Advertisement

Impact of botulinum toxin for facial aesthetics on psychological well-being and quality of life: Evidence-based review

Open AccessPublished:August 28, 2022DOI:https://doi.org/10.1016/j.bjps.2022.08.063

      Summary

      Background

      There has been a steady growth of non-surgical minimally invasive procedures. In parallel, an ever-broadening range of clinicians has been engaging with botulinum toxin (BoNT) for aesthetic procedures, with reportedly compound positive impact on social health and psychological well-being.

      Objective

      To identify and critically appraise current literature on the impact of BoNT injections into the upper face, as a sole treatment/combination with other modalities on facial aesthetics, psychological well-being, and quality-of-life.

      Methods

      An evidence-based review was performed using advanced search from PubMed, Cochrane Library of Systematic Reviews, and Central Register of Controlled Trials databases . Only literature from inception to August, 2021 were considered. Eligibility criteria included human studies, FDA-approved BoNT applications, formulations, and dosages as a sole/multimodal approach; studies including patient-reported outcome tools psychometrically validated and facial lines-specific. Observer-reported outcome instruments were also considered for a thorough evaluation of outcomes.

      Results

      Based on data investigations and participant assessments, all studies showed statistically significant improvement in psychosocial well-being and quality-of-life domains with a trend for highest impact when multiple upper facial areas are treated in a multimodal approach.

      Conclusion

      Aesthetic BoNT showed links to true health benefits for well-selected patients in addition to physical amelioration. However, the biological rational remains ambiguous. Well-designed controlled trials are needed, without pharmaceutical laboratories bias, in real clinical scenarios of patients paying for the interventions, often involving multiple areas with/without combined treatments. The persistence of positive outcomes following repetitive treatments provided by less experienced practitioners, potentially involving suboptimal patient selection and/or aesthetic results, warrants further investigation.

      Keywords

      Introduction

      Over the years, there has been a growing number of patients seeking for non-surgical aesthetic procedures,

      American Society of Plastic Surgeons. 2018 Plastic surgery statistics report. 2018. https://www.plasticsurgery.org/documents/News/Statistics/2018/plastic-surgery-statistics-full-report-2018.pdf.

      with motivational factors going beyond the improvement of physical appearance.
      • Waldman A
      • Maisel A
      • Weil A
      • et al.
      Patients believe that cosmetic procedures affect their quality of life: An interview study of patient-reported motivations.
      ,
      • Haas CF
      • Champion A
      • Secor D.
      Motivating factors for seeking cosmetic surgery: A synthesis of the literature.
      In parallel, botulinum toxin (BoNT) formulations are being increasingly used in aesthetics to temporarily weaken the muscles hypercontraction based on the toxin capacity to inhibit the release of neurotransmitter acetylcholine.
      • Camargo CP
      • Xia J
      • Costa CS
      • et al.
      Botulinum toxin type A for facial wrinkles.
      Recently, it has been suggested that using BoNT into the upper face to ameliorate facial aesthetics offers pragmatic advantages in psychological well-being and overall quality of life (QoL), even without changes in attractiveness.
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      Thus, research has been focusing on the approved cosmetic protocol for BoNT, with the potential to improve mood, as an alternative approach for preventing and treat psychological illness.
      • Qian H
      • Shao F
      • Lenahan C
      • Shao A
      • Li Y.
      Efficacy and safety of botulinum toxin vs. Placebo in depression: A systematic review and meta-analysis of randomized controlled trials.
      ,
      • Rudolph C
      • Hladik C
      • Stroup DF
      • et al.
      Are cosmetic procedures comparable to antidepressive medication for quality-of-life improvements? A systematic review and controlled meta-analysis.
      The mechanisms underlying BoNT mood-lifting effect are currently an area of active research.
      • Li Y
      • Liu T
      • Luo W.
      Botulinum neurotoxin therapy for depression: Therapeutic mechanisms and future perspective.
      The prevailing theories encompass the facial feedback hypothesis, structural or functional changes in the brain – upregulation of brain-derived neurotrophic factor, insula cortex alteration, monoamine theory, and neuroinflammation.
      • Schulze J
      • Neumann I
      • Magid M
      • et al.
      Botulinum toxin for the management of depression: An updated review of the evidence and meta-analysis.
      • Kim YJ
      • Kim J-H
      • Lee K-J
      • et al.
      Botulinum neurotoxin type A induces TLR2-mediated inflammatory responses in macrophages.
      • Piotrowska A
      • Popiolek-Barczyk K
      • Pavone F
      • Mika J.
      Comparison of the expression changes after botulinum toxin type A and minocycline administration in lipopolysaccharide-stimulated rat microglial and astroglial cultures.
      • Rojewska E
      • Piotrowska A
      • Popiolek-Barczyk K
      • Mika J
      Botulinum toxin type A-A modulator of spinal neuron-glia interactions under neuropathic pain conditions.
      • Li X
      • Ye Y
      • Zhou W
      • Shi Q
      • Wang L
      • Li T.
      Anti-Inflammatory effects of BoNT/A against complete Freund's adjuvant-induced arthritis pain in rats: Transcriptome analysis.
      The definition of appropriate measures for the evaluation of facial aesthetic intervention outcomes is continuously evolving.
      • Shah P
      • Rieder EA.
      Observer-reported outcomes and cosmetic procedures: A systematic review.
      Historically, an objective clinical assessment has been relying on the investigator focusing on anatomic measurements, standardized photographs, morbidity, and mortality.
      • Shah P
      • Rieder EA.
      Observer-reported outcomes and cosmetic procedures: A systematic review.
      However, a patient-centred approach, in line with the current concept of delivering a high-quality service, also takes into consideration the patient´s perspective and the difference that aesthetic interventions can make to people's QoL and health status.
      • Snyder CF
      • Jensen RE
      • Segal JB
      • Wu AW.
      Patient-reported outcomes (PROs): Putting the patient perspective in patient-centered outcomes research.
      Hence, the development of procedure-specific and validated patient-reported outcome measurements (PROMs) is of singular importance and standard practice of aesthetic research.
      • Chang BL
      • Wilson AJ
      • Taglienti AJ
      • Chang CS
      • Folsom N
      • Percec I.
      Patient perceived benefit in facial aesthetic procedures: FACE-Q as a tool to study botulinum toxin injection outcomes.
      A systematic review (SR) of PROMs for cosmetic indications of BoNT has summarized the psychometrically validated tools currently being used in clinical research.
      • Wang J
      • Rieder EA.
      A systematic review of patient-reported outcomes for cosmetic indications of botulinum toxin treatment.
      Specific for hyperfunctional facial rhytids, the Facial Line Treatment Satisfaction Questionnaire (FTS), Facial Line Outcome (FLO) questionnaire, Facial Line Satisfaction Questionnaire (FLSQ), Self-Perception of Age (SPA)measure, and FACE-Q scales were identified.
      • Wang J
      • Rieder EA.
      A systematic review of patient-reported outcomes for cosmetic indications of botulinum toxin treatment.
      The latter was considered the most promising and comprehensive instrument, and the only tool meeting all the current FDA criteria for PROMs.
      • Kosowski TR
      • McCarthy C
      • Reavey PL
      • et al.
      A systematic review of patient-reported outcome measures after facial cosmetic surgery and/or nonsurgical facial rejuvenation.
      ,
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      Some authors have also started to introduce the observer-reported outcomes (OROs) for a more exhaustive assessment of aesthetic procedure outcomes, taking into account the interpretation of others on the aesthetic patient´s well-being, sociability, skills, and competences.
      • Shah P
      • Rieder EA.
      Observer-reported outcomes and cosmetic procedures: A systematic review.
      While there is robust evidence to demonstrate that cosmetic surgery procedures improved mental health and QoL of treated individuals, from a scientific perspective, less is known regarding the more recent and popular injectable treatments.
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      Considering the ever-broadening range of aesthetic practitioners, with or without clinical background, engaging in BoNT delivery, it is, therefore, essential to evaluate the toxin reportedly compound positive impact on psychological well-being and QoL. The authors aimed to identify, categorize, and critically appraise current literature on the effects of BoNT injections into the upper face, independently or in combination with other treatment modalities, on facial aesthetics, psychological, and social dimensions of health. Thus, potentially promoting a safer and effective routine clinical care. The Best Evidence Topic (BestBETs)

      Best BETs - Best evidence topics and critical appraisal. https://bestbets.org/background/bets-and-cats.php (accessed 16 Dec2021).

      methodology was used with the purpose of answering the clinical question: “In adult patients who are undergoing facial aesthetics does botulinum toxin treatment on upper face improve psychological well-being and QoL?”

      Methodology

      Following the BestBET methodology,

      Best BETs - Best evidence topics and critical appraisal. https://bestbets.org/background/bets-and-cats.php (accessed 16 Dec2021).

      an evidence-based review was performed using the advance search on PubMed (MEDLINE), Cochrane Library of Systematic Reviews, and Central Register of Controlled Trials databases to screen for relevant papers. Supplementary Table-A displays the keywords and Booleans that have been used through the elective search engines.
      An initial scan of the literature on this topic anticipated limited relevant evidence in which the selected studies would be highly heterogeneous, and the outcomes were likely not suitable for a meta-analysis. For this reason, BestBETs methodology, previously fully described in the literature, was considered a suitable format.

      Best BETs - Best evidence topics and critical appraisal. https://bestbets.org/background/bets-and-cats.php (accessed 16 Dec2021).

      ,
      • Khan OA
      • Dunning J
      • Parvaiz AC
      • Agha R
      • Rosin D
      • Mackway-Jones K
      Towards evidence-based medicine in surgical practice: Best BETs.

      Data selection

      Two independent reviewers have systematically searched the databases. Figure 1 illustrates search parameters and results. The analysis yielded 11 relevant studies. These were collected into basic BETs evidence-tables, while categorized and appraised for their quality using the adapted BETs critical appraisal tool. The data extracted and appraised for each study was confirmed by reviewer consensus.
      Figure 1
      Figure 1PRISMA flowchart – search criteria & results.
      Regarding the inclusion criteria, it is worth noting that the study was streamlined to concentrate on the upper face, in areas that have been approved by the FDA for BoNTA cosmetic application. Only the studies using psychometrically validated PROMs specifically for facial rhytids and/or including prospective OROs were selected. The studies reporting the use of BoNT combined with surgical treatments were excluded.

      Study quality and risk of bias assessment

      The relevant studies found by the search strategy were firstly categorized in terms of type of study and level of evidence (LOE), following the study-quality hierarchy criteria based on the latest Oxford Centre for Evidence-Based Medicine ratings.

      OCEBM Levels of Evidence Working Group. The Oxford levels of evidence 2. https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evidence-2.1.pdf (accessed 16 Dec2021).

      Level was graded up/down based on study quality, imprecision, indirectness, inconsistencies, or effect size. We accepted the authors quality classification of their own study or included papers and did not attempt to re-classify them.
      The next step was to evaluate the detailed methodology using the adapted BETs critical appraisal checklist. The risk of bias assessment for included randomized controlled trials (RCTs) was performed according to the Cochrane Methodology for Systematic Reviews of Interventions,

      Cochrane handbook for systematic reviews of interventions. https://training.cochrane.org/handbook/current (accessed 11 Aug2021).

      and expressed in Table 1. The overall risk of bias for each RCT was determined based on the following: (1) low risk, if all domains were scored as “low” or only one as “unclear”; (2) unclear, if two or more domains were estimated “unclear”; and (3) high, if at least one domain was scored as “high”. We accepted the authors of the included SRs own risk of bias assessment for included RCTs and did not attempt to re-classify them.
      Table 1Risk of bias in included RCTs.
      Note: * Attrition bias was evaluated by screening the exclusion criteria and withdrawal.

      Data extraction and outcomes

      Two reviewers independently extracted data on study design, outcomes, and quality. Clinical and patient-related outcomes and adverse events (AEs) were reviewed in detail. When reporting, we extracted data on improvements in psychological well-being and QoL domains. Due to the number of available assessment tools and subscales to this purpose, we concentrated on outcomes most reported in the different studies. Refer to Table 2 for a brief description of the outcomes that were collected and LOE associated, where findings were simplified with symbols to facilitate comparisons. Where reported, statistically significant differences compared with control were simplified to a double plus/minus. Similarly, statistically significant differences compared with baseline were simplified to a single plus/minus.
      Table 2Key outcomes in individual trials.
      First Author, year, LOE RCTIntervention ParticipantsComparison ParticipantsIndicationPatient-Reported Outcome Measurements-PROMs/ToolsAEsFinal Visit
      FACE-Q – Quality of life domainSPAFLSQ (EID)FLO(PI)
      PFSF/CAPDAAVASPW1 itemFollow-up item 5Item 1,4,5
      Ascher, 2019

      LOE-II
      ABO 50U
      Ready-to-use liquid formulation


      (n=125)
      Baseline/Placebo (n=60)M/S

      GL
      ++
      except day 148


      +
      ++
      Most Pronounced effect: “I feel great about myself/I feel attractive/I like myself”
      ,
      Statistically significant correlation with satisfaction with facial appearance FACE-Q scale


      +
      191/189D
      Ogilvie, 2019

      LOE-II
      ONA 20U-GL/20U-FL

      cycle1 (n=290/253 completed)

      cycle 2 (n=265)

      cycle 3 (n=165)
      1-180 days (placebo-controlled, parallel-group: cycle 1), 180-360 days (open-label: cycle 2-40U(n=265)/Placebo(n=84), cycle 3-40U(n=165)/Placebo(n=60)
      Baseline/

      Parallel group/Placebo:

      cycle 1 (n=101/80 completed)

      cycle 2 (n=84)

      cycle 3 (n=60)
      1-180 days (placebo-controlled, parallel-group: cycle 1), 180-360 days (open-label: cycle 2-40U(n=265)/Placebo(n=84), cycle 3-40U(n=165)/Placebo(n=60)
      M/S GL

      FL
      ++
      Statistically significant correlation with satisfaction with facial appearance FACE-Q scale


      +

      ↑ (cycle 2/3 > cycle 1)
      ++
      Statistically significant correlation with satisfaction with facial appearance FACE-Q scale


      +

      ↑ (cycle 2/3 > cycle 1)


      (n=2) Unknown
      360D
      1-180 days (placebo-controlled, parallel-group: cycle 1), 180-360 days (open-label: cycle 2-40U(n=265)/Placebo(n=84), cycle 3-40U(n=165)/Placebo(n=60)
      Rivkin, 2019

      LOE-II
      1. ONA 20U-FL/20U-GL/24U-LCL (n=313/287 completed)

      2. ONA 20U-FL/20U-GL/Placebo-LCL (n=313/

      287 completed)

      cycle 2: 64U(n=295)/ 40U(n=294)

      cycle 3: 64U(n=197)/ 40U(n=212)
      1-180 days (placebo-controlled, parallel-group cycle 1), 180-360 days (open-label: cycle 2-64U(n=295)/40U(n=294)/Placebo(n=139), cycle 3-64U(n=197)/40U(n=212)/Placebo(n=101)
      Baseline/Parallel group/Placebo:

      cycle 1 (n=156/126 completed)

      cycle 2 (n=139)

      cycle 3 (n=101)
      1-180 days (placebo-controlled, parallel-group cycle 1), 180-360 days (open-label: cycle 2-64U(n=295)/40U(n=294)/Placebo(n=139), cycle 3-64U(n=197)/40U(n=212)/Placebo(n=101)
      M/S FL

      GL LCL
      ++
      Statistically significant correlation with satisfaction with facial appearance FACE-Q scale


      +

      ↑ (1 > 2)

      ↑ (cycle 2/3 > cycle 1)
      ++
      Statistically significant correlation with satisfaction with facial appearance FACE-Q scale


      +

      ↑ (1 >2)

      ↑ (cycle 2/3 > cycle 1)
      (n=1) Unknown 360D
      1-180 days (placebo-controlled, parallel-group cycle 1), 180-360 days (open-label: cycle 2-64U(n=295)/40U(n=294)/Placebo(n=139), cycle 3-64U(n=197)/40U(n=212)/Placebo(n=101)
      Palm, 2019

      LOE-II
      ONA 20U-FL/20U-GL/

      24U-LCL or

      ONA 20U-FL/20U-GL (n=921)

      G1(n=139)

      G2(n=782)
      Baseline/Placebo (n=257)

      G1(n=37), G2(n=219)

      Parallel-Age Groups: G1 (<35ys)

      G2 (≥35ys)
      M/S FL

      GL

      MFL
      ++
      Statistically significant correlation with satisfaction with facial appearance FACE-Q scale
      ,
      Both static and dynamic lines;


      +

      ↑ (G1 > G2)
      Higher response rate at a later time
      ,
      Both static and dynamic lines;
      ++
      Statistically significant correlation with satisfaction with facial appearance FACE-Q scale
      ͪ

      +

      ↑ (G1>G2)
      Higher response rate at a later time
      ,
      Both static and dynamic lines;
      Brow ptosis

      G1(n=1)

      G2(n=12)

      180D
      Keaney, 2019

      LOE-II
      ONA 20U-FL/20U-GL/

      24U-LCL or

      ONA 20U-FL/20U-GL (n=140) only males
      Baseline/PlaceboM/S FL++
      Both static and dynamic lines;


      +
      ++
      Both static and dynamic lines;


      +
      6.4% Headaches

      5.4% nasopharyngitis 3.6% haematoma

      3.6% eyelid ptosis 180D
      McKeown, 2021

      LOE-III
      1. ONA (n=6) 64U/40U mean:2.0±0.7 areas

      2. HA
      Hyaluronic Acid (Vycross or Hylacross range)
      (n=23)

      3. ONA + HA (n=6)
      Baseline/Control groupM/S GL

      FL LCL
      +

      ↑3
      +

      ↑3
      +
      Outcome with greatest improvement


      ↑3
      –14D
      Schlessinger2021

      LOE-IV
      ABO 50U (n=120)

      (n=113) + 50U (180D)

      (n=101) + 50U (365D)
      BaselineM/S GL(n=1) linked to procedure - mild bruising
      365D
      Cohen, 2021

      LOE-IV
      HA
      Hyaluronic Acid (Vycross or Hylacross range)
      at 1D

      ONA 20U-GL/24U-LCL at 90D

      Bimatoprost 0.03%

      (n=100/93 completed)
      BaselineM/S

      GL

      LCL

      MEH

      MVL
      ++++2% mild/moderate ONA-related: bruising, local pain, redness, swelling 120D
      Cohen, 2020

      LOE-III
      ABO 50U
      Ready-to-use liquid formulation


      (n=30) 1.5ml reconstitution

      (n=30) 2.5ml reconstitution
      Baseline/Control groupM/S GL+

      NS ᵏ
      +

      NS
      Sustained outcomes despite decrease on efficacy assessment
      –120D
      SR
      First Author, year, LOEInterventionOutcomes & toolsDomainsKey findingsQuality of evidence of the included studies
      Wang, 2019

      LOE-III
      BoNT

      LCL: ONA (2RCTs,n=445),

      ABO (1RCT,n=162)

      GL: ONA (2RCTs, 3CTs,n=325)

      LCL + GL: ONA (4RCTs,n=1726)

      GL + FL + LCL: ONA (1RCT, 1CTs,n=100), INCO (1CT,n=30)

      BoNT + HA

      ABO (1CT,n=20)

      BoNT + HA + LR

      ONA/INCO (2CTs, n=81)
      Patient-Reported Outcome Measurements-PROMs

      Validated tools:

      FTS (1RCT; n=162)

      FTS + SPA (1CT; n=58)

      FLSQ (1RCT; n=125)

      FLO + SPA (8RCTs,1CT; n=2436)

      FLO (1RCT,1CT; n=107)

      SPA (1CT; n=20)

      FACE-Q (3CTs; n=156)

      Undefined Tools: 20T
      • SHL in BoNT patients
      • Impact of upper facial lines on QoL
      • Spa with impact on health outcomes
      • SFA-QoL health related
      • SwC or negative impact of treatment
      LCL - ONA/ABO:

      ++ (QoL, SHL, Spa, SFA)
      NS between formulations
      ,
      Higher response compared to placebo (dose-related manner) Key results
      Not provided
      GL:

      ++ (SHL, Spa)

      + (SwC, SHL, Spa, SFA)
      NS between formulations
      GL + FH + LCL:

      ++ (SHL, QoL, Spa)
      Higher response with multiple areas treated
      ,
      NS between dosages
      BoNT + HA with/without LR:

      ↑ (SHL)BoNTA + HA>BoNTA

      ↑ SFA, PW, Spa, SF/C
      Shah, 2020

      LOE-IV
      24T (n=686), 8257 observations

      Surgical procedures and

      Minimally invasive:

      BoNT

      BoNT + HA + Cosmeceuticals (1RCT)
      Observer-Reported Outcomes-OROs

      Non-validated tools: FIQ (4T), distinct self-developed ORO tools (20T)
      • Aesthetics and Wellness (age, attractiveness, health)
      + (Health, PSD, GFI)
      • 17/24T of retrospective design, only 3/17 with untreated control.
      • 1/24 RCT, 6/24 prospective CTs.
      • High risk of reporting and systematic bias.
      • Overall, low to moderate quality of evidence.
      • Social capacities (trustworthiness, confidence, sociability, relationships)
      + (SA, PSS, L&F, Ap)

      ↑ (RPS, PT&C)
      • Skills and Competences (scholastics, athletics, occupation, finances)
      + (O&F, PA&S)

      ++ (PI)
      Higher response with multimodal approach


      NS (Sc)
      ++, statistically significantly improvement with Botulinum Toxin (BoNT) compared to placebo; +, statistically significantly improvement with BoNT compared to baseline; NS, no statistically significant difference between the therapy regimens; –: Outcome not reported; ↑, Relative improvement seen in outcome, but no statistical analysis performed.
      LOE, Level of evidence; SPA, Self-Perception of Age questionnaire; FLSQ(EID), Facial Line Satisfaction Questionnaire (Emotional Impact Domain); FLO(PI), Facial Line Outcome (Psychological Impact) questionnaire; FTS, Facial Lines Treatment Satisfaction-questionnaire; AEs, Adverse Effects; ABO, AboBotulinum Toxin; ONA, OnaBotulinum Toxin; INCO, IncoBotulinum Toxin; PF, Psychological Function; SF/C, Social Function or Confidence; APD, Appearance-related Psychological Distress; AAVAS, Age Appraisal Visual Analogue Scale; PW, Psychological Well-being; M/S, Moderate to Severe; GL, Glabella Lines; FL, Forehead Lines; LCL, Lateral Canthus Lines; G, Groups; D, days; MFL; Mild/less severe Forehead Lines at rest; MEH, Minimal Eyelash Hypotrichosis; MVL; Midface Volume Loss; LR, Laser Resurfacing; T, Trials; QoL, Quality of Life; FIQ, First Impression Questionnaire; PSD, Perceived Sexual Dysmorphism; GFI, General First Impression; SA; Social Anxiety; PSS, Perception of Social Skills; L&F, Likeability and friendliness; Ap, Approachability – except perception of kindness or extroversion; RPS, Relationships Perceived Success; PT&C, Perceived Trustiness and Confidence; O&F, Occupation and Finance; PA&S, Perceived Athletics and Success; Sc, Scholastics; PI, Perception of intelligence; Spa, Self-Perceived Age; SHL, Satisfaction with hyperdynamic lines; SFA, Satisfaction with facial appearance; SwC, Satisfaction with care.
      a Ready-to-use liquid formulation
      b except day 148
      c Most Pronounced effect: “I feel great about myself/I feel attractive/I like myself”
      d Statistically significant correlation with satisfaction with facial appearance FACE-Q scale
      e 1-180 days (placebo-controlled, parallel-group: cycle 1), 180-360 days (open-label: cycle 2-40U(n=265)/Placebo(n=84), cycle 3-40U(n=165)/Placebo(n=60)
      f 1-180 days (placebo-controlled, parallel-group cycle 1), 180-360 days (open-label: cycle 2-64U(n=295)/40U(n=294)/Placebo(n=139), cycle 3-64U(n=197)/40U(n=212)/Placebo(n=101)
      g Higher response rate at a later time
      h Both static and dynamic lines;
      i Hyaluronic Acid (Vycross or Hylacross range)
      j Outcome with greatest improvement
      k Sustained outcomes despite decrease on efficacy assessment
      l NS between dosages
      m NS between formulations
      n Higher response with multiple areas treated
      o Higher response with multimodal approach
      p Higher response compared to placebo (dose-related manner)Key results

      Data analysis and reporting

      The included studies were summarized in a BestBET table, providing the relevant data of each study. Data were reported according to the PRISMA guidelines.
      • Moher D
      • Shamseer L
      • Clarke M
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      Evidence was judged “high”, “moderate”, or “low” based on the conclusions of included studies and overall quality and risk of bias assessed.

      Results

      Data extraction

      See Figure 1 for the PRISMA flowchart for data abstracted.
      • Moher D
      • Shamseer L
      • Clarke M
      • et al.
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      Supplementary Table-B, illustrates the 11 relevant studies identified, considering its relevance, reliability, and credibility, based on those suggested by the latest Oxford Centre for Evidence-Based Medicine LOE.

      OCEBM Levels of Evidence Working Group. The Oxford levels of evidence 2. https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evidence-2.1.pdf (accessed 16 Dec2021).

      Supplementary Table-C presents the domains of adapted BETs critical appraisal worksheets used with an assessment for each study. Figure 2 displays the key outcomes from a clinical perspective.
      Figure 2
      Figure 2Key outcomes - clinical translation.

      Characteristics of included studies

      Eleven studies, including five double-blind, placebo-controlled RCTs, were performed in multicentre and enrolled 2681 participants (2520 completed),
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      ,
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      two SRs,
      • Shah P
      • Rieder EA.
      Observer-reported outcomes and cosmetic procedures: A systematic review.
      ,
      • Wang J
      • Rieder EA.
      A systematic review of patient-reported outcomes for cosmetic indications of botulinum toxin treatment.
      and four clinical trials (CTs) representing 335 participants (308 completed),
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      ,
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      receiving different BoNT preparations and dosages, administered either individually, combined with dermal fillers or in a multimodal approach met the inclusion criteria and were included.
      Of the two SR, one evaluated PROMs including studies presenting validated measurements tools (FTS, 2-studies; FLSQ, 1-study; FLO, 11-studies; SPA, 11-studies; and FACE-Q, 3-studies) and undefined scales, without providing a study quality or risk of bias assessment;
      • Wang J
      • Rieder EA.
      A systematic review of patient-reported outcomes for cosmetic indications of botulinum toxin treatment.
      18 of the included studies met the eligibility criteria, 10 RCTs,
      • Lowe NJ
      • Ascher B
      • Heckmann M
      • et al.
      Double-blind, randomized, placebo-controlled, dose-response study of the safety and efficacy of botulinum toxin type A in subjects with crow's feet.
      • Rivers JK
      • Bertucci V
      • McGillivray W
      • et al.
      Subject satisfaction with onabotulinumtoxinA treatment of glabellar and lateral canthal lines using a new patient-reported outcome measure.
      • Beer KR.
      Comparative evaluation of the safety and efficacy of botulinum toxin type A and topical creams for treating moderate-to-severe glabellar rhytids.
      • Carruthers J
      • Carruthers A.
      Botulinum toxin type A treatment of multiple upper facial sites: Patient-reported outcomes.
      • Fagien S
      • Cox SE
      • Finn JC
      • Werschler WP
      • Kowalski JW.
      Patient-reported outcomes with botulinum toxin type A treatment of glabellar rhytids: A double-blind, randomized, placebo-controlled study.
      • Carruthers A
      • Bruce S
      • de Coninck A
      • et al.
      Efficacy and safety of onabotulinumtoxinA for the treatment of crows feet lines: A multicenter, randomized, controlled trial.
      • Dayan S
      • Coleman WP
      • Dover JS
      • et al.
      Effects of OnabotulinumtoxinA treatment for crow's feet lines on patient-reported outcomes.
      • Moers-Carpi M
      • Carruthers J
      • Fagien S
      • et al.
      Efficacy and safety of onabotulinumtoxinA for treating crow's feet lines alone or in combination with glabellar lines: A multicenter, randomized, controlled trial.
      • Carruthers J
      • Rivkin A
      • Donofrio L
      • et al.
      A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of repeated onabotulinumtoxinA treatments in subjects with crow's feet lines and glabellar lines.
      • Solish N
      • Rivers JK
      • Humphrey S
      • et al.
      Efficacy and safety of onabotulinumtoxinA treatment of forehead lines: A multicenter, randomized, dose-ranging controlled trial.
      4 cohort studies,
      • Chang BL
      • Wilson AJ
      • Taglienti AJ
      • Chang CS
      • Folsom N
      • Percec I.
      Patient perceived benefit in facial aesthetic procedures: FACE-Q as a tool to study botulinum toxin injection outcomes.
      ,
      • Stotland MA
      • Kowalski JW
      • Ray BB.
      Patient-reported benefit and satisfaction with botulinum toxin type A treatment of moderate to severe glabellar rhytides: Results from a prospective open-label study.
      • Carruthers A
      • Carruthers J.
      A single-center dose-comparison study of botulinum neurotoxin type A in females with upper facial rhytids: Assessing patients’ perception of treatment outcomes.
      • Streker M
      • Luebberding S
      • Krueger N
      • Harrington L
      • Kerscher M.
      Patient-reported outcomes after incobotulinumtoxinA treatment for upper facial wrinkles.
      and 4 case-series.
      • Beer KR
      • Boyd C
      • Patel RK
      • Bowen B
      • James SP
      • Brin MF.
      Rapid onset of response and patient-reported outcomes after onabotulinumtoxinA treatment of moderate-to-severe glabellar lines.
      • Beer KR
      • Julius H
      • Dunn M
      • Wilson F.
      Remodeling of periorbital, temporal, glabellar, and crow's feet areas with hyaluronic acid and botulinum toxin.
      • Hibler BP
      • Schwitzer J
      • Rossi AM.
      Assessing improvement of facial appearance and quality of life after minimally-invasive cosmetic dermatology procedures using the FACE-Q scales.
      • Qureshi AA
      • Parikh RP
      • Sharma K
      • Myckatyn TM
      • Tenenbaum MM.
      Nonsurgical facial rejuvenation: Outcomes and safety of neuromodulator and soft-tissue filler procedures performed in a resident cosmetic clinic.
      The other SR focused on OROs,
      • Shah P
      • Rieder EA.
      Observer-reported outcomes and cosmetic procedures: A systematic review.
      yet to have validated measurement tools, in which the majority of included studies were of retrospective design and used the First Impression Questionnaire (FIQ); only one RCT and 6 prospective interventional trials were included,
      • Dayan S
      • Rivkin A
      • Sykes JM
      • et al.
      Aesthetic treatment positively impacts social perception: Analysis of subjects from the HARMONY study.
      • Dayan SH
      • Arkins JP
      • Patel AB
      • Gal TJ.
      A double-blind, randomized, placebo-controlled health-outcomes survey of the effect of botulinum toxin type a injections on quality of life and self-esteem.
      • Dayan SH
      • Lieberman ED
      • Thakkar NN
      • Larimer KA
      • Anstead A.
      Botulinum toxin a can positively impact first impression.
      • Fink B
      • Prager M.
      The effect of incobotulinumtoxin a and dermal filler treatment on perception of age, health, and attractiveness of female faces.
      • Dayan SH
      • Bacos JT
      • Ho T-VT
      • Gandhi ND
      • Gutierrez-Borst S
      • Kalbag A.
      Topical skin therapies in subjects undergoing full facial rejuvenation.
      presenting moderate to low quality of evidence due to systematic bias and high risk of selection bias reported.
      Of the nine individual trials,
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      ,
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      ,
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      the final assessment has ranged between 2-week to 12-month. Initial assessments were performed at 1-week in four studies, at 2-week in one study, and after 4-week in the remaining studies. OnaBoNT formulations were favoured, with doses varying between 64U-40U, depending on the targeted areas. Only one RCT and two CTs used AboBoNT preparations,
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      ,
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      ,
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      two trials reported using ready-to-use 50U liquid solutions, with one study comparing two different reconstitution approaches (1.5 ml versus 2.5 ml).
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      All trials compared the tested treatment versus baseline. While five studies used FACE-Q tool for outcome assessments,
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      ,
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      ,
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      only one was a RCT.
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      The remaining four RCTs used both FLSQ and FLO measurement tools.
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      Sample sizes ranged from 35–1178 among 3016 participants (466 males, 2490 females, and 60 unknown). Inclusion criteria varied among the studies, ranging between participants with mild, moderate to severe hyperdynamic lines, including glabella, forehead, and/or lateral canthus areas. One study included participants with also moderate to severe midface volume loss and eyelash hypotrichosis to evaluate a multimodal facial rejuvenation approach, including BoNT, hyaluronic acid filler (HA), and bimatoprost-0.03%.
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      One study was based on male-only population,
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      seven studies on male–female populations,
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      ,
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      ,
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      ,
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      and one study did not specify participants’ gender.
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      Four RCTs targeted specifically participants naive to injectable treatments (n=2449),
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      while two CTs also reported 60 participants unknown to BoNT among a study sample of 155.
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      ,
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      When reporting age, seven studies presented the included age range that was between 18–77 years.
      No meta-analysis could be performed due to the great heterogeneity of the preparations, study metrics, and outcomes.

      Study quality and risk of bias

      Of the 11 included studies, five were of LOE-II,
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      ,
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      three were of LOE-III,
      • Wang J
      • Rieder EA.
      A systematic review of patient-reported outcomes for cosmetic indications of botulinum toxin treatment.
      ,
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      ,
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      and three were of LOE-IV (see Figure 3).
      • Shah P
      • Rieder EA.
      Observer-reported outcomes and cosmetic procedures: A systematic review.
      ,
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      ,
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      The two SRs included were downgraded to LOE-III/-IV due to the inclusion of studies relying on non-validated outcome tools, as well as methodological inconsistencies (summary of the evidence was not provided, or a meta-analysis was not undertaken without reasons, or unclear if/how the study-quality and/or risk of bias assessment was performed); see Figure 4 and Figure 5. All five LOE-II randomized studies were double-blind and placebo-controlled; one had a parallel group control for BoNT injections into orbicularis oculi muscles,
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      two compared outcomes either between age groups or single versus repetitive applications.
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      ,
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      Funding conflicts could not be ruled out for all studies, except for the most recent single centre cohort study presenting a small sample size and relatively short follow-up of 6-month.
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      Risk of bias was evaluated in the five RCTs (see Table 1). All trials had a risk that was estimated low. However, although dropouts were relatively low across the trials and largely unrelated to AEs from the study treatment, attrition bias was estimated unclear for two studies due to loss to follow-up that may have created an imbalance between groups and sample-size numbers. Reporting bias was estimated unclear for three RCTs owning to crossover limitations and insufficient information to permit judgement.
      Figure 3
      Figure 3Included individual studies - characteristics and quality - level of evidence - Oxford centre for evidence-based medicine 2011 ratings.
      Abbreviations: LOE, Level of Evidence; PF, Psychological Function (FACE-Q); SF/C, Social Function or Confidence (FACE-Q); APD, Appearance-Related Psychological Distress (FACE-Q); AAVAS, Age Appraisal Visual Analogue Scale (FACE-Q); PW, Psychological Well-being (FACE-Q); SPA, Self-Perception of Age questionnaire; FLSQ(EID), Facial Line Satisfaction Questionnaire-Emotional Impact Domain; FLO(PI), Facial Line Outcome -Psychological Impact questionnaire.
      KEY. Oxford Centre for Evidence-Based Medicine 2011 ratings.
      LOE-I: Systematic review (SR) of randomized trials (RCTs) or n-of-1 trials.
      LOE-II: Individual RCTs or observational study with dramatic effect.
      LOE-III: SR of non-randomized controlled cohort/follow-up study (or individual studies).
      LOE-IV: SR of case-series, case-control studies, or historically controlled studies (or individual studies).
      LOE-V: Mechanism-based reasoning or expert opinion.
      Figure 4
      Figure 4. Included systematic review by Wang, 2019 - characteristics - level of evidence III - Oxford centre for evidence-based medicine 2011 ratings.
      Abbreviations: PROMs, Patient-Reported Outcome measures; T, Trials; RCT, Randomized Controlled Trial; CT, Clinical Trial; SPA, Self-Perception of Age questionnaire; FLSQ, Facial Line Satisfaction Questionnaire; FLO, Facial Line Outcome questionnaire; FTS, Facial Line Treatment Satisfaction questionnaire
      Figure 5
      Figure 5. Included systematic review by Shah, 2020 - characteristics - level of evidence IV - Oxford centre for evidence-based medicine 2011 ratings.
      Abbreviations: ORO, Observer-Reported Outcomes; T, Trials; FIQ, First Impression Questionnaire

      Quality of life outcome assessment

      For evaluating BoNT performance on social and psychological well-being, five studies used FACE-Q for outcome assessments (PROMs).
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      ,
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      ,
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      This consists of 41 independently functioning scales overarching four main domains: (1) AEs, (2) facial appearance, (3) process of care, and (4) QoL. Specific questionnaires reported have included psychological function (2-studies), social function or confidence (2-studies), appearance-related psychological distress (1-study), age-appraisal visual analogue scale (VAS) (3-studies), psychological well-being (3-studies), overall satisfaction with facial appearance (1-study), ageing appearance appraisal (2-studies), appraisal of lines (1-study), appraisal of lines between the eyes (1-study); noteworthy that satisfaction with facial appearance, ageing appearance or lines appraisal scales do not pertain to the QoL domain. Of the five trials using FACE-Q (QoL) scales, one CT have also used SPA (1-item scale) to evaluate its impact on health outcomes.
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      Four RCTs reported the use of two measurement tools: FLSQ (emotional impact domain, follow-up item 5) and the FLO (items-1, -4, -5, psychological impact domain).
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      The FLSQ incorporates 11-items for baseline and 13-items for the follow-up version, while the FLO tool has been shortened from 11-items to 7-items. The SR evaluating OROs grouped the study into three domains—(1) aesthetics and wellness, (2) social capacities, and (3) skills and competences. For the qualitative analysis, most included studies used the FIQ scale. The SR focusing on PROMs included studies using FTS (2-studies), FLSQ (1-study), FLO (11-studies), SPA (11-studies), and FACE-Q scales (3-studies). Overall, the scale dissimilarity created difficulty in comparing scores across studies. Six studies reported safety assessment. The statistical evaluation of BoNT treatments were reported in eight trials.
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      ,
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      ,
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      ,
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      These included comparative analysis of BoNT treatment group against baseline, or versus placebo, and/or an active control group. The descriptive statistics was performed in five trials.
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      ,
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.

      Quality of life outcomes

      Table 2 summarizes the key outcomes in the individual trials and SRs for PROMs and OROs outcomes, as well as AEs using the symbols described above. Full details of the outcomes reported in each trial are provided in Supplementary Table-B.

      Patient-reported outcome measurements

      Face-Q (QoL domain)

      Five studies used FACE-Q for outcome assessments (PROMs) in 498 participants (1-RCT, 4-CTs). Additionally, three CTs included in the SR reported this tool for evaluation in 156 participants (Table 2).
      • Chang BL
      • Wilson AJ
      • Taglienti AJ
      • Chang CS
      • Folsom N
      • Percec I.
      Patient perceived benefit in facial aesthetic procedures: FACE-Q as a tool to study botulinum toxin injection outcomes.
      ,
      • Hibler BP
      • Schwitzer J
      • Rossi AM.
      Assessing improvement of facial appearance and quality of life after minimally-invasive cosmetic dermatology procedures using the FACE-Q scales.
      ,
      • Qureshi AA
      • Parikh RP
      • Sharma K
      • Myckatyn TM
      • Tenenbaum MM.
      Nonsurgical facial rejuvenation: Outcomes and safety of neuromodulator and soft-tissue filler procedures performed in a resident cosmetic clinic.
      A numerical improvement in QoL at the end of each trial with BoNT preparations (OnaBoNT, AboBoNT, and IncoBoNT) versus baseline or versus placebo was reported in all trials. The only RCT found showed a statistically significant improvement in psychological well-being and age appraisal VAS from baseline and compared to their placebo-control, except for day 148.
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      The most pronounced effect was demonstrated for “I feel ok or great about myself/I feel attractive/I like myself”. This study also reported a statistically significant correlation between QoL outcomes with satisfaction with facial appearance FACE-Q scale outcomes.
      • Ascher B
      • Rzany B
      • Kestemont P
      • et al.
      Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
      The remaining CTs showed statistically significant improvement in psychological and social function or confidence, as well as appearance-related psychological distress, age appraisal VAS and psychological well-being. These were evaluated for different BoNT injection sites, dosages, or formulations (OnaBoNT 64U or 40U; AboBoNT 50U), for a single or repetitive 6-month treatments, either applied independently or combined with HA with/without bimatoprost-0.03%. From the two Level-III controlled CTs, showing statistically significant improvement from baseline, one demonstrated no statistically significance between two different reconstitutions (1.5 ml and 2.5 ml) of AboBoNT and reported sustained positive effects despite the decrease on efficacy assessment,
      • Cohen JL
      • Kaufman J
      • Peredo MI
      • Down R
      • Mashburn J.
      Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
      while the other study revealed that appearance-related psychological distress was the outcome with greatest improvement.
      • McKeown DJ.
      Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
      Overall, CTs showed mean ameliorations in favour of repetitive BoNT treatments and multimodal approaches but did not report any formal statistical analysis for the observed changes from baseline. The results of individual trials were in line with the FACE-Q outcomes from the three CTs (2-case-series and 1-cohort) included in the SR by Wang et al.,
      • Wang J
      • Rieder EA.
      A systematic review of patient-reported outcomes for cosmetic indications of botulinum toxin treatment.
      which confirmed an improvement in psychological well-being, social functioning, perception of younger age with impact on health outcomes, and satisfaction with facial appearance (Table 2).

      SPA-Self-Perception of Age , FLSQ(EID)Facial Line Satisfaction Questionnaire (Emotional Impact Domain), FLO(PI)-Facial Line Outcome (Psychological Impact)

      SPA, FLSQ(EID), and FLO(PI) questionnaires for PROMs evaluation were used in 2178 participants from five individual studies (4 RCTs and 1 CT),
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      ,
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      ,
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      and in 2908 participants from 15 studies (11 RCTs and 4 CTs) included in the SR (Table 2).
      • Lowe NJ
      • Ascher B
      • Heckmann M
      • et al.
      Double-blind, randomized, placebo-controlled, dose-response study of the safety and efficacy of botulinum toxin type A in subjects with crow's feet.
      • Rivers JK
      • Bertucci V
      • McGillivray W
      • et al.
      Subject satisfaction with onabotulinumtoxinA treatment of glabellar and lateral canthal lines using a new patient-reported outcome measure.
      • Beer KR.
      Comparative evaluation of the safety and efficacy of botulinum toxin type A and topical creams for treating moderate-to-severe glabellar rhytids.
      • Carruthers J
      • Carruthers A.
      Botulinum toxin type A treatment of multiple upper facial sites: Patient-reported outcomes.
      • Fagien S
      • Cox SE
      • Finn JC
      • Werschler WP
      • Kowalski JW.
      Patient-reported outcomes with botulinum toxin type A treatment of glabellar rhytids: A double-blind, randomized, placebo-controlled study.
      • Carruthers A
      • Bruce S
      • de Coninck A
      • et al.
      Efficacy and safety of onabotulinumtoxinA for the treatment of crows feet lines: A multicenter, randomized, controlled trial.
      • Dayan S
      • Coleman WP
      • Dover JS
      • et al.
      Effects of OnabotulinumtoxinA treatment for crow's feet lines on patient-reported outcomes.
      • Moers-Carpi M
      • Carruthers J
      • Fagien S
      • et al.
      Efficacy and safety of onabotulinumtoxinA for treating crow's feet lines alone or in combination with glabellar lines: A multicenter, randomized, controlled trial.
      • Carruthers J
      • Rivkin A
      • Donofrio L
      • et al.
      A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of repeated onabotulinumtoxinA treatments in subjects with crow's feet lines and glabellar lines.
      • Solish N
      • Rivers JK
      • Humphrey S
      • et al.
      Efficacy and safety of onabotulinumtoxinA treatment of forehead lines: A multicenter, randomized, dose-ranging controlled trial.
      • Stotland MA
      • Kowalski JW
      • Ray BB.
      Patient-reported benefit and satisfaction with botulinum toxin type A treatment of moderate to severe glabellar rhytides: Results from a prospective open-label study.
      • Carruthers A
      • Carruthers J.
      A single-center dose-comparison study of botulinum neurotoxin type A in females with upper facial rhytids: Assessing patients’ perception of treatment outcomes.
      • Streker M
      • Luebberding S
      • Krueger N
      • Harrington L
      • Kerscher M.
      Patient-reported outcomes after incobotulinumtoxinA treatment for upper facial wrinkles.
      • Beer KR
      • Boyd C
      • Patel RK
      • Bowen B
      • James SP
      • Brin MF.
      Rapid onset of response and patient-reported outcomes after onabotulinumtoxinA treatment of moderate-to-severe glabellar lines.
      • Beer KR
      • Julius H
      • Dunn M
      • Wilson F.
      Remodeling of periorbital, temporal, glabellar, and crow's feet areas with hyaluronic acid and botulinum toxin.
      A statistically significant improvement in FLSQ and FLO emotional and psychological domains versus baseline or placebo was reported in the four RCTs, regardless of age or gender, with a statistical improvement from baseline in a further CT study based on SPA questionnaire report.
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      Three RCTs have also demonstrated statistically significant correlation between high satisfaction rates and amelioration in negative psychosocial impacts with clinical effectiveness.
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      A numerical incremental improvement without any formal statistical assessment was observed for repetitive treatments, addition of lateral canthus injections to the treatment plan, and in younger patients (<35 years). The 15 studies included in the SR by Wang et al.
      • Wang J
      • Rieder EA.
      A systematic review of patient-reported outcomes for cosmetic indications of botulinum toxin treatment.
      were aligned with the outcomes of individual trials (Table 2). Overall, it demonstrated statistically significant clinical benefits of BoNT therapy, in a dose-dependent manner, on QoL health related in terms of mood, attractiveness, or confidence, self-perceived age with impact on physical functioning, QoL and mental health, and satisfaction, compared to baseline or placebo. These were confirmed where either targeting one or more upper facial areas, without significant difference among BoNT preparations. A numerical higher improvement was observed in a dual approach combining BoNT and HA compared to BoNT therapy alone or when targeting multiple upper facial areas.

      Observer-reported outcomes

      First impression questionnaire and distinct self-developed tools

      OROs using FIQ and 41 distinct self-developed tools were used in 24 studies included in the SR by Shah et al. (Table 2).
      • Shah P
      • Rieder EA.
      Observer-reported outcomes and cosmetic procedures: A systematic review.
      Overall, a total of 686 participants were evaluated, and 8257 observations were performed in the context of surgical and minimally invasive aesthetic treatments. Particularly for BoNT therapy, only one RCT for repetitive and combined approach with HA, and 6 prospective interventional trials were identified. All studies showed a statistically significant improvement in one or more of the post-treatments measured parameters in each domain, including aesthetic and wellness (perception of attractiveness, sexual dysmorphism, health, age, and general first impression), social capacities (social anxiety, perception of social skills, friendliness, likeability, and approachability), and skills and competences (occupation, finance, and perception of intelligence). A dose response-like relationship between repetitive combined treatments and wellness was also reported in one high-quality included trial.
      • Fink B
      • Prager M.
      The effect of incobotulinumtoxin a and dermal filler treatment on perception of age, health, and attractiveness of female faces.
      Limited studies showed mixed results in achieving statistically significance changes in scholastics, perception of kindness, and extroversion, while there was limited evidence to demonstrate the reported statistical significance in improvements of perceived trustworthiness, confidence, athletic ability, and relationship success.

      Safety outcomes

      AEs were assessed in six studies (2141 participants) (Table 2). Two RCTs reported 3 unknown AEs from a sample of 860 participants.
      • Ogilvie P
      • Rivkin AZ
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
      ,
      • Rivkin AZ
      • Ogilvie P
      • Dayan S
      • Yoelin SG
      • Weichman BM
      • Garcia JK.
      OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
      One RCT reported 13 brow ptosis among 921 participants, of which only one subject was below 35 years old.
      • Palm MD
      • Few J
      • Patel T
      • et al.
      Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
      Mild AEs were observed in one RCT and two CTs (n=360).
      • Keaney TC
      • Cavallini M
      • Leys C
      • et al.
      Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
      ,
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      ,
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
      In one CT, there was only 1 case of mild bruising considered to be linked with BoNT procedure.
      • Schlessinger J
      • Cohen JL
      • Shamban A
      • et al.
      A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
      Another CT reported 2% of 100 participants suffering from mild to moderate AEs, including bruising, local pain, redness, and swelling. A further RCT showed mild self-limiting AEs of headaches, nasopharyngitis, haematoma, and eyelid ptosis.
      • Cohen JL
      • Rivkin A
      • Dayan S
      • et al.
      Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.

      Discussion

      This evidence-based review was performed to provide a summary of the available evidence concerning the impact of BoNT injections into the upper face, as a sole treatment or in combination with other modalities on facial aesthetics, psychological well-being, and QoL. The current evidence of BoNT clinical effects in this context comes largely from level-II/III/IV studies relying on qualitative data. In general, most studies included in this review reported positive results for each of the key outcomes assessed. However, there was a high degree of heterogeneity in the assessment of study outcomes across all studies. Publication bias cannot be ruled out and may account for the positive results presented in all the identified studies. Moreover, there was only one single centre cohort study with a small sample size not funded by a pharmaceutical laboratory, which may have impacted the magnitude of perceived benefit. Although it was not the purpose of this review, it was reassuring to confirm the safety profile of BoNT therapy, with a low number of AEs reported.
      The validity of an evidence-based review is largely dependent on the study design and quality of the included studies. There was considerable variability in the assessment of outcomes supported on few different assessment tools focusing on various QoL domains among the included studies. This anticipated heterogeneity meant that a meta-analysis could not be conducted. The key parameters assessed for improvements in psychosocial well-being and health-related QoL using different BoNT preparations and treatment approaches, considering the patients reports, were change in psychological function and well-being, including mood, perceived attractiveness, fresh or balanced look and self-confidence, social function, age appraisal and satisfaction with upper facial lines or appearance with impact on emotional health and QoL outcomes, satisfaction with care, or negative effects of intervention. The outcomes most reported considering the observers’ perspectives assessment were change in perceived age, attractiveness, health, trustworthiness, confidence, sociability, relationships success, scholastics, athletics, occupation, and finances. However, it is well-recognized that the definition of appropriate measures in the aesthetics world and the perception of “facial beauty” is rather complex, continuously evolving,
      • Shah P
      • Rieder EA.
      Observer-reported outcomes and cosmetic procedures: A systematic review.
      and therefore difficult to achieve irrefutable conclusions.
      The five included RCTs, representing the strongest LOE supporting the beneficial impact of BoNT formulations on PROMs, while demonstrating improvements in participants satisfaction with self-image and QoL post-treatment, were double-blinded and placebo-controlled with blinded assessment of study outcomes. Among the included RCTs, risk of bias was generally low. However, only one RCT used FACE-Q scales, which is currently considered the most promising tool in aesthetic clinical investigation among the identified psychometrically validated tools.
      • Wang J
      • Rieder EA.
      A systematic review of patient-reported outcomes for cosmetic indications of botulinum toxin treatment.
      All the trials employing patient-reported assessment validated scales reported data showing a consistent statistically improvement in psychosocial well-being, functionality, and QoL. This was proven for different BoNT formulations in a dose-dependent manner, across gender, skin types, and age. More limited data and without a formal statistically analysis were reported for repetitive treatments and multimodal approaches. Nevertheless, patient-reported incremental improvements were confirmed and largely consistent with clinical effectiveness, facial appearance objective, or subjective measurements. One study focusing on male-only participants presented contradictory results, where less clinical effectiveness in facial lines severity did not preclude significant high satisfaction with BoNT therapy with proven statistically significant improvements in appearance-related emotional impacts achievements. This may put an end to previous controversy surrounding the lack of correlation between high patient satisfaction commonly being reported and improvements in psychosocial well-being. Younger patients were shown to benefit the most regarding satisfaction rates and facial appearance negative impacts. However, the duration of benefit is not fully defined, despite some studies reported a rapid onset with sustained improvement beyond aesthetic effects. This may further elucidate on the different motivators underlying the desire for aesthetic treatment, as well as on the importance of a good patient selection to optimize the outcomes.
      Overall, the results of the four CTs (2 Level-III, 2 Level-IV) were consistent and supportive of the findings seen in the RCTs. The two Level-III CTs presented a control group, one showed no statistically significant difference in PROMs between distinct AboBoNT reconstitution, whereas the other corroborated a treatment difference in favour of a combined approach with HA versus the use of HA or BoNT alone. The results are not unexpected considering that a multimodal approach may address different aesthetic concerns.
      With regards to the prospective SR centred on OROs to evaluate the impact of BoNT therapy in psychosocial domains, most included studies were of retrospective design, without active control groups or placebo. None of the questionnaires used appear to have been validated yet. Only one RCT combining BoNTA and HA could be found, which provided the highest evidence. Considering that OROs in aesthetic medicine are a relatively new concept, not surprisingly limited evidence exists, with overall quality presented as low to moderate; hence, the results should be interpreted with caution. However, it is worth noting that it was demonstrated statistically significance in many outcomes reflecting the domains of aesthetic and wellness, social capacities, and skills and competence, following BoNT interventions. A formal validation of OROs tool may prove beneficial to a more comprehensive analysis, and meaningful results regarding BoNT therapy impacts beyond aesthetic amelioration.
      To the authors’ knowledge, this is the first evidence-based review summarizing the results regarding the impact of BoNT in psychosocial well-being and QoL, including both PROMs and OROs evaluations, while also providing a clear assessment of study quality and risk of bias. This article may contribute to promote a more coherent manner for measuring BoNT treatment impact. The authors highlighted limitations of the study designs, including the sample populations (predominantly Caucasian females and limited reporting of ethnicity), lack of studies free from any financial conflicts and representing real clinical scenarios, with less experienced injectors delivering BoNT treatment and potentially with less practice in appropriate patient selection or achievement of ideal aesthetic results. This review concentrated on the use of BoNT for upper facial aesthetics. Expanding the targeted areas (e.g., lower face) or indications (e.g., scar management, jawline sculpting, and hypertrophic masseters), where BoNT has been used off-label to improve aesthetics, may consolidate the results reported in this review.

      Limitations

      Limitations of the present evidence-based review are recognized. The authors acknowledged that the search was conducted using limited databases. Thus, it is possible that some evidence may have been missed. The inclusion/exclusion criteria may have limited other BoNT applications of interest able to amplify the results. By accepting the results of the included SRs regarding the own judgement of quality and risk of bias assessment for the included primary studies or by excluding these from individual analysis, there is the risk of over generalization of results. Finally, challenges exist to evaluate the impact of aesthetic interventions on psychological well-being and QoL, and there were limited high-quality studies using FACE-Q(QoL) domain tools, which is currently seen as the most suitable instrument in this context.

      Future directions

      Future studies may help to determine which patient physical characteristics (e.g., ethnicity and severity of facial aesthetic concern) or psychological motivator factor for BoNT aesthetic treatment (e.g., appearance-related psychological distress or self-confidence) best predict a positive response. The persistent of benefit in mental and social well-being following BoNT treatment, particularly when involving associated costs and practitioners with less experience, with/without clinical background, remains to be elucidated. Validated PROMs and patient-reported experience measures may also be useful to understand how aesthetic practitioners’ performance, including communication skills and ability to interpret the motivator factors behind their patients’ desire for BoNT interventions, may influence post-treatment QoL domains outcomes in comparison with clinical effectiveness in ameliorating facial aesthetics. The validation of OROs instruments may help to a more thorough evaluation. Features that may be helpful to define in future studies include the biological rational behind BoNT links to true health, with validated objective measurement tools for assessment (e.g., degree of appearance-related psychological distress). This is essential considering the recent advancements in our knowledge regarding BoNT mechanism of action. Understanding the mechanisms behind the positive effect of BoNT aesthetic therapy on psychosocial dimensions of health may expand its clinical applications. One example is the current research on BoNT aesthetic protocol in depression, anxiety, and stress management. Research may potentially be extended to any medical condition where appearance-related psychological illness may cause or contribute to disease progression (e.g., periodontal diseases).

      Conclusion

      Overall, based on qualitative data, all level-II/-III/-IV studies showed numerical or statistically significant improvement in psychological well-being and QoL domains, with a trend for the highest significant impact when multiple areas are treated in a multimodal approach. BoNT for upper facial aesthetics showed links to true health benefits to well-selected patients in addition to aesthetic amelioration and was consistently associated with a low risk of AEs when provided by experienced practitioners. However, the biological rational remains ambiguous. More well-designed controlled trials are needed, without pharmaceutical laboratories bias, in real clinical scenarios of patients paying for the interventions, often involving multiple areas with/without combined treatments. The persistence of positive outcomes following repetitive treatments provided by less experienced practitioners, potentially involving suboptimal patient selection and/or aesthetic results, warrants further investigation.

      Contributors

      Both authors contributed to data collection, data analysis, and critical revisions of the article. Both authors read and approved the final version of the submitted article and title page.

      Funding

      This study received no funding.

      Ethical approval

      Not required

      Conflict of interest statement

      None. Both authors declare that they have no conflict of interest in this study.

      Acknowledgements

      The authors thank Reem Al-Barazanchi for the assistance in proofreading this review.

      Appendix. Supplementary materials

      REFERENCES

      1. American Society of Plastic Surgeons. 2018 Plastic surgery statistics report. 2018. https://www.plasticsurgery.org/documents/News/Statistics/2018/plastic-surgery-statistics-full-report-2018.pdf.

        • Waldman A
        • Maisel A
        • Weil A
        • et al.
        Patients believe that cosmetic procedures affect their quality of life: An interview study of patient-reported motivations.
        J Am Acad Dermatol. 2019; 80: 1671-1681
        • Haas CF
        • Champion A
        • Secor D.
        Motivating factors for seeking cosmetic surgery: A synthesis of the literature.
        Plast Surg Nurs. 2008; 28: 177-182
        • Camargo CP
        • Xia J
        • Costa CS
        • et al.
        Botulinum toxin type A for facial wrinkles.
        Cochrane Database Syst Rev. 2021; 7CD011301
        • Keaney TC
        • Cavallini M
        • Leys C
        • et al.
        Efficacy, patient-reported outcomes, and safety in male subjects treated with onabotulinumtoxinA for improvement of moderate to severe horizontal forehead lines.
        Dermatol Surg. 2020; 46: 229-239
        • Qian H
        • Shao F
        • Lenahan C
        • Shao A
        • Li Y.
        Efficacy and safety of botulinum toxin vs. Placebo in depression: A systematic review and meta-analysis of randomized controlled trials.
        Front Psychiatry. 2020; 11603087
        • Rudolph C
        • Hladik C
        • Stroup DF
        • et al.
        Are cosmetic procedures comparable to antidepressive medication for quality-of-life improvements? A systematic review and controlled meta-analysis.
        Facial Plast Surg. 2019; 35: 549-558
        • Li Y
        • Liu T
        • Luo W.
        Botulinum neurotoxin therapy for depression: Therapeutic mechanisms and future perspective.
        Front Psychiatry. 2021; 12584416
        • Schulze J
        • Neumann I
        • Magid M
        • et al.
        Botulinum toxin for the management of depression: An updated review of the evidence and meta-analysis.
        J Psychiatr Res. 2021; 135: 332-340
        • Kim YJ
        • Kim J-H
        • Lee K-J
        • et al.
        Botulinum neurotoxin type A induces TLR2-mediated inflammatory responses in macrophages.
        PLoS One. 2015; 10e0120840
        • Piotrowska A
        • Popiolek-Barczyk K
        • Pavone F
        • Mika J.
        Comparison of the expression changes after botulinum toxin type A and minocycline administration in lipopolysaccharide-stimulated rat microglial and astroglial cultures.
        Front Cell Infect Microbiol. 2017; 7: 141
        • Rojewska E
        • Piotrowska A
        • Popiolek-Barczyk K
        • Mika J
        Botulinum toxin type A-A modulator of spinal neuron-glia interactions under neuropathic pain conditions.
        Toxins (Basel). 2018; 10: E145
        • Li X
        • Ye Y
        • Zhou W
        • Shi Q
        • Wang L
        • Li T.
        Anti-Inflammatory effects of BoNT/A against complete Freund's adjuvant-induced arthritis pain in rats: Transcriptome analysis.
        Front Pharmacol. 2021; 12735075
        • Shah P
        • Rieder EA.
        Observer-reported outcomes and cosmetic procedures: A systematic review.
        Dermatol Surg. 2021; 47: 65-69
        • Snyder CF
        • Jensen RE
        • Segal JB
        • Wu AW.
        Patient-reported outcomes (PROs): Putting the patient perspective in patient-centered outcomes research.
        Med Care. 2013; 51: S73-S79
        • Chang BL
        • Wilson AJ
        • Taglienti AJ
        • Chang CS
        • Folsom N
        • Percec I.
        Patient perceived benefit in facial aesthetic procedures: FACE-Q as a tool to study botulinum toxin injection outcomes.
        Aesthet Surg J. 2016; 36: 810-820
        • Wang J
        • Rieder EA.
        A systematic review of patient-reported outcomes for cosmetic indications of botulinum toxin treatment.
        Dermatol Surg. 2019; 45: 668-688
        • Kosowski TR
        • McCarthy C
        • Reavey PL
        • et al.
        A systematic review of patient-reported outcome measures after facial cosmetic surgery and/or nonsurgical facial rejuvenation.
        Plast Reconstr Surg. 2009; 123: 1819-1827
        • Ascher B
        • Rzany B
        • Kestemont P
        • et al.
        Significantly Increased patient satisfaction following liquid formulation abobotulinumtoxinA treatment in glabellar lines: FACE-Q outcomes from a phase 3 clinical trial.
        Aesthet Surg J. 2020; 40: 1000-1008
        • McKeown DJ.
        Impact of minimally invasive aesthetic procedures on the psychological and social dimensions of health.
        Plast Reconstr Surg Glob Open. 2021; 9: e3578
      2. Best BETs - Best evidence topics and critical appraisal. https://bestbets.org/background/bets-and-cats.php (accessed 16 Dec2021).

        • Khan OA
        • Dunning J
        • Parvaiz AC
        • Agha R
        • Rosin D
        • Mackway-Jones K
        Towards evidence-based medicine in surgical practice: Best BETs.
        Int J Surg. 2011; 9: 585-588
      3. OCEBM Levels of Evidence Working Group. The Oxford levels of evidence 2. https://www.cebm.net/wp-content/uploads/2014/06/CEBM-Levels-of-Evidence-2.1.pdf (accessed 16 Dec2021).

      4. Cochrane handbook for systematic reviews of interventions. https://training.cochrane.org/handbook/current (accessed 11 Aug2021).

        • Moher D
        • Shamseer L
        • Clarke M
        • et al.
        Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
        Syst Rev. 2015; 4: 1
        • Palm MD
        • Few J
        • Patel T
        • et al.
        Efficacy, patient-reported outcomes, and safety for millennial subjects treated with onabotulinumtoxinA for moderate to severe horizontal forehead lines.
        Dermatol Surg. 2020; 46: 653-661
        • Ogilvie P
        • Rivkin AZ
        • Dayan S
        • Yoelin SG
        • Weichman BM
        • Garcia JK.
        OnabotulinumtoxinA for treatment of forehead and glabellar lines: Subject-reported satisfaction and impact from a phase 3 double-blind study.
        Dermatol Surg. 2019; 45: 689-699
        • Rivkin AZ
        • Ogilvie P
        • Dayan S
        • Yoelin SG
        • Weichman BM
        • Garcia JK.
        OnabotulinumtoxinA for simultaneous treatment of upper facial lines: Subject-reported satisfaction and impact from a phase 3 study.
        Dermatol Surg. 2020; 46: 50-60
        • Cohen JL
        • Kaufman J
        • Peredo MI
        • Down R
        • Mashburn J.
        Assessment of psychological well-being after abobotulinumtoxinA treatment: A comparison of 2 reconstitution volumes.
        Dermatol Surg. 2020; 46: 289-292
        • Schlessinger J
        • Cohen JL
        • Shamban A
        • et al.
        A multicenter study to evaluate subject satisfaction with two treatments of abobotulinumtoxinA a year in the glabellar lines.
        Dermatol Surg. 2021; 47: 504-509
        • Cohen JL
        • Rivkin A
        • Dayan S
        • et al.
        Multimodal facial aesthetic treatment on the appearance of aging, social confidence, and psychological well-being: HARMONY study.
        Aesthet Surg J. 2022; 42: NP115-NP124
        • Lowe NJ
        • Ascher B
        • Heckmann M
        • et al.
        Double-blind, randomized, placebo-controlled, dose-response study of the safety and efficacy of botulinum toxin type A in subjects with crow's feet.
        Dermatol Surg. 2005; 31: 257-262
        • Rivers JK
        • Bertucci V
        • McGillivray W
        • et al.
        Subject satisfaction with onabotulinumtoxinA treatment of glabellar and lateral canthal lines using a new patient-reported outcome measure.
        Dermatol Surg. 2015; 41: 950-959
        • Beer KR.
        Comparative evaluation of the safety and efficacy of botulinum toxin type A and topical creams for treating moderate-to-severe glabellar rhytids.
        Dermatol Surg. 2006; 32: 184-197
        • Carruthers J
        • Carruthers A.
        Botulinum toxin type A treatment of multiple upper facial sites: Patient-reported outcomes.
        Dermatol Surg. 2007; 33: S10-S17
        • Fagien S
        • Cox SE
        • Finn JC
        • Werschler WP
        • Kowalski JW.
        Patient-reported outcomes with botulinum toxin type A treatment of glabellar rhytids: A double-blind, randomized, placebo-controlled study.
        Dermatol Surg. 2007; 33: S2-S9
        • Carruthers A
        • Bruce S
        • de Coninck A
        • et al.
        Efficacy and safety of onabotulinumtoxinA for the treatment of crows feet lines: A multicenter, randomized, controlled trial.
        Dermatol Surg. 2014; 40: 1181-1190
        • Dayan S
        • Coleman WP
        • Dover JS
        • et al.
        Effects of OnabotulinumtoxinA treatment for crow's feet lines on patient-reported outcomes.
        Dermatol Surg. 2015; 41: S67-S74
        • Moers-Carpi M
        • Carruthers J
        • Fagien S
        • et al.
        Efficacy and safety of onabotulinumtoxinA for treating crow's feet lines alone or in combination with glabellar lines: A multicenter, randomized, controlled trial.
        Dermatol Surg. 2015; 41: 102-112
        • Carruthers J
        • Rivkin A
        • Donofrio L
        • et al.
        A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of repeated onabotulinumtoxinA treatments in subjects with crow's feet lines and glabellar lines.
        Dermatol Surg. 2015; 41: 702-711
        • Solish N
        • Rivers JK
        • Humphrey S
        • et al.
        Efficacy and safety of onabotulinumtoxinA treatment of forehead lines: A multicenter, randomized, dose-ranging controlled trial.
        Dermatol Surg. 2016; 42: 410-419
        • Stotland MA
        • Kowalski JW
        • Ray BB.
        Patient-reported benefit and satisfaction with botulinum toxin type A treatment of moderate to severe glabellar rhytides: Results from a prospective open-label study.
        Plast Reconstr Surg. 2007; 120: 1386-1393
        • Carruthers A
        • Carruthers J.
        A single-center dose-comparison study of botulinum neurotoxin type A in females with upper facial rhytids: Assessing patients’ perception of treatment outcomes.
        J Drugs Dermatol. 2009; 8: 924-929
        • Streker M
        • Luebberding S
        • Krueger N
        • Harrington L
        • Kerscher M.
        Patient-reported outcomes after incobotulinumtoxinA treatment for upper facial wrinkles.
        Dermatol Surg. 2015; 41: S29-S38
        • Beer KR
        • Boyd C
        • Patel RK
        • Bowen B
        • James SP
        • Brin MF.
        Rapid onset of response and patient-reported outcomes after onabotulinumtoxinA treatment of moderate-to-severe glabellar lines.
        J Drugs Dermatol. 2011; 10: 39-44
        • Beer KR
        • Julius H
        • Dunn M
        • Wilson F.
        Remodeling of periorbital, temporal, glabellar, and crow's feet areas with hyaluronic acid and botulinum toxin.
        J Cosmet Dermatol. 2014; 13: 143-150
        • Hibler BP
        • Schwitzer J
        • Rossi AM.
        Assessing improvement of facial appearance and quality of life after minimally-invasive cosmetic dermatology procedures using the FACE-Q scales.
        J Drugs Dermatol. 2016; 15: 62-67
        • Qureshi AA
        • Parikh RP
        • Sharma K
        • Myckatyn TM
        • Tenenbaum MM.
        Nonsurgical facial rejuvenation: Outcomes and safety of neuromodulator and soft-tissue filler procedures performed in a resident cosmetic clinic.
        Aesthetic Plast Surg. 2017; 41: 1177-1183
        • Dayan S
        • Rivkin A
        • Sykes JM
        • et al.
        Aesthetic treatment positively impacts social perception: Analysis of subjects from the HARMONY study.
        Aesthet Surg J. 2019; 39: 1380-1389
        • Dayan SH
        • Arkins JP
        • Patel AB
        • Gal TJ.
        A double-blind, randomized, placebo-controlled health-outcomes survey of the effect of botulinum toxin type a injections on quality of life and self-esteem.
        Dermatol Surg. 2010; 36: 2088-2097
        • Dayan SH
        • Lieberman ED
        • Thakkar NN
        • Larimer KA
        • Anstead A.
        Botulinum toxin a can positively impact first impression.
        Dermatol Surg. 2008; 34: S40-S47
        • Fink B
        • Prager M.
        The effect of incobotulinumtoxin a and dermal filler treatment on perception of age, health, and attractiveness of female faces.
        J Clin Aesthet Dermatol. 2014; 7: 36-40
        • Dayan SH
        • Bacos JT
        • Ho T-VT
        • Gandhi ND
        • Gutierrez-Borst S
        • Kalbag A.
        Topical skin therapies in subjects undergoing full facial rejuvenation.
        J Cosmet Dermatol. 2019; 18: 798-805