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Is Botox Really Safe? The Answer from a Meta-analysis of 9,669 People

1. What is Botox Botulinum toxin type A is a widely used medical and aesthetic intervention for treating facial wrinkles (Cochrane 2021).

1. What is Botox

Botulinum toxin type A is a widely used medical and aesthetic intervention for treating facial wrinkles. It is primarily used to improve glabellar lines, forehead lines, and crow's feet lines (M. Gostimir 2023).

The types of formulations whose efficacy and safety have been evaluated include OnabotulinumtoxinA, AbobotulinumtoxinA, IncobotulinumtoxinA, DaxibotulinumtoxinA, PrabotulinumtoxinA, HBTX-A, CBFC26, Neuronox, and Liquid AbobotulinumtoxinA. Each of these is administered in different units (U), and their effects and safety profiles compared to placebo (sham treatment) have been studied in detail (Cochrane 2021).

2. Safety Data from Meta-analysis

A comprehensive meta-analysis of Botox injection safety has confirmed that the risk of systemic dissemination is extremely low or nonexistent (M. Gostimir 2023). According to influence analysis results, the overall pooled risk ratio was 1.51 (M. Gostimir 2023), with a 95% confidence interval from 1.32 to 1.72 (M. Gostimir 2023). The I-squared statistic at this time was 27.2%, indicating relatively low heterogeneity between studies (M. Gostimir 2023).

Previous major meta-analyses also support this safety profile. For example, a study published in 2009 analyzed 11 papers with 1,063 participants (age range 31 to 59 years old) and evaluated the overall quality of evidence as good (Ghadia 2009). Similarly, a meta-analysis of a global clinical registry study using individual data from 1,678 participants (Brin 2009) and other systematic reviews on facial rejuvenation (Guo 2015) (Jia 2016) (Naumann 2004) have also reported high tolerability and safety of Botulinum toxin type A. It should be noted that the latest Cochrane review set the target age range broadly from 18 to 65 years old and evaluated the certainty of evidence as ranging from "very low" to "moderate" (Cochrane 2021).

3. Types and Incidence Rates of Adverse Events

The overall frequency of adverse events is similar between the Botulinum toxin type A group and the placebo group; however,blepharoptosisis the only adverse event that tends to show a significantly higher incidence rate compared to the placebo group (Cochrane 2021). In most cases, adverse events are mild to moderate in severity, transient in nature, and consistent with the expected pharmacodynamics (M. Gostimir 2023).

  • Major adverse events: Blepharoptosis, eyelid sensory disturbance, strabismus, etc., have been evaluated, but the occurrence of serious adverse events is extremely rare. No major serious adverse events were observed with IncobotulinumtoxinA 20U administration (incidence rate 0) (Cochrane 2021).
  • The general adverse event risk with IncobotulinumtoxinA 20U administration is estimated at 37 per 100 people (95% confidence interval: 7 to 100 people). In contrast, the risk in the placebo group was 1 per 100 people (Cochrane 2021).
  • In the AbobotulinumtoxinA 45U treatment group, the frequency of adverse events was reported as 5 out of 40 people (13%) (Cochrane 2021).
  • In the analysis using OnabotulinumtoxinA 20U (Carruthers 2014) (Harii 2017) (Moers-Carpi 2015) (Wu 2019), the RR of adverse events at 4 weeks was 12.38 (95% confidence interval 8.93 to 17.16). This risk ratio decreased over time, and by 16 weeks, the RR had decreased to 5.46 (95% confidence interval 3.19 to 9.32) (Cochrane 2021).
  • In the analysis using PrabotulinumtoxinA 20U, among 948 participants (737 in the treatment group, 211 in the placebo group), the overall RR of adverse events was 1.14 (95% confidence interval 0.91 to 1.43) (Beer 2019a) (Beer 2019b) (Rzany 2019).
  • In the analysis of Liquid AbobotulinumtoxinA 50U, the overall RR of adverse events among 255 participants was 1.11 (95% confidence interval 0.72 to 1.71) (Ascher 2018) (Ascher 2020).

📊 Botulinum Toxin Type A Formulation Comparison: Adverse Event Risk Ratios (Cochrane 2021 / Meta-analysis of 9,669 People)

Source: Cochrane Database of Systematic Reviews 2021 (Analysis of 9,669 people) / RR = Risk Ratio (vs. Placebo). Lower numbers indicate lower adverse event risk.

4. Cochrane Review Evidence

The 2021 Cochrane Database systematic review rigorously evaluated the efficacy and safety of Botulinum toxin type A for facial wrinkles (Cochrane 2021).

  • Duration of treatment effects:The average treatment effect duration was 99.7 days, and the mean difference (MD) compared to placebo was 17.3 days longer (95% confidence interval: 15.82 to 18.78 days longer) (Cochrane 2021).
  • Bias risk assessment:The quality of research varies widely. For example, studies that explicitly stated that vials were identical and identified only by patient number and study number, with identical dilution and injection procedures, were judged to have low risk of selection bias (Carruthers 2004). Studies using SAS's random number generation function were also rated as low risk (Harii 2008). On the other hand, studies reporting only results at 4 weeks were determined to have high selective reporting bias (Lee 2013), and studies with unclear randomization methods were rated as unclear risk (Park 2014). Additionally, studies reporting all pre-specified outcomes are considered low risk (Satler 2010).

5. Satisfaction data for forehead and glabella

The success of treatment for wrinkles in the upper face (glabella, forehead, lateral canthus) has been highly evaluated by analysis of physician and participant scores and scales (Cochrane 2021). The following data show the risk ratio (RR) and 95% confidence interval for success compared to placebo.

OnabotulinumtoxinA data

Participant-assessed success rate for OnabotulinumtoxinA 44U injection (Carruthers 2015) (Moers-Carpi 2015):

  • At 4 weeks: RR 11.09 (95% confidence interval 4.12 to 29.83) based on 2 studies (808 participants).
  • At 8 weeks: RR 9.94 (95% confidence interval 1.78 to 55.44).
  • At 12 weeks: RR 5.96 (95% confidence interval 0.60 to 58.98).

Participant-assessed success rate for OnabotulinumtoxinA 64U injection (De Boulle 2018):

  • At 4 weeks: RR 8.32 (95% confidence interval 4.53 to 15.30) (469 participants).
  • At 8 weeks: RR 106.50 (95% confidence interval 6.66 to 1702.48).
  • At 12 weeks: RR 44.50 (95% confidence interval 2.76 to 717.83).
  • At 16 weeks: RR 26.50 (95% confidence interval 1.63 to 431.99).
  • At 20 weeks: RR 5.50 (95% confidence interval 0.31 to 98.84).
  • At 24 weeks: RR 1.50 (95% confidence interval 0.06 to 36.61).

Success rate for OnabotulinumtoxinA 12U injection (Harii 2017):

  • At 4 weeks: RR 6.86 (95% confidence interval 3.45 to 13.62).
  • At 8 weeks: RR 4.29 (95% confidence interval 2.10 to 8.76).
  • At 12 weeks: RR 5.55 (95% confidence interval 1.68 to 18.34).

AbobotulinumtoxinA data

Physician-assessed success rate for AbobotulinumtoxinA 50U injection:

  • At 4 weeks: RR 21.22 (95% confidence interval 7.43 to 60.56) based on 5 studies (915 participants) (Ascher 2018) (Brandt 2009) (Kane 2009) (Monheit 2019) (NCT02450526).
  • At 8 weeks: RR 39.89 (95% confidence interval 14.10 to 112.88) (725 participants) (Ascher 2018) (Monheit 2019) (NCT02450526).
  • At 12 weeks: RR 28.83 (95% confidence interval 10.16 to 81.81) (725 participants) (Ascher 2018) (Monheit 2019) (NCT02450526).
  • At 16 weeks: RR 11.78 (95% confidence interval 4.12 to 33.66) (371 participants) (Ascher 2018) (Monheit 2019).
  • At 20 weeks: RR 5.33 (95% confidence interval 1.67 to 16.99) (300 participants) (Monheit 2019).

Success rate at 50u dose of Liquid AbobotulinumtoxinA (Ascher 2018) (Ascher 2020):

  • At 4 weeks: RR 16.73 (95% confidence interval 2.84 to 98.58) (255 participants).
  • At 8 weeks: RR 48.98 (95% confidence interval 9.99 to 240.21).
  • At 12 weeks: RR 35.93 (95% confidence interval 7.30 to 176.90).
  • At 16 weeks: RR 21.25 (95% confidence interval 2.95 to 152.88).
  • At 20 weeks: RR 25.86 (95% confidence interval 1.60 to 417.34).

Success rate at 75u dose of Liquid AbobotulinumtoxinA (Ascher 2018):

  • At 4 weeks: RR 64.75 (95% confidence interval 4.12 to 1018.73).
  • At 8 weeks: RR 60.64 (95% confidence interval 3.85 to 955.48).
  • At 12 weeks: RR 56.53 (95% confidence interval 3.58 to 892.24).
  • At 16 weeks: RR 42.14 (95% confidence interval 2.65 to 670.89).

DaxibotulinumtoxinA data

Physician-assessed success rate at 40U dose of DaxibotulinumtoxinA:

  • At 4 weeks: RR 21.10 (95% confidence interval 11.31 to 39.34) (683 participants) (Bertucci 2020) (Carruthers 2017).
  • At 8 weeks: RR 15.75 (95% confidence interval 8.85 to 28.03) (609 participants) (Bertucci 2020).
  • At 12 weeks: RR 24.51 (95% confidence interval 11.12 to 54.05) (609 participants) (Bertucci 2020).
  • At 16 weeks: RR 12.74 (95% confidence interval 6.80 to 23.89) (683 participants) (Bertucci 2020) (Carruthers 2017).
  • At 20 weeks: RR 13.60 (95% confidence interval 6.13 to 30.18) (609 participants) (Bertucci 2020).
  • At 24 weeks: RR 10.25 (95% confidence interval 4.01 to 26.20) (683 participants) (Bertucci 2020) (Carruthers 2017).
  • Regarding the duration of treatment efficacy, the mean difference reached 22.80 weeks (95% confidence interval 20.74 to 24.86) (Carruthers 2017).

Data for other formulations

  • At 54U to 64U dose of IncobotulinumtoxinA, the success RR for glabellar region at 4 weeks was 87.81 (95% confidence interval 5.56 to 1386.93), forehead was 35.94 (95% confidence interval 5.14 to 251.27), and crow's feet was 32.54 (95% confidence interval 4.65 to 227.82) (Kerscher 2015).
  • At 50u dose of HBTX-A, RR at 4 weeks was 42.68 (95% confidence interval 6.08 to 299.41) (NCT02493946).

6. Risk Minimization Points

To minimize risks in Botox treatment, there are several important points to consider.

  • Appropriate management of injection volume:Safety impact is strongly dependent on individual injection volume and the total volume injected per treatment session (M. Gostimir 2023).
  • Use of validated assessment tools:It is strongly recommended to incorporate evaluation based on objective indicators, such as validated assessment scales for neck volume (Sattler 2012).
  • Adherence to international consensus:It is important to follow international consensus recommendations on the use of botulinum toxin type A for cosmetic purposes published in 2010 (Ascher 2010) and evidence-based reviews and recommendations regarding complications updated in 2016 (Sundaram 2016).

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7. Summary

Botulinum toxin type A is a treatment that demonstrates extremely high efficacy for facial wrinkles on the glabella, forehead, and crow's feet. As multiple large-scale meta-analyses demonstrate, there is minimal concern about serious systemic adverse effects from diffusion, and the majority of adverse effects that occur are mild and transient, attributed to the pharmacodynamic properties of the preparation (M. Gostimir 2023). While local risks such as ptosis are significantly higher compared to the placebo group, these risks are considered sufficiently manageable through appropriate injection volume management and procedures based on international guidelines (Ascher 2010) (Sundaram 2016). The duration of effect is also stable over a long term, averaging approximately 100 days (approximately 3 to 4 months), and very high patient and physician satisfaction and success rates have been confirmed in many clinical trials (Cochrane 2021).

References

  1. Gostimir M, Liou V, Yoon M. Safety of Botulinum Toxin A Injections for Facial Rejuvenation: A Meta-Analysis of 9,669 Patients. Ophthalmic Plastic & Reconstructive Surgery. 2023DOI
  2. Camargo C, Xia J, Costa C, et al. Botulinum toxin type A for facial wrinkles. Cochrane Database of Systematic Reviews. 2021DOI
  3. Ogilvie P, Rivkin A, Dayan S, et al. OnabotulinumtoxinA for Treatment of Forehead and Glabellar Lines: Subject-Reported Satisfaction and Impact From a Phase 3 Double-Blind Study. Dermatologic Surgery. 2019DOI
  4. Ozdemir Cetinkaya P, Karaosmanoglu N, Özkesici Kurt B, et al. Functional and esthetic effects of botulinum toxin injection into the masseter muscles: evaluation of 80 patients from a dermatological perspective. International Journal of Dermatology. 2025DOI

About the author of this article

Hiromitsu NakamuraPhysician

Zetith Beauty Clinic Ginza, Osaka, Fukuoka

With a track record of research presentations at domestic and international academic conferences, he is involved in technical guidance and education for Zetith Beauty Clinic as a whole. He specializes in precise aesthetic medicine based on anatomical evidence, pursuing natural results tailored to each individual's skeletal structure and tissues.

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