adults. PrabotulinumtoxinA is supplied as a vacuum-dried powder in a single-dose vial containing 100 units.

DaxibotulinumtoxinA — In 2022, the FDA approved daxibotulinumtoxinA (Daxxify) for the temporary improvement in the appearance of moderate to severe glabellar lines in adults [25]. The drug is supplied in vials containing 50 or 100 units of daxibotulinumtoxinA sterile lyophilized powder. Commercial availability is pending.

RimabotulinumtoxinB — RimabotulinumtoxinB is commercially available as Myobloc or NeuroBloc. Myobloc, which is distributed in the United States, Canada, and Korea, is supplied in liquid form in vials that contain 5000 units of botulinum toxin type B per milliliter plus human serum albumin, sodium succinate, and sodium chloride. It is the primary agent used for the treatment of cervical dystonia, and compared to botulinum toxin type A, has been less studied for cosmetic indications. However, rimabotulinumtoxinB has been used successfully for the treatment of facial rhytides [26-29].

Topical botulinum toxin A — Topical formulations of botulinum toxin type A may have promise for the treatment of dynamic rhytides [30-32]. In a randomized trial of 36 adults with moderate to severe lateral canthal lines, two 30-minute applications of a gel containing botulinum toxin type A separated by four weeks were superior to placebo for treatment [30]. Additional studies are necessary to determine the role of topical botulinum toxin for cosmetic indications.

Other — Other botulinum toxin products available or in development include the following:

●Chinese botulinum toxin A (CBTX-A) – Available in China, marketed as Prosigne in Brazil

●Neuronox – A formulation of botulinum toxin type A widely used in Korea and Southeast Asia

●Botulinum toxin E (EB-001) – A formulation under development that may have a relatively fast onset and short duration of effect [33]

COSMETIC USE — Since 1992, botulinum toxin has been used cosmetically in a number of clinical settings, ranging from the simple treatment of facial lines to more advanced facial sculpting. Examples of conditions that have been treated successfully with botulinum toxin include:

●Glabellar rhytides (picture 1)

●Horizontal lines on the forehead (picture 2)

●Lateral canthal lines (crow's feet) (picture 3)

●Depressed brow (picture 4)

●Hypertrophic orbicularis oculi muscle (small palpebral aperture)

●Rhytides from upper nasalis muscle contraction (bunny lines) (picture 5A-B)

●Nostril flare

●Drooping nasal tip

●Nasolabial folds (selected patients) (picture 6)

●Vertical perioral rhytides (picture 7)

●Mouth frown (picture 8)

●Gummy smile

●Melomental folds (marionette lines) (picture 9)

●Mental crease (horizontal crease on the chin) (picture 10)

●Peau d'orange chin (picture 11)

●Masseteric hypertrophy (square jaw)

●Horizontal neck lines (picture 12)

●Platysmal bands on the neck (picture 13)

The approach to the treatment of specific clinical features with botulinum toxin is reviewed separately. (See "Botulinum toxin for cosmetic indications: Treatment of specific sites".)

Efficacy — In general, the clinical effects of botulinum toxin begin to appear in one to three days, peak in one to four weeks, and gradually decline after three to four months [12]. However, the duration of response is dependent upon the injection site, dose, and specific formulation of botulinum toxin utilized [34]. Some patients, particularly those who have received repeated injections in the same area, may experience benefits for six months or longer. This may be at least partially due to the development of muscle atrophy [35].

OnabotulinumtoxinA — The results of multiple randomized trials support the efficacy of onabotulinumtoxinA for the treatment of dynamic rhytides [36-41]. As examples:

●A randomized, 120-day trial of 264 patients with moderate to severe glabellar lines found that treatment with 20 units of onabotulinumtoxinA was superior to placebo at all study time points [36]. By day seven, glabellar line severity at maximum frown was scored as absent or mild in 167 out of 203 patients treated with botulinum toxin compared with 3 out of 61 patients treated with placebo (82 versus 5 percent). Similar results were noted at 30 days, but treatment effect was substantially reduced by day 120 (26 versus 0 percent).

●Similar findings were noted in a second placebo-controlled randomized trial that used a similar protocol in 273 patients with moderate to severe glabellar lines [37]. Glabellar line severity at maximum frown was much more likely to be mild or absent at 30 days after treatment with onabotulinumtoxinA (77 versus 7 percent), but the amount of benefit was reduced at 120 days (24 versus 3 percent).

●In a randomized dose-response trial of onabotulinumtoxinA for moderate or severe crow's feet in 162 patients, all doses of onabotulinumtoxinA were superior to placebo for improvement in rhytid severity [38]. Thirty days after treatment, improvement was detected in 85, 87, 52, 46, and 16 percent of patients who received bilateral injections of botulinum toxin (18 units, 12 units, 6 units, or 3 units) or placebo, respectively. Higher doses of onabotulinumtoxinA were associated with a longer duration of action and a greater magnitude of effect.

AbobotulinumtoxinA — The efficacy of abobotulinumtoxinA for dynamic rhytides is supported by randomized trials [42-44]. As examples:

●In a phase 3 randomized trial that investigated the efficacy of 50 units of abobotulinumtoxinA for the treatment of moderate to severe glabellar lines in 158 patients, treatment with abobotulinumtoxinA was superior to placebo [43]. Glabellar line severity at maximum frown was much more likely to be mild or absent at 30 days with abobotulinumtoxinA (90 versus 8 percent). A significant difference in effect between treatment and placebo remained at day 120, but was no longer statistically significant by day 150.

●Similar findings were noted in a second phase 3 randomized trial in which 816 patients were randomly assigned to receive 50 to 80 units of abobotulinumtoxinA (dose based upon muscle mass) or placebo [44]. Glabellar line severity at maximum frown was much more likely to be mild or absent at 30 days (85 versus 3 percent). The median duration of treatment effect in the botulinum toxin group was 109 days.

IncobotulinumtoxinA — The efficacy of incobotulinumtoxinA was investigated in two unpublished randomized trials in which patients with moderate to severe glabellar lines at maximum frown were treated with either 20 units of incobotulinumtoxinA (n = 366) or placebo (n = 181) [45]. Successful treatment was defined as improvement from severe lines to mild or absent lines or from moderate lines to absent lines. Thirty days after injection, 77 and 71 percent of patients treated with incobotulinumtoxinA achieved treatment success compared with none of the patients treated with placebo.

RimabotulinumtoxinB — The efficacy of rimabotulinumtoxinB for dynamic wrinkles has been supported by the results of randomized trials and open-label studies [26,29,46-48]. RimabotulinumtoxinB also may be useful for patients who fail to respond to botulinum toxin type A. RimabotulinumtoxinB was effective in an open-label study of 20 women with vertical glabellar rhytides that were refractory to or had a diminishing response to onabotulinumtoxinA [27].

PrabotulinumtoxinA — Efficacy of prabotulinumtoxinA for glabellar lines has been demonstrated in randomized trials. In two identical phase 3 trials (n = 330 and n = 324), adults with moderate to severe glabellar lines were randomly assigned in a 3:1 ratio to receive either 20 units of prabotulinumtoxinA or placebo [49]. At day 30, 68 and 70 percent of patients in the prabotulinumtoxinA groups achieved at least a two-point improvement on a four-point glabellar line severity scale compared with 1 percent of patients in the placebo groups.

DaxibotulinumtoxinA — Two placebo-controlled, phase 3, randomized trials (SAKURA 1 and SAKURA 2) support efficacy of daxibotulinumtoxinA for glabellar lines [50]. In SAKURA 1 (n = 303), patients who received daxibotulinumtoxinA were more likely to achieve at least a two-point improvement in glabellar line severity at maximum frown at week 4 than patients in the placebo group (74 versus 0 percent). Similarly, in SAKURA 2 (n = 306), 74 percent of patients in the daxibotulinumtoxinA group and 1 percent of patients in the placebo group achieved this endpoint. The SAKURA 1 and SAKURA 2 trials suggested prolonged response as a benefit of daxibotulinumtoxinA; the median durations of response in the two trials were 28 and 26 weeks, respectively.

Comparative efficacy — Few randomized trials have directly compared different formulations of botulinum toxin for cosmetic indications. The results of small randomized trials suggest the following differences among the agents [48,51-53]:

●The onset of action of rimabotulinumtoxinB appears to be faster than that of onabotulinumtoxinA [48,51,53].

●OnabotulinumtoxinA provides longer duration of efficacy than rimabotulinumtoxinB [51,53].

●Pain with injection is less with onabotulinumtoxinA than with rimabotulinumtoxinB [51]. The increased pain associated with injection of rimabotulinumtoxinB is thought to be related to its acidic pH (pH = 5.6), a property necessary for the product to remain stable in solution. Dilution of rimabotulinumtoxinB with preserved saline appears to decrease the pain associated with injection [54].

Additional studies are necessary to confirm these findings. Dose conversions among the formulations are not standardized, and it is conceivable that studies utilizing different doses of these agents might find conflicting results. As an example, the duration of action of botulinum toxin is dose-dependent. In a randomized trial that compared two different doses of rimabotulinumtoxinB, the duration of efficacy was longer with the higher dose (10 to 12 weeks versus 6 to 8 weeks) [53].

Based upon studies in patients with hyperhidrosis and cervical dystonia, it has been proposed that abobotulinumtoxinA may diffuse more extensively within tissue than onabotulinumtoxinA, which may contribute to a higher incidence of adverse effects [55-58]. However, additional studies are necessary to confirm whether these findings are applicable to cosmetic use [59,60].

Studies suggest that incobotulinumtoxinA and onabotulinumtoxinA have similar levels of clinical potency, safety, and duration of effect when used for medical indications [23,61-65], and randomized trials have compared the efficacy of incobotulinumtoxinA and onabotulinumtoxinA for cosmetic use. In a 12-week trial comparing treatment of moderate to severe glabellar lines with incobotulinumtoxinA (n = 284) versus onabotulinumtoxinA (n = 97), the two agents were similarly effective [66]. In addition, an intraindividual trial with 12 patients found similar efficacy between these agents in the treatment of periorbital rhytides [67].

Randomized trials support comparable efficacy of prabotulinumtoxinA and onabotulinumtoxinA for glabellar lines and crow's feet [68,69].

Contraindications — Absolute contraindications to botulinum toxin injection include infection at the site of injection or known hypersensitivity to any component of the product. AbobotulinumtoxinA should not be given to patients with allergies to cow's milk protein; this limitation does not apply to onabotulinumtoxinA, incobotulinumtoxinA, or rimabotulinumtoxinB.

Relative contraindications to treatment include neuromuscular disorders that could amplify the effect of the toxin, such as myasthenia gravis, Eaton-Lambert syndrome, myopathies, or amyotrophic lateral sclerosis. Caution should also be exercised in patients taking drugs that can interfere with neuromuscular transmission (eg, aminoglycosides, cholinesterase inhibitors, quinidine, magnesium sulfate, succinylcholine, and curare-type nondepolarizing blockers) [70,71].

OnabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB injection generally should be avoided in pregnant women. A similar approach is taken for prabotulinumtoxinA, given that data are considered insufficient to confirm the level of risk of adverse developmental outcomes [72]. The risks of maternal-infant transmission of botulinum toxin in lactating women are unknown; thus, we avoid their use in this population.

TREATMENT — Familiarity with facial anatomy and facial muscle function is essential for proper technique (figure 1). Improper injection can result in cosmetically unfavorable results or functional disability. For example, botulinum toxin injection for horizontal forehead lines may result in unsightly lowering of the brow if the frontalis muscle is excessively weakened. (See 'Complications' below.)

Preparing for treatment — Prior to treatment, the clinician should determine whether the patient's concerns are appropriate for treatment with botulinum toxin. Botulinum toxin is effective for aesthetic concerns that are caused by underlying muscle contraction. Individuals with other signs of aging, such as lentigines, telangiectasias, textural changes, and skin laxity often require additional cosmetic procedures to achieve satisfactory rejuvenation. (See 'Use as adjunctive therapy' below.)

If the cosmetic defect can be improved with botulinum toxin, and patient characteristics do not indicate that treatment is contraindicated, the patient should then be thoroughly informed about the expected duration of treatment benefit, the need for retreatment, and the potential adverse effects of botulinum toxin injection. Patients who have unrealistic expectations for treatment results are likely to remain dissatisfied regardless of the clinical outcome. We have found that digital photographs, taken both before and after treatment are useful for assessing improvement. (See 'Side effects and complications' below.)

Because botulinum toxin weakens or paralyzes muscles, the effect of injections on other bodily functions also must be considered. For example, singers or individuals who play wind instruments are not always good candidates for perioral injections.

Reconstitution — Botulinum toxin A must be reconstituted in saline prior to use. Preferred dilution volumes vary widely among clinicians. Package inserts suggest use of the following dilutions when treating glabellar lines: 20 units of onabotulinumtoxinA, incobotulinumtoxinA, or prabotulinumtoxinA and 50 units of abobotulinumtoxinA:

●OnabotulinumtoxinA and incobotulinumtoxinA – 2.5 mL of sterile 0.9% sodium chloride added to the 100 unit vial or 1.25 mL of 0.9% sodium chloride to the 50 unit vial. Both dilutions result in a dose of 4 units/0.1 mL.

●PrabotulinumtoxinA – 2.5 mL of 0.9% sodium chloride added to a 100 unit vial. The resulting dose is 4 units per 0.1 mL.

●AbobotulinumtoxinA – 2.5 mL or 1.5 mL of 0.9% sodium chloride added to the 300 unit vial. This results in doses of 10 units/0.08 mL and 10 units/0.05 mL, respectively.

We often prefer to use smaller dilution volumes to allow more precise administration of the toxin. In our experience, this appears to improve the duration of effect and reduce the risk of side effects secondary to excessive spread of the toxin to adjacent tissues [73]. We customarily utilize concentrations 100 units/mL of onabotulinumtoxinA in our practice. The use of larger dilution volumes may be beneficial in settings in which treatment of large areas is desired [74].

Unpreserved saline is the diluent recommended by the manufacturers of onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and prabotulinumtoxinA; however, in clinical practice, many clinicians in North America reconstitute these products in saline containing benzyl alcohol to reduce the pain associated with injection [75]. In a small randomized trial in which patients with dynamic rhytides on the upper face were treated with onabotulinumtoxinA in either preservative-containing or preservative-free saline, use of preserved saline reduced patient discomfort and did not alter treatment efficacy [76]. Similar findings were observed in a small randomized trial with abobotulinumtoxinA [77]. The possibility of allergy to benzyl alcohol must be considered when using preserved saline for reconstitution.

Opinion varies on the delayed use of botulinum toxin after reconstitution [75]. Although the package inserts for onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and prabotulinumtoxinA recommend refrigerating these products at 2 to 8°C and then discarding them if they are not used within 24 or 4 hours after reconstitution, respectively, many clinicians refrigerate reconstituted vials for longer periods of time in anticipation of future use. One randomized trial in which 85 patients were treated with onabotulinumtoxinA that was reconstituted in preservative-free 0.9% saline and refrigerated at 4°C for periods of time ranging from one day to six weeks found no significant difference in efficacy among solutions of different ages [78]. In addition, other randomized trials have documented retained treatment efficacy with botulinum toxin type A reconstituted one to two weeks prior to use [79-81].

Dose conversion — Dose conversions among the formulations of botulinum toxin A are not standardized. The results of a systematic review and subsequent randomized trials suggest that abobotulinumtoxinA:onabotulinumtoxinA dose ratios lower than 3:1 (eg, 2:1 or 2.5:1) are appropriate [82-84]. We typically utilize a dose ratio of 2.5:1 when transitioning between these products. In clinical practice, incobotulinumtoxinA, onabotulinumtoxinA, and prabotulinumtoxinA are administered in a 1:1 ratio; however, further study is necessary to determine whether this conversion is accurate [85,86].

Pain and bruising — The pain from injection is well-tolerated by many patients. In addition to the use of preserved saline, pain from injection can be minimized with application of ice to the treatment site prior to treatment or the use of topical anesthetic agents or vibrational anesthesia.

Bruising is most likely to occur after periorbital and perioral injections. Avoidance of inhibitors of platelet function for 7 to 10 days prior to periorbital injection (eg, aspirin, vitamin E, alcohol) is preferable in patients who can discontinue these agents safely.

During treatment — A small-volume (eg, 0.3 mL) insulin syringe with a small-diameter needle is typically used for injection. An impact of needle diameter on patient discomfort was found in a randomized trial (n = 20) that compared the pain associated with injection of onabotulinumtoxinA with a 30-gauge needle into one side of the forehead to injection with a 32-gauge needle on the contralateral side [87]. Clinically significant pain was more likely to occur with 30-gauge needles (40 percent of patients) than with 32-gauge needles (15 percent of patients; odds ratio 3.80, 95% CI 1.05-13.78), suggesting that patients who experience significant pain during facial injection may benefit from use of a smaller-gauge needle.

In our practice, we typically use a 31-gauge needle for injection. Use of a syringe that lacks a needle hub will minimize product waste.

The appropriate dose of botulinum toxin is determined by the treatment location and muscle mass; men typically have stronger and larger facial muscles and require higher doses than women. The number of injections and appropriate spacing of injections is dependent on the specific cosmetic defect. Local anatomic landmarks are used to guide the placement of injections.

Many clinicians, including ourselves, sometimes massage the treatment site after injection in an attempt to spread the toxin, which theoretically could increase the efficacy of treatment. The benefit of this procedure has not been formally studied, and if performed, care should be taken to avoid massaging in a direction that could promote movement of the toxin to untargeted areas. We generally avoid massage for injection sites above the brow due to a concern for inducing brow ptosis. (See 'Complications' below and "Botulinum toxin for cosmetic indications: Treatment of specific sites", section on 'Horizontal forehead rhytides'.)

After treatment — When treating the periorbital region, we apply gentle direct pressure immediately after withdrawal of the needle to reduce the occurrence of bruising.

Although there is a lack of data to confirm the efficacy of these measures, we and many other clinicians instruct patients to engage in actions that theoretically may minimize excessive diffusion of the toxin to untargeted areas and improve the efficacy of treatment. To minimize excessive spread of the toxin, we instruct patients to remain upright for at least two to four hours after injection and recommend that they avoid pressing or rubbing the treated areas for 24 hours. We also tell patients to contract and relax the treated muscles as much as possible for two to three hours after the procedure. In theory, contracting muscles may facilitate uptake of the toxin by neurons, accelerating the appearance of clinical benefit [51].

The manufacturers of onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and prabotulinumtoxinA recommend that treatments should be spaced by at least three months. However, for patients in whom the response to treatment is unpredictable (patients receiving an initial treatment or a dosing change), we schedule an appointment for reassessment two to three weeks after treatment. If the desired effect has not been achieved, we perform additional injections at that time to improve treatment results; subsequent injections are performed at longer intervals. In patients who have received large doses (eg, greater than 100 units of onabotulinumtoxinA), we wait one to two months before administering touch-up injections in an attempt to reduce the risk for immunogenicity. (See 'Immunogenicity' below.)

SIDE EFFECTS AND COMPLICATIONS — When patients are appropriately selected and proper dosing and injection technique are utilized, the use of botulinum toxin for cosmetic indications appears to be relatively safe [21,88]. Side effects are usually mild and transient and most commonly include swelling or bruising at the injection site, mild headache, or flu-like symptoms [89]. Undesired impairment of muscle function may also occur, but is usually associated with poor injection technique or inappropriate patient selection. Because smaller doses are less likely to cause unintended adverse effects, a conservative approach to treatment is advisable.

Complications — Diffusion of botulinum toxin occasionally results in effects on muscles or glands adjacent to the targeted musculature. Diffusion of toxin in the upper face can result highly undesirable adverse effects that last for 2 to 12 weeks, including brow ptosis (excessive weakening of the frontalis muscle) and eyelid ptosis (weakening of the upper eyelid levator muscle secondary to diffusion into the orbital septum). In addition, a quizzical or "cockeyed" appearance ("Mr. Spock" eyebrow) can result from preferential weakening of the medial frontalis muscles, which allows unaffected lateral muscle fibers of the frontalis to elevate the lateral brow. Other adverse effects that can occur in the upper face include diplopia, ectropion, lower eyelid droop, epiphora (excessive tearing), decreased strength of eye closure, and dry eye [73].

In the lower face, complications of treatment typically involve effects on muscle function and facial expression. These adverse effects usually are due to the use of excessive doses or injection into inappropriate locations. Flaccid cheek, incompetent mouth, asymmetrical smile, and loss of the ability to whistle are most likely to occur when injections are placed too close to the mouth, injections are performed in the mental fold, or when botulinum toxin interacts with the orbicularis oris muscle. The administration of high doses in the neck area can lead to dysphagia and weakness of the neck flexors.

Eyelid ptosis can be partially improved with apraclonidine drops given two to three times per day until resolution. This usually results in 1 to 2 mm of eyelid elevation. The quizzical-appearing brow can be remedied through injection of the lateral frontalis musculature. Other functional adverse effects that cannot be improved with compensatory treatment resolve as the effect of botulinum toxin diminishes.

Clinical safety record — Examination of the available data on botulinum toxin reveals an impressive safety record. The authors of a 2004 systematic review and meta-analysis of randomized trials (n = 1425) found no reports of serious adverse effects in patients treated with onabotulinumtoxinA for medical or cosmetic purposes [90]. Serious adverse effects reported to the FDA have also been low in number; between 1989 and 2003, only 36 serious adverse effects associated with cosmetic use were reported. Examples of the serious adverse effects that were documented included injection site reactions, headache, focal facial paralysis, muscle weakness, flu-like symptoms, dysphagia, respiratory compromise, cardiac arrhythmia, seizure, ocular abnormalities, and allergic reactions. Of note, 13 of the patients who experienced serious adverse effects had underlying medical conditions that may have contributed to the observed event (eg, respiratory compromise in a patient with asthma and cardiac arrhythmia in a patient with a history of heart murmur).

Although the risk of serious adverse effects is low with cosmetic use, side effects such as aspiration, dysphagia, pneumonia, anaphylaxis, botulism, and death have been reported in association with the use of botulinum toxin [91-96]. As a result, in 2009, the US FDA instituted a requirement for boxed warnings on product labels and a Risk Evaluation and Mitigation Strategy (a consumer guide outlining the risks associated with treatment) for all botulinum toxin products [97-99].

Because the effect of botulinum toxin is temporary, patients require additional treatment to maintain improvement. The safety of repetitive treatment with botulinum toxin was evaluated in a retrospective study of more than 4000 treatments in 945 patients treated for lines in the upper face [100]. Patients had to have received a minimum of three consecutive treatment cycles. Only mild to moderate adverse effects were detected; bruising and ptosis were most common. In addition, the incidence of side effects decreased with repeated injections, a finding that has been reported in studies of the medical use of botulinum toxin type A [101,102]. Repeat injections with abobotulinumtoxinA have also been well tolerated in large open label studies [103,104].

Immunogenicity — The commercially available preparations of onabotulinumtoxinA, abobotulinumtoxinA, and prabotulinumtoxinA are complexed with clostridial proteins, a characteristic that may have an effect on the immunogenicity of these agents [12,105,106]. Although antibody formation against botulinum toxin has been linked to reduced treatment efficacy in some reports [107-110], the occurrence of this phenomenon appears to be rare, particularly in patients treated for cosmetic indications [111,112]. In a meta-analysis composed of randomized trials and open label studies published between 1999 and 2007, out of 2240 patients treated with onabotulinumtoxinA for a variety of indications (including 718 patients treated for glabellar lines), only 11 patients exhibited seroconversion. A lack of response to treatment followed conversion to seropositivity in only three patients, none of whom were treated for purely aesthetic indications [111].

Injecting the lowest effective doses, with the longest feasible intervals between injections, may minimize the potential for immunogenicity [101,113]. Because incobotulinumtoxinA is free of complexing proteins, the immunogenicity of this product may be different from the previously available complexed products [23,24,105].

USE AS ADJUNCTIVE THERAPY — Botulinum toxin is highly effective in the treatment of dynamic rhytides. However, deeper rhytides and skin folds or other signs of skin aging are often best treated with botulinum toxin plus soft tissue augmentation, laser skin resurfacing, microfocused ultrasound, or surgical intervention [114].

Soft-tissue augmentation — The use of cosmetic fillers in conjunction with botulinum toxin can be of value, particularly when treating the brow, nasojugal folds, perioral region, and the neck [115]. This technique may be particularly useful in patients who present for the treatment of deep rhytides that are evident at rest. (See "Injectable soft tissue fillers: Overview of clinical use" and "Injectable soft tissue fillers: Temporary agents" and "Injectable soft tissue fillers: Permanent agents".)

When given one week prior to treatment with fillers, botulinum toxin decreases the dynamic component of the targeted rhytid, leading to increased longevity of the filling agent in tissue [115-118]. In small randomized trials and a retrospective study, combination therapy with botulinum toxin A and cosmetic fillers has been associated superior efficacy and improved patient satisfaction compared to monotherapy with either procedure [118-121].

Lasers/light therapy — Traditional and fractional laser resurfacing are effective treatments for features of skin aging, including the treatment of rhytides. Impairment of muscle action with botulinum toxin before resurfacing may improve healing and collagen remodeling after laser treatment, contributing to improved aesthetic results [117,122-124]. In addition, postoperative injections may prolong the results of laser resurfacing by reducing the rate of wrinkle recurrence [122,125,126]. In one randomized bilateral comparison trial of 33 patients treated with periorbital injections of onabotulinumtoxinA or placebo prior to and after erbium:yttrium aluminum garnet (Er:YAG) laser resurfacing, greater improvement in rhytides, and other signs of photoaging were observed in sites treated with botulinum toxin [127]. Postoperative onabotulinumtoxinA also prolonged the correction of dynamic rhytides in a placebo-controlled randomized bilateral comparison trial of 40 patients treated with carbon dioxide laser resurfacing [126]. (See "Ablative laser resurfacing for skin rejuvenation", section on 'Approach to therapy'.)

The addition of botulinum toxin injections to the treatment of photoaging with intense pulsed light (IPL) was associated with increased overall aesthetic benefit in two small, randomized trials. Further studies are necessary to explore the effects of combination therapy with botulinum toxin and IPL.

Microfocused ultrasound with visualization — Microfocused ultrasound with visualization (MFU-V) involves the use of ultrasound energy to stimulate collagen remodeling through heating of dermal and subdermal tissues. This treatment results in tissue tightening and lifting without epidermal damage [128]. If botulinum toxin injections and MFU-V are to be performed on the same area of skin on the same day, treating with MFU-V first followed by botulinum toxin has been suggested based upon the risk for contamination of multiuse ultrasound transducers and the potential risk for increased spread of the neurotoxin during MFU-V treatment [114].

In general, caution should be exercised when using neuromodulators after MFU-V treatments. The increased blood flow caused by the MFU-V treatment might increase spread of the neuromodulator and increase the risk of associated side effects.

Surgery and wound healing — Chemodenervation with botulinum toxin is a useful adjunct to many aesthetic surgeries. Treatment before and after surgical procedures can be of value for stabilizing musculature during healing, thereby reducing the risk for wound dehiscence and improving outcomes of surgical procedures for facial aging (eg, brow lifts, blepharoplasty, facelifts) [117]. Moreover, pretreating the underlying musculature with botulinum toxin type A can allow for the use of finer sutures, contributing to improved aesthetic outcomes [129-132]. Botulinum toxin also reduces tension on the wound edge, allowing for faster healing with less prominent scarring [133,134].

SUMMARY AND RECOMMENDATIONS

●Overview – Botulinum toxin, the causative agent of botulism, is used clinically for a variety of indications. Through the controlled inhibition of local neurotransmission, botulinum toxin injections improve aesthetic concerns that are caused or exacerbated by muscular contraction. The effect of treatment is temporary; muscle recovery often becomes clinically evident a few months after treatment. (See 'Mechanism of action' above.)

●Serotypes – The mechanisms of action and clinical properties of botulinum toxin vary according to serotype. Botulinum toxin type A is the primary form of botulinum toxin utilized for cosmetic treatment. Botulinum toxin type B has been less extensively studied for cosmetic indications, but also appears to be effective in this setting. (See 'Formulations' above and 'Cosmetic use' above.)

●Formulations – Various formulations of botulinum toxin A are available worldwide. OnabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and prabotulinumtoxinA are the formulations available for clinical use in North America. Few high-quality studies have directly compared the efficacy of different formulations of botulinum toxin. (See 'Formulations' above and 'Cosmetic use' above.)

●Contraindications – Absolute contraindications to treatment with botulinum toxin include infection at the injection site and hypersensitivity to product components. AbobotulinumtoxinA should not be given to patients who are allergic to cow's milk protein. (See 'Contraindications' above.)

●Treatment principles – Careful patient selection and patient education, as well as thorough understanding of head and neck anatomy and appropriate injection technique are critical for the achievement of desired results and minimization of adverse effects. Common complications of botulinum toxin injection include transient swelling, bruising, and headache. When administered appropriately, serious adverse effects associated with the use of botulinum toxin for cosmetic indications are rare. (See 'Treatment' above and 'Side effects and complications' above.)

●Complications – Improper placement of injections or diffusion of the toxin to untargeted areas after injection can result in excessive muscle weakness that can cause temporary disfigurement or functional impairments. Some cosmetic defects such as eyelid ptosis and a quizzical-appearing brow can be improved with therapeutic interventions. In other cases, improvement is dependent upon the diminishing effect of botulinum toxin over time. (See 'Side effects and complications' above.)

●Use as adjunctive therapy – Botulinum toxin can be used in conjunction with other aesthetic procedures to improve clinical outcomes. Patients undergoing injection of cosmetic fillers, ablative laser resurfacing, microfocused ultrasound, or facial cosmetic surgeries may benefit from the concomitant use of botulinum toxin. (See 'Use as adjunctive therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Alastair Carruthers, FRCPC, who contributed to an earlier version of this topic review.