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AbobotulinumtoxinA for Facial Rejuvenation: What Affects the Duration of Efficacy?

Warren, Hermine DNP, APRN, CANS, CNM; Welch, Kim BSN, RN, CANS; Coquis-Knezek, Sarah PhD

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doi: 10.1097/PSN.0000000000000292
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Abstract

INTRODUCTION TO ABOBOTULINUMTOXINA

AbobotulinumtoxinA (Dysport) has a long history of use for aesthetic rejuvenation. The origin of Dysport began in the early 1980s at the Centre for Applied Microbiology and Research in the United Kingdom. The first marketing approval for Dysport came in 1990 for the use of blepharospasm and dystonia in the United Kingdom (Dover, 2017). Dysport had its aesthetic approval in the United States for the treatment of glabellar lines in 2009 (U.S. Food and Drug Administration [FDA], 2009). Since then, numerous non-FDA-approved aesthetic uses have been discovered for Dysport, including the treatment of forehead wrinkles, periorbital lines, lateral canthal lines, and perioral lines.

Dysport is produced from the botulinum toxin Type A Hall strain, as are all currently available Type A botulinum toxins (BoNT-A) (Daewoong Pharmaceutical Co. Ltd, 2019; Walker & Dayan, 2014). BoNT-As are composed of the core 150-kDa neurotoxin and accessory proteins (Eisele, Fink, Vey, & Taylor, 2011). Although accessory proteins vary among products, accessory proteins dissociate after reconstitution and the 150-kDa neurotoxin is the same across all BoNT-As (Eisele et al., 2011). The 150-kDa neurotoxin acts by decreasing muscular contraction through inhibition of acetylcholine release from the neuron, removing the stimulus for muscle contraction. A recent study found that in three commercially available BoNT-As, the 150-kDa neurotoxin has the same pharmacological activity (Field et al., 2018), confirming the similarity of the 150-kDa neurotoxin.

The mechanism of action is the same among all BoNT-As, but differences in the clinical effects of BoNT-A have been noted. Dysport typically acts within 2–3 days, and clinical effects can last up to 5 months (Brandt, Swanson, Baumann, & Huber, 2009; Galderma Laboratories, L.P., 2017b; Rubin, Dover, Maas, & Nestor, 2009). In a recent study, around one third of subjects noted effects at 24 hr postinjection and more than 70% of subjects noted effects at 48 hr (Kaufman et al., 2019). At 6 months posttreatment, 17.2% and 28.1% of subjects still had at least a 1-grade improvement in their glabellar lines in a study comparing two reconstitution volumes (Punga et al., 2016).

Subject satisfaction with aesthetic Dysport treatment is consistently high (Redaelli et al., 2019). Recent clinical studies support this; in one study, more than 70% of subjects were satisfied at 120 days posttreatment (Kaufman et al., 2019). In another study, nearly all subjects (93%–100%) between months 1 and 6 found the results natural-looking (Punga et al., 2016). When asked at 6 months whether they would have the treatment again, 98.3% responded yes and 96.8% would recommend the treatment to others (Punga et al., 2016). In addition, subject satisfaction was consistently high over three treatment cycles, with 99.3% of subjects and 100% of physicians satisfied with Dysport treatment at 3 weeks after the third injection (Gubanova et al., 2018).

The persistence of clinically meaningful results is one of the key measures of efficacy of botulinum toxins. Although the molecular mechanism underlying the duration of BoNT-A toxins remains unknown, toxin remains in the nerve terminal for months (Rossetto, Pirazzini, & Montecucco, 2014), and it is suggested that this determines its duration of effect (Hallett, 2015). The SNARE proteins, which allow signaling of the muscle contraction, are constantly resynthesized, but with toxin within the nerve terminal, SNARE proteins will be damaged, maintaining muscle relaxation (Hallett, 2015). Information on toxin metabolization, and thus removal, is limited (Rossetto et al., 2014). However, it is clear that many clinical factors also affect the duration of efficacy of toxins (Hallett, 2015). In this article, we review the clinical factors affecting the duration of efficacy with Dysport.

FACTORS AFFECTING DURATION

Dose

Clinical evidence shows that duration of efficacy is correlated with the dose of botulinum toxins, with a higher dose leading to longer durations (Joseph, Eaton, Robinson, Pontius, & Williams, 2016; Maas, 2018). Animal studies show that higher doses lead to a longer inhibition of muscular activity (Keller, 2006). One hundred twenty units (U) of Dysport injected into the glabella resulted in a median duration of 150 days (Joseph et al., 2016). Injections of incobotulinumtoxinA at three increasing doses found a linear increase in duration as the dose increased (Maas, 2018). Although toxin units cannot be directly compared between products as each are based on different standard tests, a recent study measured the amount of active core 150-kDa neurotoxin injected with on-label doses in three commercial toxins (Field et al., 2018), allowing a comparison not based on units. The amount of core 150-kDa active neurotoxin in the recommended dose for glabellar lines differed between toxins, with Dysport having the greatest amount injected at on-label doses (Field et al., 2018). The amount of 150-kDa active neurotoxin in Dysport is one explanation (Field et al., 2018) for the duration observed in studies with Dysport (Kassir, Kolluru, & Kassir, 2013; Nestor & Glynis, 2011; Punga et al., 2016).

Although only the glabellar line indication is FDA-approved in the United States, researchers have investigated its use in other areas. Dysport has been used to treat other areas of the face such as the forehead, crow's feet, and lower face, with doses varying depending on the muscle injected (Kane et al., 2010; Table 1). Although higher doses, in general, mean that subjects will need treatment less frequently (Maas, 2018), the dose must be balanced with subject satisfaction and safety. Doses of BoNT-A that are too great for the subject have been suggested to create a “frozen” look (Kane et al., 2012). Table 1 shows the most common areas and dosages a consensus panel recommended for aesthetic indications for Dysport (Kane et al., 2010).

TABLE 1 - Common Areas and Dosages Used With Dysport
Area Total dose Number of injection points Dose per injection Dose range
Glabellar lines 50 U 5 10 U 30–70 U for women
50–80 U for men
Forehead 40 U 4 10 U 20–60 U
Crow's feet 30 U per side 3 10 U 20–60 U per side; optional fourth injection
Bunny lines 10–20 U 2 5–10 U 10–20 U
Perioral lip lines—upper 8 U 4 2 U 2.5–16 U
Perioral lip lines—lower 4 U 2 2 U 2.5–7.5 U
Gummy smile 5 U per side 1 5 U 2.5–10 U per side
Downturned oral commissures; marionette lines 10 U per side 1 10 U 2.5–10 U per side
Dimpled chin 10 U per side 2 5 U 5-20 U
Note. Adapted from Expanding the Use of Neurotoxins in Facial Aesthetics: A Consensus Panel's Assessment and Recommendations,” by M. Kane, L. Donofrio, B. Ascher, D. Hexsel, G. Monheit, B. Razny, et al., 2010, Journal of Drugs in Dermatology, 9(1), pp. s7–s22; quiz s23–s25. Copyright 2010 by Journal of Drugs in Dermatology.

Individual Patient Variation

Anatomy also plays a significant role in the duration of efficacy. Size, thickness, and depth of muscles differ, and actual insertion points of the muscles may vary (Choi et al., 2016). The corrugator supercilii and frontalis muscles in particular exhibit large variations in size and strength (Lorenc, Smith, Nestor, Nelson, & Moradi, 2013). Duration of effect is shorter with increasing muscle mass (Kane et al., 2009), and consensus guidelines recommend higher doses for larger muscles (Ascher et al., 2010). In line with guidelines, it is recommended to use a higher dose for men based on evaluated muscle mass (Keaney et al., 2018; Rappl et al., 2013), as men tend to have more muscle mass and to experience a shorter duration of effect than women (Keaney & Alster, 2013). However, even when dosing was tailored to muscle mass, there were significantly more responders among women than among men (Kane et al., 2009), suggesting other anatomical factors may play a role as well.

Skin type, skin thickness, sweating intensity, and behavior have also been shown to affect the clinical effect of Dysport (Nestor, Ablon, & Pickett, 2017; Sycha et al., 2007). Subjects with less severe rhytids at baseline and thin corrugator muscles may experience a longer duration (Joseph et al., 2016; Rappl et al., 2013). Facial rhytids that are etched into the skin at rest may show less of a response to treatment initially, though over time with repeated treatments dermal remodeling can occur and rhytids can reduce (Humphrey, 2017). Subjects who are frequently exposed to sunlight in the days following treatment may experience a significant decrease in the effect of Dysport (Sycha et al., 2007). Age also plays a role, with older subjects experiencing a decline in the number of motor neurons (Gonzalez-Freire, de Cabo, Studenski, & Ferrucci, 2014). There is also some evidence linking increased age to lower response rates (Nestor et al., 2017). Therefore, older subjects may require additional adjustments to dose prior to injections. In short, it is critical to assess individual subject anatomy and behavior before injecting to determine placement and dosage.

Technique

Proper injection technique is necessary to ensure good clinical outcomes. This includes correct pre- and postinjection procedures, reconstitution, and storage (Dover, Monheit, Greener, & Pickett, 2018). Two reconstitution volumes are approved for Dysport in the United States: 1.5 and 2.5 ml (Galderma Laboratories, L.P., 2019). Reconstitution volumes at common aesthetic volumes do not play a large role in duration of efficacy (Carruthers, Carruthers, & Cohen, 2007). Some evidence exists that larger reconstitution volumes may initially lead to larger fields of effect and faster onset of effect (Abbasi, Durfee, Petrell, Dover, & Arndt, 2012; Hsu, Dover, & Arndt, 2004; Kaufman et al., 2019), perhaps due to the physical dispersion of toxin from the force of injection. However, in studies that have looked at differing reconstitution volumes over a longer period of time, no difference in efficacy was seen (Figure 1; Carruthers et al., 2007; Kaufman et al., 2019), suggesting that over longer periods of time only the amount of toxin injected matters. Recent studies have shown no difference in efficacy after 24 hr when comparing common Dysport aesthetic reconstitutions in the glabellar lines (Kaufman et al., 2019; Punga et al., 2016). In both studies, subjects were followed for 4–6 months after a single injection of a 50-U dose with 0.05, 0.08, or 0.1 ml per injection. There was no difference in duration of efficacy (Figure 1) or subject satisfaction with treatment. Similarly, use of very different reconstitution volumes (0.03–0.6 ml per injection) in the glabella did not lead to differences in efficacy (Carruthers et al., 2007). However, many practitioners believe that specific reconstitution volumes can help achieve desired results for different areas (Kaplan, 2016; Lorenc et al., 2013).

FIGURE 1.
FIGURE 1.:
Two studies comparing the proportion of subjects with at least a 1-grade improvement after 50 U injected in the glabellar lines with common reconstitution volumes used in aesthetic preparations (A and B). No significant difference between the two reconstitution volumes was seen at any time point in either study except at 24 hr postinjection in the Kaufman et al. (2019) study (B).

Although clinical efficacy is similar, different volumes have their advantages and disadvantages for the practitioner in ease of use (Table 2). The goal for any injector should be to correctly dose the patient (50 U for glabellar lines); how you achieve the correct dosing can vary. If the dose is not correct, you will not see the desired clinical results. Choosing an option with straightforward mathematics can make the reconstitution process easier and more consistent. In the authors' opinion, the simplest practice is to reconstitute with the FDA-approved 1.5 ml of saline and use an insulin syringe to inject. This combination allows the practitioner to inject 10 U of Dysport in easy-to-measure increments of 0.05 ml in the glabellar lines. An alternative option is to use volumes used with other toxins—whether the FDA-approved 2.5 ml or other volume—to obtain the correct dose (Table 2). There is no conversion ratio recommended by manufacturers, but ratios of 1:2.5 or 1:3 for Botox: Dysport units are commonly used (Abbasi et al., 2012; Alam, 2012). It should be noted, however, that when using a conversion ratio of 1:3, greater than the label-recommended amount of toxin will be delivered with each injection and therefore the injector should anticipate potentially increased clinical efficacy and larger fields of effect (Dover et al., 2018).

TABLE 2 - Common Reconstitution Volumes Used With Dysport and Advantages and Disadvantages of Each
Reconstitution volume (300-U vial) Draw (for glabellar lines) Inject Units injected per injection Suggested for Advantages Disadvantages
U.S. on-label reconstitution 1.5 ml 0.25 ml 0.05 ml 10 U All levels of practitioners Simple, easy-to-measure injection volume; smaller volume injected May be more difficult to calculate injection volume for those experienced with other toxins
2.5 ml 0.40 ml 0.08 ml 10 U Experienced with injecting botulinum toxins May be difficult to measure injection volumes
U.S. off-label reconstitution 3 ml 0.50 ml 0.10 ml 10 U All levels of practitioners Easy calculations; injection volumes similar to other toxins Not well studied
X ml—Other preferred volume used to inject other toxins (100 U vial) X × (20/100) X × (4/100) 12 U Very experienced with injecting botulinum toxins Reconstitution process remains similar for all toxins Greater number of units injected; more potential for a larger field of effect; not well studied

Using injection techniques that help more precisely deliver toxin to the muscle can lead to a longer duration of effect. Narrower gauge needles (31 or 32 gauge), angle and speed of injection, and techniques such as marked needles allow the injector to accurately measure how deep and where the injection is placed (Alam et al., 2015; Pickett, 2009; Pickett, Dodd, & Rzany, 2008). However, deeper injections of botulinum toxins do not necessarily lead to longer durations (Alam & Tung, 2018) but rather should be used when appropriate to ensure accurate placement of the toxin in the muscle belly (Kaplan, 2017). For optimal efficacy, injections should be made into relaxed muscles (Stephan & Wang, 2011). In addition, evidence exists that using preserved saline, although contrary to the manufacturer's recommendations, can lead to less pain with injection (Allen & Goldenberg, 2012).

Syringe selection varies with practitioner preference. In the authors' experience, three syringe types are commonly used to inject Dysport: insulin syringes, syringes with low dead space, and Luer lock/Luer slip syringes (Foglietti, Wright, & Foglietti-Fostyk, 2018; Kaplan, 2016; Table 3). The volumes injected with Dysport are generally smaller than those injected with other neurotoxins. Because of this, there are two types of syringes that the authors frequently use: insulin syringes and low dead space syringes. Table 3 summarizes the advantages and disadvantages of each. As the rubber stopper may dull needles, some practitioners have recommended removal of the cap when using insulin syringes (Kaplan, 2016), which can also help reduce the amount of retained toxin (Solinsky & Kirshblum, 2018). However, removing the cap contaminates the vial and therefore the cap should only be removed if the entire contents of the vial will be used in a single session as is recommended by the manufacturer (Galderma Laboratories, L.P., 2019).

TABLE 3 - Common Syringe Options Used for Aesthetic Injections of Neurotoxins and Advantages and Disadvantages of Each Based on Authors' Experience
Common syringe types Description Example Advantages Disadvantages
Insulin syringes Orange-capped syringes with a smaller volume and attached needle (range from 0.3 to 1 ml) BD 0.3-ml insulin syringes (Becton, Dickinson and Company, Franklin Lakes, NJ) Easy to read; smaller volume (Kaplan, 2016) Dulls quickly when pushed through the stopper of the vial (Kaplan, 2016)
Syringes with low dead space Syringe with plastic extension to enter needle hub Norm-ject 1-ml Tuberculin (Henke-Sass Wolf, Tuttlingen, Germany) Low dead space, needle removable (Kaplan, 2016) Generally more expensive per syringe
Luer lock or Luer slip syringes Needle twists or slips onto syringe to connect BD 1-ml tuberculin Luer slip (Becton, Dickinson and Company, Franklin Lakes, NJ) Needle connects securely and is removable Dead space at the tip can lead to lost product (Foglietti, 2018)

CLINICAL RELEVANCE OF DURATION OF EFFICACY MEASUREMENTS

The duration of clinical effect has been measured in many different ways. In the Dysport pivotal trials, duration of efficacy was originally determined using a responder rate defined as a rating of none (0) or mild (1) on the Glabellar Line Severity Scale (GLSS; Figure 2), leading to an estimated 4-month duration (Brandt et al., 2009; Carruthers et al., 2002; Kane et al., 2009; Moy, Maas, Monheit, Huber, & Reloxin Investigational Group, 2009). More recently, a 1-grade improvement in GLSS rating has been shown to be clinically relevant (Kane et al., 2012) and to standardize clinical improvement between each grade. For example, under the responder rate definition, subjects with a GLSS rating of severe (3) were not considered responders if they improved to moderate (2), whereas subjects who improved from moderate (2) to mild (1) were responders (Figure 2). Other ways to measure duration of efficacy, such as time to return to baseline GLSS score (Joseph et al., 2016), have also been used.

FIGURE 2.
FIGURE 2.:
Visual representation of the GLSS using subject photographs rated during a clinical trial (Galderma Laboratories, L.P., 2017a). In the pivotal trials, subjects who moved from GLSS rating of 3 to 2 were not responders whereas subjects who moved from GLSS rating of 2 to 1 were responders. GLSS = Glabellar Line Severity Scale.

A recent systematic literature review of 42 Dysport studies (28/39 relevant studies ≥4 month efficacy [72%]) found that in most studies, the reported duration of subjects treated with Dysport was longer than 4 months (Cohen, Nestor, et al., 2019). Re-treatment periods from observational studies show a median re-treatment period of 5–6.5 months (Gubanova et al., 2018; Rzany et al., 2007). Perhaps, unsurprisingly, a recent post hoc analysis of the pivotal Dysport trials showed that at 5 months, a 1-grade improvement or more in GLSS rating is maintained in more than a third of subjects (Figure 3). As 60% of subjects in the Dysport phase III pivotal trials had a baseline GLSS rating of severe (3) and experienced clinical improvement not counted in the responder rate, a 1-grade improvement in GLSS rating might more accurately reflect real-world clinical efficacy. However, although the clinical relevancy of different measures of duration of efficacy can be debated, perhaps the most important outcome measure is the subject's satisfaction.

FIGURE 3.
FIGURE 3.:
Duration of efficacy lasts up to 5 months based on a 1-grade improvement or more from baseline in GLSS score, investigator-rated. Data from GL-1 (A) and GL-3 (B) pivotal Phase III Dysport trials, assessed with a post hoc analysis (Galderma Laboratories, L.P., 2007a , 2007b , 2017b). GLSS = Glabellar Line Severity Scale.

Patient-reported outcomes are a key measure, as treatment of aesthetic indications is primarily to improve the subject's satisfaction with his or her appearance. Patient-reported outcomes have been a significant component of recent Dysport studies. In a recent study with 60 subjects, at 30 days posttreatment, 89.7% and 82.8% of the two groups felt attractive, a feeling that was maintained through the end of study at day 120 (Cohen, Kaufman, Peredo, Down, & Mashburn, 2019). Even at 6 months postinjection, subject satisfaction remains high. Two studies have evaluated subject satisfaction of a 50-U dose in the glabellar lines through 6 months (Ascher et al., 2004; Punga et al., 2016). In both studies, subject satisfaction remained high through month 6, with more than 85% of subjects satisfied or very satisfied with their treatment. As satisfaction with Dysport treatment is high, it can easily function as a gateway, encouraging patients to try other aesthetic treatments.

Although studies have focused on glabellar lines, efficacy has been shown in many other facial areas (Kane et al., 2010). At 5 months after treatment with Dysport in the lateral canthal lines, 22% had a 1-grade improvement or more (Elridy, Zaki, & Elshinawy, 2017). When used as a treatment of frontalis lines, Dysport was shown to last for a median duration of 119 days (Nestor & Glynis, 2011).

CONCLUSION

Dysport has a long history as a treatment option for aesthetic facial rejuvenation. Numerous clinical studies support its fast onset of action and long duration. The duration of efficacy of Dysport is affected by many factors but largely depends on three main areas: dose, patient variation, and technique. Dosing the patient based on evaluated muscle mass, skin variation, and age can help ensure your patients have their desired results. Using techniques that allow accurate and precise placement of the toxin into the muscle belly helps ensure the toxin can reach the neuromuscular junction to take effect.

Although there are several ways to measure duration of efficacy, some measures more closely match reported subject satisfaction. With more than a third of subjects reporting a 1-grade improvement or more at 5 months (Figure 3), subjects may experience a longer duration of efficacy with Dysport than previously reported. In addition, subject satisfaction with Dysport is generally very high, with studies reporting that satisfaction is maintained through 6 months and across multiple treatment cycles. Dysport has a legacy of safety, efficacy, and high subject satisfaction, demonstrated through numerous clinical studies and clinical experience. Building on that legacy by correctly dosing the subject, properly accounting for the specific subject anatomy and behavior, and using specific injection techniques can help ensure that your patients have the longest lasting results.

ACKNOWLEDGMENT

Funding was provided by Galderma Laboratories, L.P., for development of the manuscript.

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