Botulinum toxin in aesthetic applications: ‘How often misused words generate misleading thoughts’

Sirs,

The use of type A botulinum toxin (BoNT‐A) in aesthetic indications has brought to clinicians an important tool for patient treatment. BoNT‐A has consistently demonstrated that results can be obtained which persist for significant periods and which can be reproduced on re‐treatment (1,2). Although the potency units of different BoNT‐A products are not interchangeable, this issue has been discussed in the literature for 15 years (see, for example, (3)) and has been overshadowed by the overlying benefits available.

There is, however, a further persistence with regard to the BoNT‐A products that is serving to confuse clinicians with incorrect information, based upon poorly designed clinical studies and, essentially, marketing hype.

We have recently written on the ‘confusion about diffusion’ issue (4) in an attempt to provide clinicians with correct, scientifically based data and facts upon which to make valued (and valuable) judgements. Through this and other publications (5–7) we have tried to stem the tide of errors that have become perpetuated and which have now become facts simply by repetition, not by scientific discovery and data. We attempt here, once again, to correct these errors for the benefit of both patients and clinicians.

In a poorly designed and executed study, De Boulle (8) has attempted to demonstrate that one BoNT‐A product (Botox^®) is preferred to another (Dysport^®). The study is described as a clinical trial but is, however, a clinical trial prone to various bias that does not enlighten but clouds the readers’ sight. What makes a good, unbiased and comparative clinical trial? The answer: randomization and blinding (9). This study has neither of these important characteristics. Furthermore, the study design comprises both retrospective and prospective parts, making an unbiased comparison of the two treatments impossible. This is not a design to be recommended when comparing two different preparations. Last, but not least, only 40 subjects were recruited, which cannot give statistical power to the results of a null‐hypothesis.

No safety data were recorded for one of the products and therefore comparisons cannot be made on this key aspect. This is a major deficiency for such a study. Details of adverse events for only one product are given and these are unexpected in certain respects. For example, the listings of eyelid heaviness (perhaps ptosis), heavy or unnatural eyebrow, inability to show facial expressions and eyebrow asymmetry are abnormally high (30% or more in some cases) for the ‘new’ Ipsen BoNT‐A product. An inability to show facial expressions indicates that too high a dose of product was used. This is reflected, for example, by the mean dosage for the glabella area for the ‘new’ BoNT‐A (Ipsen) that, at 63 units, is higher than the recommended dosage, as used in other trials, of 50 units (5). But this is still insufficient to adequately explain the differences‐doses of 75 units of the product have still shown a good safety profile in the glabella (5). Therefore, the area of safety cannot really be assessed, one product against another, according to modern clinical standards.

For the same reasons, there is little ground to regard the assumptions that have been made by the author about patient satisfaction with either the one or the other product. By including only satisfied or extremely satisfied patients with the clinical benefits of a well‐defined previous treatment, further evaluations of satisfaction with any new treatment can only decrease.

Based on these data, it cannot be concluded that a switch from the ‘old’ BoNT‐A (Allergan) to the ‘new’ BoNT‐A (Ipsen) for patients should not be recommended.

The subject of toxin ‘migration’ (nowadays an incorrect term: this should be ‘diffusion’) from the injection site has, once again, been raised by the author to highlight potential differences between the BoNT‐A products. We have recently reported on the errors of these statements (4,7). They are not based on scientific fact for a number of reasons. The most important is that BoNT‐A complex dissociates under physiological conditions, freeing the neurotoxin molecule. This is an essential and absolute part of the mode of action of the neurotoxin, since the molecule cannot act to bind to target receptors when associated with the other proteins of the toxin complex. All BoNT‐A complexes must behave the same way for the neurotoxin molecule to act and therefore, by definition, must have the same diffusion characteristics for their neurotoxin components. Any differences observed are due to differences in administered toxin concentration alone. Again, by Fick’s Laws of Diffusion (10), the diffusion characteristics will be due to the concentration present‐more toxin will simply diffuse more until bound to the appropriate acceptors (11,12). In such studies, the higher diffusion with associated adverse events for one product is due to an inappropriate so‐called dose conversion factor, often coupled with an inadequate, non‐standardized injection technique (13). When a suitable dose conversion factor is employed with a highly standardized injection technique, the results for both products are equal at equal doses (14,15).

We encourage authors and clinicians to examine studies, such as those by De Boulle (8), both carefully and critically before concluding anything about the BoNT‐A products used. We also advocate and encourage the use of evidence‐based medicine when considering product comparisons‐evidence based upon scientific fact and not marketing‐driven urban legends (7). Without these approaches, the potential for misleading information and the fact that ‘… misused words generate misleading thoughts’ in the clinical arena is high. (Herbert Spencer, The principles of ethics, 1879)