Duration of Neuromodulators – What You Need to Know

 

There is renewed interest in neuromodulator/neurotoxins because of 2 newcomers to the US aesthetic market. Jeuveau is FDA approved and Revance will be approved early 2020. To differentiate themselves, these 2 have focused on duration of action of their products. Here’s the lowdown on what patients need to know about these wrinkle eradication injections.

There is a well-recognized scale that grades the glabellar lines at full contraction. Grade zero being no lines and 4 being the most severe dynamic lines. Keep in mind that this scale references only lines which appear during motion, not the static lines found at rest. In order for the FDA to approve injectable neuromodulators for the glabellar lines, there must be a demonstrable 2 point improve in this scale after 30 days. The take home messages of these FDA studies are:

1. The FDA considers a one-point improvement a failure, but the companies do not. There is literature and marketing by several companies stating their 4 or even 5 month duration for one-point improvements.
2. At FDA approved dosing, most grade 4 glabellar lines will not relax to the grade-zero score. In fact, with any dosing, grade 4 patients will most likely still have movement and wrinkles after treatment.
3. Not all patients had a 2 grade improvement in the FDA trials of any of the neuromodulators. Approximately 88-92% of patients responded to the FDA approved dosing.
4. The effect of muscle relaxation peaks at about 2-4 weeks, and then gradually tapers off. Muscle strength eventually returns to baseline at 3-6 months, depending on the dosing and the product used.
5. At 3-4 months, the FDA approved duration of the current modulators, a minority of patients still have 2 grade improvements in their glabella grade.

A well-established phenomenon with all the neuromodulators is the dose-response curve. The higher the dosing, the more effective the relaxation of the muscle injected. Additionally, the higher the dosing, the longer duration of the relaxation. Dr. John Josephs has performed studies on Dysport using dosing of 120 units (FDA approval is 50u) and has shown up to 6 months of 2 grade improvements in a significant proportion of patients. One “trick” he used when using these higher doses was to minimize the reconstitution volume to only 1cc. (Most practitioners use 1.5-3cc). Dr. Joseph refers to this technique as “A big dog on a short leash”. In other words, high dosing with limited spread in order to limit adverse events.

An as yet to be approved neuromodulator from Revance will be after a 6 month approval of their product. While at first glance, their 40 unit dosing will appear to be using the phenomenon of higher dosing – longer duration, this is not the case. Neuromodulators units, unfortunately, are not uniform between companies. A study Revance performed on the actually molecular weight of the active neurotoxin in their dosing showed that it was equal to that of the 20 unit dosing of Botox. They also evaluated Dysport’s weight, which was shown to be 50% higher than Botox and Revance, while Xeomin was actually 50% less than Botox/Revance.

What makes Revance’s neuromodulator last longer? It’s an associated proprietary protein that does not dissociate upon reconstitution. It is hypothesized that this protein’s ionic charge leads to better attraction to the receptor at the neuromuscular endplate. Revance’s product is essentially “more efficient” at binding, and therefore blocks more of the muscle movement than the other neuromodulators on the market at FDA approved dosing. Normally, there is some “wasted” neuromodulator which doesn’t bind and is swept away by the lymphatics and blood stream. The proprietary protein mimics what higher dosing would accomplish.

Neuromodulators work by blocking the release of acetylcholine at the neuromuscular endplate of the nerves. Return of function of the muscle is established when new nerve fibers are grown and re-establish contact with the muscle. If more nerves are blocked, it will take longer for the return of muscle function. If all the endplates were blocked to a muscle, studies have shown it takes 9 months for return of function.

After explaining all the numbers, it must be remembered that each patient reacts differently to the neuromodulators. As previously explained in another blog, once water/saline is added to the vials of Botox/Dysport/Xeomin/Jeuveau, there is only active protein in the vial within about a minute. The differences between the products are related to dosing, spread, and experience of the injector. As previously mentioned, Dysport has the highest weight of active neurotoxin in its FDA approved dosing and is the author’s choice amongst the current FDA approved neuromodulators.