Botulinum toxin has become a popular drug in aesthetic dermatology and plastic surgery and is used to diminish wrinkles as well as for a number of medical indications. However, current reports suggest the loss of a therapeutic effect over a period of time.
In this descriptive review, we have identified factors that contribute to this declinefd4e3, including commercial presentations, antigenicity, clinical practice and patient lifestyle. It is also based on up-to-date medical evidence with practical strategies to prolong clinical usefulness.
The clinical use of botulinum toxin type A (BoNT-A) has transformed the field of dermatology and cosmetic plastic surgery because it has provided an efficient non-invasive treatment for facial rejuvenation. Traditionally, reports indicate the duration of the action of botulinum toxin as four to six months, but patients often complain about a shortened effect thus questioning the reasons for, and possibilities of, interfering factors that affect the duration of action (DOA), which include immunogenicity and immune escape – the body’s production of neutralising BoNT-A antibodies markedly limits its long-term efficacy. This risk is substantially enhanced with frequent and subtherapeutic dose exposure [1].
Characteristics of BoNT-A
Usage and dosage
Safe aesthetic injectables in the modern world have become a burgeoning source of popularity among patients. Not only is this less risky than surgery, but it also has much less downtime, interfering less with patients’ work and social schedules. In this respect, it is crucial to identify patient-related factors which will influence the treatment regimen and potentially allow the doctor to tailor injection patterns [2].
Underdosing or over dilution lead to significant decrease in the DOA. Individualised therapeutic strategies involving optimal dosage and application at appropriate intervals minimise the risk of immunogenicity [3,4]. Emphasis should be placed on anatomic accuracy, suggesting the use of ultrasound-directed injection methods in more complex cases [5].
Role of metabolic aspects and personal lifestyle
It is clear that vigorous exercise results in raised systemic metabolism and as a consequence, the efficacy time of BoNT-A decreases [6]. Chronic stress, sleep and nutritional status may also negatively impact effectiveness [7].
Commercial product formulations and variability
Among commercial preparations of the main BoNT-As in use in Europe, there is considerable variability in production and preparation “which depend on their specific biotypes and manufacturing processes [and] lead to clinically relevant pharmacotherapeutic dissimilarities.” The factors may further affect both efficacy and DOA [8].
Practical tips for prolonging the duration of botulinum toxin
Pre-injection patient evaluation is essential and should be accompanied by a comprehensive history of lifestyle (i.e. exercise regime and stress levels), comorbidities (including autoimmune and metabolic disorders), and past history of BoNT-A use. The importance of questioning whether prior injections have been given, which brand of toxin has been used, the dose and technique of injection and, most importantly, the length of time the clinical effect of the toxin lasted cannot be overemphasised. This knowledge facilitates personalised treatment regimens, improves therapeutic responses and helps to predict resistance or suboptimal therapy.
Patient physical activity management
According to the results and restrictions found in a study by Morhy, et al., higher levels of physical activity exert a negative influence on the aesthetic permanence of BoNT-A, since the P-BOT-A administration reduces the effect of its paralysing activity on frontal, corrugator supercilii muscle and diminishes, on average, the duration of the neuromodulation [6].
Product choice and immunological analysis
It is important to select a product with strong clinical evidence and minimal immunogenicity. Immunological neutralising antibodies are indicated in patients in whom a clear clinical response to the BoNT-A has disappeared. Botulinum toxin type A nonresponse has been previously described in both medical and cosmetic indications. Secondary nonresponse (SNR) is a phenomenon in which BoNT-A is effective at onset but becomes ineffective later. The largest number of reports of SNR are in aesthetics. A number of features of this morbid complication need further clarification and remain controversial [9].
Chronic disease patients
The DOA of BoNT-A is variable from one patient to another. One study by Ledda, et al. questioned the average duration of botulinum toxin efficacy in movement disorders [10]. The average DOA was found to be about 78.5 days. Dose, toxin, patient age and clinical condition were predictive of DOA.
Another study considered the DOA of the various human serotypes of botulinum toxin and found that serotype A, which is predominantly used, has a long DOA compared to other serotypes such as type F, which had a shorter recovery [11]. Additionally, it has been noted that toxin concentration can affect recovery of paralysis from botulinum toxin, with BoNT-A causing sustained paralysis, while BoNT-B and BoNT-E do not [12].
In conclusion, the response duration of botulinum toxin in patients with chronic disorders would be exaggerated due to effects of dose, type of toxin or patient’s clinical characteristics. These also need to be considered during treatment to avoid potential adverse effects and maximise its effectiveness.
The role of genetics
Several genetic and molecular factors complicate the longevity of the botulinum toxin. Notably, the work of Pellett et al. mention that the light chain (LC) of BoNT-A, which mediates its endopeptidase activity, is a crucial factor for its duration of action and has an extended half-life, which may help maintain its long-lasting biological effects [13].
Furthermore, Tsai et al. identify the deubiquitinating enzyme VCIP135 as a determinant for the duration of BoNT-A intoxication. This enzyme associates with the LC to avoid its proteasomal degradation, so that the latter can maintain activity in the cells [14]. This molecular mechanism implies that the control of ubiquitination / deubiquitination of LC must be essential for the duration of toxin actions.
The duration of the action of the BoNT-A LC can be changed by sequence variations. Certain mutations in the C-terminus of the LC can modify the onset and duration of toxin paralysis.
These studies highlight the critical role of the BoNT-A LC in complex formation and suggest a role for enzymes such as VCIP135 in regulating the duration of botulinum toxin intoxication. Moreover, genetic polymorphisms and structural modifications of the toxin might provide opportunities for the development of better therapeutic applications.
Antibodies causing a change in the duration of botulinum toxin use
A novel mechanism in BoNT-A persistence: the BoNT-A LC protects BoNT-A from the protease activity of the cell: deubiquitinating enzyme VCIP135. Antibodies neutralising the duration of BoNT-A effects tend to inhibit the LC by interfering with its catalytic activity. The use of alpha-exosite-binding mAbs to inhibit the BoNT-A catalytic activity has been previously reported. These antibodies interact with the LC at sites different from the active site, thus preventing substrate binding and inhibiting the enzymatic action of the toxin [15]. Furthermore, single heavy chain antibodies (VHHs) have also been generated for the protease region of BoNT-A, which contains the LC. These VHHs can also bind to non-competing epitopes in the LC and have an inhibitory effect via an occupation of the substrate-recognition exosites or the scissile pocket, thereby excluding substrate binding [16].
Although the antibodies do not bind to VCIP135 themselves, they block the enzymatic activity of the LC, which is important for continuous action of the toxin. They can also compensate for the activity of the LC, leading to a shortened persistence of BoNT-A’s effects right under conditions including VCIP135, shielding the LC from degradation [13].
Dilutions
Botulinum toxin is diluted, depending on the brand and kind of toxin used and, consequently, may affect the DOA. Botulinum toxin type A is widely available, including AbobotulinumtoxinA (Dysport), OnabotulinumtoxinA (Botox), and IncobotulinumtoxinA (Xeomin), with unique dilution and dosing guidance for each of these product forms.
For AbobotulinumtoxinA (Dysport), one study examined dilution to a 500-unit vial with 2.5ml and 4ml of saline, but the more concentrated dilution (2.5ml) seems to lead to a modestly longer duration of effect, albeit that difference did not reach statistical significance [17].
As for OnabotulinumtoxinA (Botox), administration is diluted according to Food & Drug Administration (FDA)-approved dilution guidelines in the US (where available). For instance, 100-U by the manufacturer into anywhere between 1ml to 10ml of saline, to the desired dose in 0.1ml injections [2]. The sample dilution for axillary hyperhidrosis is 50-U per axilla in 2ml of saline (dilution 100-U/2ml) [18].
IncobotulinumtoxinA (Xeomin) additionally has its own guidelines for dilution but these are not described in the literature.
The botulinum toxin LC is the part responsible for the enzymatic activity, which blocks the release of acetylcholine, and is therefore primarily responsible for the DOA. Antibody-mediated neutralisation of this activity limits the duration of impact of the toxin [19].
Personal experience
In my clinical experience, I have noted some patients with an unusually short DOA after BoNT-A injections. These two cases are of special interest because they do not belong to the commonly accepted causes discussed in the literature.
A subset of these patients participates in high-impact sports, such as CrossFit or long-endurance exercise, which could potentially result in an increased metabolism or raise neuromuscular activity levels and affect the duration of BoNT-A efficacy.
In some cases, the rotation with the three BoNT-A brands approved in Argentina (OnabotulinumtoxinA, AbobotulinumtoxinA, IncobotulinumtoxinA) was implemented, however the duration of the clinical action was always short (from 15 to 20 days).
This suggests that other, possibly genetic, immunologic or metabolic factors beyond the ones already identified may be responsible for BoNT-A treatment response in selected patients and should be further characterised.
Conclusion
Shortened botulinum toxin efficacy is multicausal. Both dermatologists and plastic surgeons need to critically evaluate products, tailor dosing and protocols, and educate technicians to inform patients about lifestyle changes. Following such holistic approaches may help in optimising and extending treatment efficacy leading to maximised patient satisfaction and compliance.
References
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[All links last accessed May 2025]
Declaration of competing interests: None declared.
