Dosing Strategies of Botulinum Toxin for Primary Axillary Hyperhidrosis: A Meta-Analytic Review

Introduction

Primary axillary hyperhidrosis is a condition of excessive underarm sweating that can significantly impair quality of life. Intradermal botulinum toxin type A (BoNT-A) injections are an established second-line therapy for focal hyperhidrosis unresponsive to topical agents. BoNT-A acts by inhibiting acetylcholine release at eccrine sweat glands, thereby reducing sweat production. While BoNT-A (in various formulations such as onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA) is highly effective, its effects are temporary (typically lasting several months) and treatments are costly.

An important clinical question is the optimal dose per axilla that balances efficacy, duration of effect, cost, and safety. Early uncontrolled reports suggested that using higher doses might prolong the sweat-free interval. However, higher doses raise concerns about increased side effects and neutralising antibody formation that could reduce long-term efficacy. To guide best practices, we conducted a meta-analytic review focusing on randomised controlled trials (RCTs) that directly compared different BoNT-A dosing regimens for primary axillary hyperhidrosis.

Methods

A literature search was performed for RCTs (of any year) that evaluated different doses of BoNT-A for treating primary axillary hyperhidrosis. We included trials of any BoNT-A brand (e.g. onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA), provided they compared at least two dosing regimens. Key outcomes extracted were: dose per axilla (and total dose), sweating reduction and duration of effect (time to symptom recurrence or re-treatment), and reported side effects (frequency and severity).

Data from each trial were compiled into summary tables, and results were compared qualitatively given differences in study design and outcome measures. No new statistical meta-analysis was performed due to heterogeneity of metrics; instead, we synthesised trends across studies with appropriate source citations.

Results

OnabotulinumtoxinA (Botox) Dose-Comparison Trials

Multiple RCTs have examined dosing of onabotulinumtoxinA in axillary hyperhidrosis. A large multicentre trial by Lowe et al. (2007) randomised 322 patients to receive 50 U or 75 U of onabotulinumtoxinA per axilla (compared to placebo). Both the 50 U and 75 U doses produced robust and equivalent improvements: at 4 weeks post-injection, ~75% of treated patients achieved a ≥2-point improvement on the Hyperhidrosis Disease Severity Scale (HDSS), compared to only 25% in the placebo group.

Gravimetric sweat production measurements corroborated these self-reported outcomes, with >50% sweat reduction in the majority of treated patients. Importantly, no significant efficacy difference was observed between 75 U and 50 U – the higher dose did not yield greater sweat reduction or higher responder rates. The median duration of effect in this trial was about 6.5–6.7 months for both doses (197 days for 75 U vs 205 days for 50 U), indicating that increasing the dose to 75 U did not appreciably prolong the therapeutic effect.

A more recent RCT by Siri-Archawawat and Tawanwongsri (2023) explored even lower dosing. In this single-blinded, side-by-side trial, 25 U vs 50 U of onabotulinumtoxinA were injected (one dose in each axilla) in 12 patients. After 2 weeks and throughout 3 months of follow-up, no significant differences were found between 25 U and 50 U in terms of sweat rate reduction, hyperhidrotic area (starch-iodine test), HDSS scores, or quality-of-life improvements.

Summary (OnabotulinumtoxinA)

Collectively, RCT evidence indicates that for onabotulinumtoxinA (Botox), doses in the range of 25–75 U per axilla yield similar outcomes in axillary hyperhidrosis. Sweating is typically reduced by ~75–80% from baseline within 1–2 weeks, regardless of dose, and the average duration of relief is about 6–7 months for these doses. Little to no dose-response benefit is seen by increasing above 50 U in terms of either efficacy or duration of effect.

AbobotulinumtoxinA (Dysport) Dose-Comparison Trials

AbobotulinumtoxinA (Dysport) has a different potency unit such that 1 U of Dysport is roughly 1/3 of a Botox unit in clinical effect (though exact equivalence is debated). Early clinical practice often used a whole 500 U vial of Dysport per patient (≈250 U per axilla), but subsequent studies evaluated lower doses. Heckmann et al. conducted a pivotal side-by-side RCT comparing 100 U vs 200 U of Dysport per axilla in patients with severe axillary hyperhidrosis.

In this trial, 43 patients were treated with 100 U in one underarm and 200 U in the other, with a follow-up period of 48 weeks for the first treatment cycle (and a second treatment followed by another 48-week observation). Both 100 U and 200 U doses produced dramatic sweat reductions: by 2 weeks post-injection, sweat production in each axilla fell to ~10–20% of baseline on average. Crucially, there was no significant difference in efficacy between 100 U and 200 U at any time point during the 48-week follow-up.

Summary (AbobotulinumtoxinA)

RCT data indicate that 100 U of Dysport per axilla is sufficient for maximal therapeutic benefit in severe axillary hyperhidrosis, with higher doses (≥200 U) providing no added benefit. Both 100 U and 200 U reduce sweating by ~80–90% at 1 month and require re-treatment in about 6–8 months as sweating returns.

Cross-Formulation Comparisons

Comparing different botulinum toxin brands is challenging due to their differing potency units. However, a few randomised trials have directly compared formulations by using an appropriate conversion ratio. Talarico-Filho et al. conducted a double-blind RCT in which patients received onabotulinumtoxinA 50 U in one axilla and abobotulinumtoxinA 150 U in the other (a 1:3 dose ratio) in the same treatment session.

This head-to-head comparison in 10 patients (with 9 completing 1-year follow-up) found no difference in efficacy between Botox and Dysport when dosed at 1:3 equivalence. At 1 month, all treated axillae achieved ≥50% reduction in sweat production, with mean sweat reductions of ~98% on the Botox side and ~99% on the Dysport side.

Duration of Effect and Re-Treatment Intervals

Across the RCTs reviewed, the duration of anhidrotic effect of BoNT-A in the axilla was consistently on the order of 4 to 9 months, regardless of dose or product. The median time to return of significant sweating (often defined as HDSS score returning to ≥3 or gravimetric sweat ≥50 mg/5 min) was 6–7 months in large trials.

Notably, higher doses did not reliably push the duration beyond this range. For instance, giving 75 U vs 50 U did not extend median duration beyond 7 months, and 200 U vs 100 U Dysport did not delay recurrence past 1 year. In practice, repeat injection is typically recommended when the clinical effect has waned to a bothersome level.

Adverse Effects and Safety Profile

One of the most favourable aspects of intradermal BoNT-A for hyperhidrosis is its excellent safety profile. All the RCTs reviewed reported minimal side effects, and importantly no serious systemic effects or muscle weakness attributable to toxin spread at the doses used. The key reported adverse events include:

• Injection site pain: This is the most common complaint, reported to some degree in virtually all studies.
• Localised skin reactions: Mild erythema, swelling, or bruising at injection sites were occasionally noted.
• Compensatory sweating: A few patients noted slight increase in sweating in body areas outside the axillae.
• Muscle weakness: Importantly, no clinically significant muscle weakness in the arms or shoulders was observed.

Crucially, there was no increase in adverse effects with higher doses in any trial. Patient satisfaction across all dose groups has been high, with most patients willing to continue with repeat treatments given the magnitude of benefit and minimal side effect burden.

Discussion

Efficacy vs Dose

The aggregate evidence from RCTs clearly indicates a plateau in the dose-response curve of botulinum toxin for axillary hyperhidrosis. Low-to-moderate doses (around 50 U Botox or equivalent) already achieve near-maximal sweat suppression (often >90% reduction in sweat production at peak). Increasing the dose two-fold or more does not yield a proportional increase in efficacy.

This is likely because once all functional sweat glands in the area are effectively denervated by the toxin, extra toxin confers no further benefit. In other words, there is a saturation effect in blocking cholinergic input to the sweat glands. All reviewed trials found no statistically significant advantage to higher dosing in terms of percent sweat reduction or responder rates.

Duration vs Dose

A key question has been whether higher doses can produce a longer duration of effect (i.e., delay the time to recurrence of sweating). Intuitively, one might expect a larger amount of toxin to "last" longer before neural function recovers. However, the RCT data did not demonstrate a clinically meaningful prolongation of effect with higher doses.

These findings suggest that duration of anhidrosis is governed more by patient-specific factors (such as nerve regeneration rates, initial sweat gland load, etc.) than by the exact toxin dose, at least once a threshold dose is exceeded.

Safety and Immunogenicity

The compiled evidence reinforces that intradermal botulinum toxin is remarkably safe for treating axillary hyperhidrosis. Even at the upper end of doses tested, adverse effects were minimal and localised. This safety profile is an advantage over more invasive treatments (like surgery or systemic medications).

One concern with repeated toxin injections is the potential for neutralising antibody development that can cause secondary non-response. High cumulative doses and short injection intervals are risk factors for antibody formation. By using the lowest effective dose and treating no more frequently than necessary, we likely mitigate this risk.

Practical Recommendations

Based on this review, we recommend starting treatment at 50 U per axilla of onabotulinumtoxinA or incobotulinumtoxinA (or 100 U per axilla of abobotulinumtoxinA) for adults with primary axillary hyperhidrosis, as this dose is proven effective in most patients. For smaller patients or those with moderate (not severe) hyperhidrosis, an initial dose of 25 U/axilla (Botox/Xeomin) could be tried, as it may suffice and would reduce cost.

Conclusion

For treatment of primary axillary hyperhidrosis, randomised trials consistently demonstrate that lower doses of botulinum toxin are as effective as higher doses in reducing sweat and providing symptom relief. OnabotulinumtoxinA doses of 50 U (and even 25 U) per axilla achieve equivalent outcomes to higher doses up to 75 U. Similarly, abobotulinumtoxinA 100 U per axilla is just as efficacious as 200 U.

The duration of effect averages 6–9 months and is not significantly extended by using larger doses. All tested regimens have excellent safety profiles, with only minor transient side effects and no serious adverse events reported. Given the lack of added benefit from higher dosing, the preferred strategy is to use the lowest dose that reliably controls sweating, which reduces cost and theoretically lowers the risk of antibody development.

Patients can be reassured that Botox (or other BoNT-A) injections, at appropriate doses, are a safe, effective, and repeatable therapy that significantly improves the quality of life in axillary hyperhidrosis. Future directions should include studies to identify patient factors that might necessitate dose adjustments, as well as continued pharmacoeconomic analyses of using lower toxin doses. Nonetheless, the current evidence firmly supports that "more is not better" when it comes to botulinum toxin dose for axillary hyperhidrosis – standard dosing is already optimal in achieving anhidrosis with minimal risk.

Citations