Treatment of crow’s feet lines and forehead lines with Botox (onabotulinumtoxinA): Development, insights, and impact

Abstract

Extrinsic and age-related intrinsic factors contribute to the development of facial lines, including lateral canthal lines (called crow’s feet lines [CFL]) and horizontal forehead lines (FHL).

OnabotulinumtoxinA is a highly effective treatment for facial lines that inhibits acetylcholine release at the neuromuscular junction. This temporary chemical denervation leads to localized muscle relaxation and subsequent wrinkle reduction. Early studies of onabotulinumtoxinA treatment for facial neuronal disorders such as dystonia documented improvements in FHL and CFL. After the neurotoxin was approved for treating frown lines (glabellar lines [GL]), individuals requested treatment for other rhytids, and physicians continued assessing use in new areas. Once onabotulinumtoxinA was in clinical trial development, its efficacy and safety for CFL and FHL were successively evaluated as required by the US Food and Drug Administration and by key global health authorities, including those in the European Union, Japan, and China.

Allergan, collaborating with leading physicians, established clinical programs that included novel safety and efficacy measures to meet regulatory requirements. Global, phase 3, randomized, controlled studies of CFL and FHL met rigorous primary endpoints. Some countries mandated clinical trial data beyond US and European regulations, and Allergan conducted 11 studies in total, fulfilling diverse regulatory and study population data requirements.

Adverse events associated with local spread, including brow and eyelid ptosis, diplopia, headache, and eyelid sensory disorder, were infrequent and well tolerated. Consequently, onabotulinumtoxinA treatment of upper facial lines is now established globally as a highly effective, minimally invasive treatment for patients to achieve a natural appearance and look younger.

1. Aesthetic treatment of facial lines

Facial lines are formed by repetitive contraction of underlying facial muscles, and dynamic lines observed during muscle contraction (eg, smiling) may progress over time to static lines that are visible at rest.^[1,2] Age-related intrinsic processes that contribute to facial lines involve loss of skin elasticity, hyperactive muscles, atrophy of collagen and fat, and bone loss.^[3,4] Extrinsic factors that lead to skin damage, such as sun exposure and cigarette smoking, also contribute to the formation of facial lines.^[5,6] Facial changes include the formation of lateral canthal lines, also called crow’s feet lines (CFL), and horizontal forehead lines (FHL), which are largely attributed to contractions of the orbicularis oculi, as well as frontalis muscle and glabellar complex (procerus and corrugator) muscles, respectively.^[7,8] These facial changes negatively impact self-esteem, body image, and perceptions of attractiveness.^[9,10] In particular, CFL have been reported to be the most bothersome facial feature in women between 30 and 65 years of age.^[11] The appearance of facial lines represents the first visible sign of aging and may impact an individual’s self-perception of facial balance, which is commonly associated with youth and beauty.

Dr. J. Carruthers: “It’s the ultimate expression of ageism…a discrimination based on a person’s appearance. We behave differently to people depending on how old we perceive them to be. In every employment situation, people have to look the part of a hard-working, not tired, not stressed person.”

The following historical narrative was compiled based on review of the literature and interviews with the authors, and the quoted portions reflect the personal observations and reflections of the individuals who were interviewed. In some instances, this article describes uses for which Allergan has not sought and/or received regulatory approval in individual countries and are mentioned for historical context or background only.

2. Evolution of the indications

2.1. Unmet need

Before the introduction of onabotulinumtoxinA, facial line treatments included topical agents such as retinoids and peels, ablative and nonablative lasers, radiofrequency, and injectable fillers. Topical retinoids were associated with skin irritation, termed retinoid dermatitis, which was especially concerning in the area around the eyes. Furthermore, topical treatments typically required at least 6 months to produce visible effects. Surgical interventions for facial lines included facelifts, blepharoplasty, and brow lift procedures.^[12] Other procedures included deep ablative laser resurfacing and dermabrasion to improve skin texture, fine wrinkles, and hyperpigmentation. These procedures were associated with risk of permanently altering one’s appearance and long recovery times. The limitations of these facial treatments created a need for a safe, minimally invasive yet effective treatment procedure.

Dr. J. Carruthers: “The problem with brow lift surgery was that they lifted too high, and because the brows frame the eyes and are what others notice first, a drastic change in appearance can impact nonverbal communication and emotional connection.… Redos were not uncommon.”

2.2. OnabotulinumtoxinA

OnabotulinumtoxinA, a potent neurotoxin protein derived from Clostridium botulinum,^[1] acts at the neuromuscular junction by inhibiting acetylcholine release and causing temporary chemical denervation.^[13] When small quantities of onabotulinumtoxinA are injected into overactive facial muscles, localized muscle relaxation occurs with smoothing of the overlying skin and reduction in wrinkles.^[1] Previous studies have demonstrated that onabotulinumtoxinA can improve both dynamic and static facial lines.^[14–16]

The therapeutic application of onabotulinumtoxinA has evolved over the years and across different medical subspecialties. A number of early discoveries, including those by Drs. Alan Scott,^[17,18] Mitchell Brin and Andrew Blitzer,^[19–21] Jean and Alastair Carruthers,^[22,23] Richard Clark and Craig Berris,^[24] and others, laid the groundwork for onabotulinumtoxinA use as a cosmetic therapy for the treatment of upper facial lines. As described in the previous chapter, these discoveries ultimately led to the 2001 (Canada) and 2002 (USA) approvals for the first aesthetic indication for onabotulinumtoxinA, the treatment of glabellar complex muscles that form frown lines (eg, glabellar lines [GL]).^[1]

Facial muscles are unique because they have soft tissue attachments to the skin in contrast to most other muscles, which have bony attachments. Thus, it was logical to consider onabotulinumtoxinA use in other facial areas and, with knowledge of the specific muscles associated with CFL and FHL, physicians continued to experiment with onabotulinumtoxinA in these areas. Following patient reports of reduced CFL and FHL after injections with the toxin, Allergan decided to pursue registration studies. OnabotulinumtoxinA was approved for treatment of CFL and FHL by the US Food and Drug Administration (FDA) in 2013 and 2017, respectively.^{[1,2,8,13,14]}

Dr. De Boulle: “The request for use in other indications really came from the patients…not the physicians.”

With the growing popularity of botulinum toxins and the expanding competitive market, global health authorities implemented new requirements with respect to approvals for aesthetic treatments. These requirements featured more extensive efficacy and safety data to characterize product profiles for aesthetic use. When Allergan initially proposed studying the effects of onabotulinumtoxinA on upper facial lines (GL, CFL, and FHL) treated together, the FDA stipulated a sequential approach for studying facial lines associated with a discrete muscle group. To address regulatory requirements, Allergan, in collaboration with leading physicians, established clinical programs that included novel safety and efficacy measures to meet regulatory requirements. These included implementation of a 2-grade composite primary efficacy endpoint, weighting patient-reported outcomes (PROs) equally with physician-assessed outcomes, as requested by the FDA. To address European regulatory health requirements, Allergan generated evidence supporting the psychological impact benefits of onabotulinumtoxinA treatment. In the CFL development program, Allergan pioneered a structured neurologic exam adapted for aesthetic physicians to detect potential distant spread of onabotulinumtoxinA.^[25] Results of the exam were consistent with adverse event reporting. Allergan also extensively monitored for immunogenicity in North American, European, and Asian patient populations, with no positive neutralizing antibody results among patients receiving up to 5 treatments of onabotulinumtoxinA. In all, Allergan conducted 8 registration studies (6 phase 3 and 2 phase 2 studies) for CFL,^{[8,14,16,26–30]} including several specifically designed for Japan and China.^[28,30] Based on the neurologic exam and immunogenicity data generated from the CFL program, these assessments were not required for the subsequent FHL registration studies.

As global health authorities increasingly recognized the importance of capturing the patient “voice” in the aesthetic treatment experience, the FDA further stipulated development requirements for PRO instruments.^[31] Consequently, the PRO instrument used to generate co-primary data for a labeled GL indication for onabotulinumtoxinA was insufficient for CFL and FHL assessments. Allergan developed de novo PROs precisely aligned with the aesthetic indication studied and fully compliant with FDA guidance. Allergan’s prioritization of health outcomes research, detailing the perspectives and experiences of aesthetic treatment‐seeking populations, enhanced the evidence generated for the CFL and FHL programs. Ultimately, Allergan’s Facial Lines Satisfaction Questionnaire (FLSQ) data were included in United States labeling for FHL treatment.

An important consideration for clinical development was selecting the optimal dose of onabotulinumtoxinA for phase 3 studies. Allergan’s dose-ranging studies supported the use of a fixed 24 U dose for CFL^[32] and a fixed 40 U dose for FHL, simultaneously treated together with GL, as providing sustained benefits without increasing adverse event rates.^[33] The injection patterns employed in these studies were designed to minimize adverse events, reflecting expert understanding of local anatomy and injection techniques.

As the United States, European Union, Japan, and China required phase 3 studies in respective populations, health authority meetings confirming the CFL and FHL dosing and injection patterns ensued. The United States, European Union, and China accepted CFL 24 U for pivotal studies, Japan required a dose range of 12 to 24 U, and all accepted Allergan’s proposed injection flexibility aligned with CFL pattern. From the evidence Allergan provided with respect to how best to optimize treatment outcome and minimize risk, both the United States and European Union agreed with the FHL 20 U dose and pattern in conjunction with GL 20 U for a total of 40 U. Throughout these meetings, Allergan’s leading position meant defining the aesthetic indication, treatment, and outcomes measures in an innovative and comprehensive manner that raised health authorities’ awareness of its clinical relevance and determined the pathway to approval.

Dr. Brin: “When Allergan began studying onabotulinumtoxinA for facial lines, there was no template for development. No similar therapies existed. We designed novel study outcome measures and sought to determine the extent of changes on these measures that would be meaningful for patients.”

3. Efficacy and safety highlights

3.1. Crow’s feet lines

Two pivotal, double-blind, placebo-controlled, randomized, multicenter, phase 3 studies were conducted in North America and Europe to evaluate the efficacy and safety of onabotulinumtoxinA in the treatment of CFL.^[16,34] In the first pivotal study, eligible adults with moderate to severe bilaterally symmetrical CFL at maximum muscle contraction (ie, smiling) based on the Facial Wrinkle Scale (FWS; 0=none, 1=mild, 2=moderate, and 3=severe) were randomized to receive onabotulinumtoxinA 24 U (n=222) or placebo (n=223).^[16]

The co-primary endpoints were the proportion of subjects achieving an FWS grade of none or mild at 30 days after treatment based on investigator and subject assessment. Responder rates were significantly higher with onabotulinumtoxinA compared with placebo on investigator assessment (67% vs 7%, respectively) and on subject assessment (58% vs 5%, respectively; Fig. 1). Statistically significant differences were maintained during the 5-month study period following a single treatment of onabotulinumtoxinA. The proportion of patients achieving at least a 2-grade improvement on both investigator and subject FWS from baseline at maximum smile at day 30, the composite primary endpoint required by the FDA, was achieved by significantly more subjects treated with onabotulinumtoxinA (26%) compared with placebo (1%). At day 30, 60% of subjects treated with onabotulinumtoxinA were “satisfied” or “very satisfied” with their appearance compared with 8% of subjects who received placebo.

Figure 1.

Responder rates for subjects achieving a severity of none or mild based on the Facial Wrinkle Scale in crow’s feet lines at maximum contraction (smiling) as assessed by (A) the investigators and (B) the subjects. *P≤0.001 vs placebo. Adapted with permission from Carruthers et al. Dermatol Surg. 2014;40:1181-1190.

The second pivotal study also assessed simultaneous treatment of CFL and GL.^[34] Subjects were randomly assigned to receive onabotulinumtoxinA 24 U for CFL (n=306) and placebo for GL (n=306), onabotulinumtoxinA 24 U for CFL and an additional 20 U for GL (n=305), or placebo (n=306) for both facial lines. CFL-specific responder rates—ie, rates of subjects achieving none or mild on the FWS based on investigator CFL assessments at day 30—were 55%, 59%, and 3.3% for subjects receiving onabotulinumtoxinA 24 U for CFL, onabotulinumtoxinA 44 U for CFL and GL, and placebo, respectively.^[34] Subject assessments yielded similar responder rates of 46%, 49%, and 3%, respectively. The composite endpoint was significantly greater for subjects treated with onabotulinumtoxinA (24 U, 21%; 44 U, 21%) compared with placebo (0 U, 0%).

In both studies, most adverse events were mild to moderate in severity.^[16,34] No treatment-related adverse events led to study discontinuation. Treatment-related adverse events that occurred more frequently in onabotulinumtoxinA groups versus placebo were headache, injection site hematoma, and injection site hemorrhage. No events were deemed to be related to the distant spread of toxin, and no subject developed neutralizing antibodies in either study.

Dr. Brin: “As our development programs progressed over the decades, we gained a greater appreciation of potential adverse events that were facial region specific, such as the distinction of eyelid versus eyebrow ptosis. In addition, the international adverse event coding dictionary (MedDRA) was updated in June 2008 whereby ‘eyelid sensory disorder’ became a MedDRA Preferred Term and was introduced into the first safety manuscript^[35] we published.”

Four additional phase 3 studies in CFL included a 5-month extension of the second pivotal study, accumulating 1-year safety exposure for CFL and CFL+GL treatment,^[36] 2 phase 3 studies conducted in Japan (CFL and CFL+GL),^[28,37] and 1 phase 3 study conducted in China (CFL).^[30] These studies yielded consistent efficacy and safety findings over single and repeat treatment cycles and in different populations, enabling global registration of this indication; region-specific information regarding safety and efficacy can be found in local labeling.

3.2. Forehead lines

The efficacy and safety of onabotulinumtoxinA for treatment of FHL was evaluated in 2 pivotal, double-blind, multicenter, phase 3 trials.^[8,14] In the first study, eligible subjects were adults with moderate to severe FHL at maximum eyebrow elevation and moderate to severe GL at maximum frown based on investigator and subject assessment using the FWS. For the initial 6-month, double-blind period, subjects were randomized 3:1 to receive onabotulinumtoxinA 40 U (FHL, 20 U and GL 20 U; n=290) or placebo (n=101). During the second period of the study (6–12 months), subjects could receive up to 2 additional open-label treatments if investigator-assessed facial line severity at maximum contraction was at least moderate.

FHL severity was reduced by at least 2 grades on both investigator and subject FWS ratings (composite primary endpoint) in a significantly greater proportion of subjects receiving onabotulinumtoxinA (61%) compared with those receiving placebo (0%) at day 30. This effect was first observed at the study day 7 visit and was maintained through day 120. Subjects receiving onabotulinumtoxinA had significant improvements in the achievement of FWS ratings of none and mild for FHL at day 30, which reflected significant improvements with onabotulinumtoxinA for FHL severity (investigator, 94%; subject, 86%) compared with placebo (investigator, 2%; subject, 20%).

The second pivotal study was designed in a similar manner to the first study but subjects were also required to have moderate to severe, bilaterally symmetrical CFL at maximum smile.^[14] During the double-blind, placebo-controlled treatment period of 6 months, subjects were randomized (2:2:1) to receive onabotulinumtoxinA 64 U (FHL, 20 U; GL, 20 U; CFL, 24 U; n=313), onabotulinumtoxinA 40 U (FHL, 20 U; GL, 20 U; CFL, placebo [0 U]; n=318), or placebo (FHL, 0 U; GL, 0 U; CFL, 0 U; n=156) for all facial lines.

Beginning at study visit day 7 and maintained through day 120, significantly higher proportions of subjects receiving onabotulinumtoxinA 64 U and 40 U achieved at least a 2-grade improvement from baseline in FHL severity on both investigator and subject FWS rating compared with placebo. At day 30, responder rates were 53%, 46%, and <1%, respectively. Significantly higher proportions of subjects receiving onabotulinumtoxinA achieved FHL FWS ratings of none and mild compared with placebo (Fig. 2).

Figure 2.

Responder rates for subjects achieving a severity of none or mild based on the Facial Wrinkle Scale (FWS) in forehead lines (FHL) at maximum contraction as assessed by (A) the investigators and (B) the subjects. *P≤0.001. ^‡P<0.005 vs placebo. Adapted with permission from De Boulle et al. Dermatol Surg. 2018;44:1437-1448.

At day 60, 90% of subjects in the first study and 82% of subjects in the second study reported being “mostly satisfied” or “very satisfied” with onabotulinumtoxinA compared with 1% and 3%, respectively, for subjects treated with placebo.^[13] In both studies, onabotulinumtoxinA treatment response was maintained across subsequent open-label treatment cycles.

The majority of treatment-emergent adverse events were mild or moderate in severity.^[8,14] During the first 6 months and over the entire 1-year study period, the most common adverse events were injection site bruising, injection site hematoma, and headache. In the first study of FHL and GL, eyebrow ptosis occurred in 5 (2%) subjects and eyelid ptosis occurred in 7 (2.4%) subjects receiving onabotulinumtoxinA during the first 6 months. Over subsequent treatment cycles, the incidence of these events decreased. In the second study, mild eyelid ptosis and brow ptosis occurred in 2 (<1%) subjects each receiving onabotulinumtoxinA 64 U, in 5 (2%) and 6 (2%) subjects, respectively, receiving onabotulinumtoxinA 40 U, and in no subjects in the placebo group during the first 6 months. The decreased incidence of injection-related adverse events in subsequent treatment cycles was likely the result of improved preparation and injection technique as physicians gained experience with the treatment paradigm.^[38]

Dr. Brin: “Whereas in the glabellar lines development program, the FDA required retreatment every 4 months, and subsequent phase 3 programs allowed for a longer observation period to gain a broader view of the treatment effect.”

The onabotulinumtoxinA doses selected from the CFL and FHL dose-ranging studies (2 phase 2 studies for CFL, and 1 phase 3b study for FHL) were accepted by global health authorities; however, some variations in labeled doses evolved from country-level approvals. Canada, for example, approved onabotulinumtoxinA treatment of upper facial rhytids with a CFL dose ranging from 12 to 36 U and an FHL dose ranging from 8 to 24 U. Australia, Russia, India, and Brazil similarly included flexible dosing for these facial lines, as each considered the onabotulinumtoxinA risk-benefit profile sufficiently characterized for aesthetic use within this range.

4. Emerging treatment patterns and lessons learned

The development of onabotulinumtoxinA for GL, CFL, and FHL led to several innovations for optimizing treatment approaches. For CFL, the use of 2 different injection patterns suggested by physicians allowed for customization of onabotulinumtoxinA administration based on the patient’s individual CFL pattern (Fig. 3A).^[2] CFL appear in 4 distinct patterns: full fan, lower fan, upper fan, and central fan, with the central fan pattern being the least common.^[39] In clinical studies assessing onabotulinumtoxinA for treatment of CFL, the first injection was made in the orbicularis oculi at the level of the lateral canthus for all patients.^[2] Subsequent injections were made either (1) above and below the first injection at a 30-degree angle medially for patients with lines at or above the lateral canthus; or (2) in a line angling from superoposterior to anteroinferior. The 2 patterns were approved by health authorities,^[13,40] providing flexibility to tailor treatment to optimize the appearance of CFL.

Figure 3.

Injection patterns for onabotulinumtoxinA to treat crow’s feet lines (CFL) and forehead lines (FHL). (A) Injection pattern (left) and allowed modification (right) for the treatment of CFL. The first, second, and third injection sites are marked as AX, BX, and CX, respectively. If the CFL were primarily below the lateral canthus, the injector had the option to inject below the lateral canthus in a line angling from anteroinferior to superoposterior. (B) Injection pattern for the treatment of FHL. Injection sites are indicated by stars in the diagram. Injections were made with the needle bevel tip point up and oriented away from the eye. Adapted with permission from Carruthers et al. Dermatol Surg. 2014;40:1181-1190 and De Boulle et al. Dermatol Surg. 2018;44:1437-1448.

Dr. De Boulle: “The surface anatomy of CFL dictated the pattern of injection.”

Dr. Brin: “We recognized that clinicians needed to have flexibility within the constraints of a development program and therefore implemented an innovative clinical trial design. This was the first time we had 2 injection patterns in clinical development and included in the product label.”

Another step taken to optimize treatment approaches was studying onabotulinumtoxinA to treat multiple facial areas in a single session, focusing on individualizing the approach to injection patterns. Several studies showed that combined onabotulinumtoxinA injections (eg, GL and FHL; GL, FHL, and CFL) are safe and effective.^[14,41,42] Additional studies showed that subjects receiving onabotulinumtoxinA treatment for GL and CFL had higher response rates on PROs than subjects receiving only treatment for CFL, supporting increased benefits of combined treatment.^[34,36] Allergan also determined that concurrent treatment of GL and FHL reduced eyebrow ptosis incidence to <2% compared with 8% to 25% previously reported with FHL treatment alone.^[8,14] Injection of GL and FHL maintains a balance between elevator muscles and depressor muscles that make up the glabellar complex to minimize eyebrow ptosis. Thus, the recommended injection pattern for onabotulinumtoxinA to treat FHL includes 5 injections in the frontalis and 5 injections in the glabellar complex. Figure 3B shows a representative diagram of the recommended injection pattern. The treatment of multiple upper facial areas simultaneously allows for a holistic, natural-looking result compared with treating individual facial areas separately.^[14]

In clinical practice, the flexibility to use of onabotulinumtoxinA for treatment of GL, CFL, and FHL in different combinations underscores the importance of individualized treatment to match a patient’s personal motivations. Several patient- and technique-related variables may influence the aesthetic indication treatment plan.^[43,44] Before onabotulinumtoxinA injection, it is important to carefully examine the muscle at rest and during animation to identify variations in anatomy and function to guide injection placement.^[13]

Dr. Lowe: “Everyone has a different pattern of muscular activity, and treatment needs to target those muscles that are most active. Each patient needs an individual treatment plan for optimal results.”

Dr. Brin: “We appreciated patients’ individual treatment goals related to maturity and aging. For example, I had a patient who, early in her career, wanted her glabellar lines treated, but not her crow’s feet lines, as she felt the latter signaled maturity in her role as an assistant professor in an academic medical center. About 5 years later when she had been promoted to associate professor and her crow’s feet lines had deepened, she wanted them treated as well.”

5. Impact of indication

OnabotulinumtoxinA is a well-established and highly effective treatment for upper facial lines, including GL, CFL, and FHL. The phase 3 studies of onabotulinumtoxinA for treatment of CFL and FHL met all prespecified efficacy endpoints, including the composite endpoint required by the FDA.^[8,14,16,34] After regulatory approval, the growing popularity of onabotulinumtoxinA treatment led to increased physician education on the use of the product.

Dr. De Boulle: “Gaining the official approval of onabotulinumtoxinA for CFL and FHL was a huge step forward in that it allowed open discussions at scientific meetings and in the media. Allergan was on the forefront to educate physicians and made efforts to engage in training on the proper use of onabotulinumtoxinA.”

Dr. Brin: “The regulatory approval of onabotulinumtoxinA for expanded aesthetic indications was important for establishing acceptance in the scientific community that once frowned upon the use of a neurotoxin for aesthetic treatment.”

In clinical practice, onabotulinumtoxinA is used in combination with other facial aesthetic treatments. Furthermore, as a minimally invasive alternative to surgery, it has become accessible and popular, impacting society’s perceptions of age and beauty. For example, multimodal, personalized facial treatment such as that reported for the HARMONY study, in which patients received a combination of on-label treatment with hyaluronic fillers, bimatoprost, and onabotulinumtoxinA, has yielded significant changes in self-perceived satisfaction and age following treatment in addition to improvements in clinical effectiveness (as assessed by investigator and patient).^[45]

Dr. De Boulle: “Botox Cosmetic is one of the key elements of a combination treatment program that will combine Botox Cosmetic with lasers, with radiofrequency, with topical therapy, and, most of all…fillers.”

Dr. Brin: “Botox Cosmetic broadened the conversation on aesthetic treatments. Many people who wouldn’t consider aesthetic surgery sought Botox Cosmetic treatment due to its accessibility, combined with its safety and efficacy profile. Its popularity has had a substantial impact on the way individuals and society view facial appearance and beauty.”

Dr. J. Carruthers: “People have logged on to the fact that they can do something without downtime…. If people are suffering ageism at work [being treated differently depending on how old they are perceived] and also ‘sandwiched’ by looking after their own kids, looking after their parents, there’s a time constraint on them as well.”

As treatment with onabotulinumtoxinA became more common, patients began to request a more nuanced and “natural” look. Originally, the CFL treatment goal was to eliminate all appearance of lines; however, these lines are associated with smiling and laughing, which convey positive emotions. Similarly, for FHL, some appearance of lines supports genuine facial expressions, such as surprise or happiness. In contrast, frown lines (GL) are often associated with only negative emotions. Thus, over time, patients’ treatment preferences evolved beyond the requirements for clinical studies toward a lighter treatment approach that refreshes their look while preserving authentic facial expression, particularly for positive emotions. This is an important development given the influence of dynamic facial emotions on social perception and judgements.^[46–48] For example, the evolutionary biologist Charles Darwin noted that “the movements of expression give vividness and energy to our spoken words,”^[46] and the neurologist Duchenne de Boulogne specifically noted that contraction of the orbicularis oculi muscle that causes CFL creates a genuine smile.^[47,49]

Dr. J. Carruthers: “The fear of toxin safety was replaced [over time] by the fear of an unnatural result. We knew from treatment of benign essential blepharospasm, Meige syndrome, and hyperhidrosis about dosage safety. Botox then stopped being perceived as a poison and rather as a treatment.”

Dr. A. Carruthers: “It’s not at all uncommon when people smile for their lower eyelid to come right up and occlude the pupil. If their loved ones are accustomed to seeing them with a normal smile…if you change it, they can feel quite uncomfortable about the result.”

Dr. J. Carruthers: “If you nipped someone’s frown, you must not get rid of all their horizontal forehead lines and their crow’s feet [lines] because otherwise they look like masks. You can’t relate to people, show compassion, show concern. It’s very important that you are very light on the horizontal forehead lines and crow’s feet [lines].”

In conclusion, the clinical development program for Botox Cosmetic, subsequent regulatory approvals achieved globally, and integration into clinicians’ daily aesthetic treatment toolbox for CFL and FHL fulfilled an unmet need worldwide—and had a clear, lasting, and evolving scientific and societal impact.

Acknowledgments

Writing and editorial assistance was provided to the authors by Michelle McDermott, PharmD of Peloton Advantage, LLC, an OPEN Health company, and was funded by AbbVie.

Author contributions

Conceptualization: All authors.

Project administration: Mitchell F. Brin.

Supervision: Mitchell F. Brin.

Writing–original draft: Mitchell F. Brin.

Writing–review & editing: All authors.