Some Relaxing News: Exploring How The Neuromodulator Landscape Is Evolving From Botox to Revance

More on Neuromodulators

Neuromodulators, also termed neurotoxins that are used in plastic surgery are derived from botulinum toxin A, a substance produced by Clostridium botulinum bacteria. Botox is the original product, with Dysport, Xeomin and Jeuveau also on the market in the United States.  I like the term relaxers for these medicines as it points out the muscle relaxing mechanism by which they work.

History of Cosmetic Use

Botulinum toxin A medicine and the illness botulism are totally different.  Many medicines are metabolic blockers –they block a specific pathway.  If they are very specific and precise that can be helpful for therapeutic purposes.  The relaxer medicines are very specific with a very high therapeutic index (the difference between the effective dose and the toxic dose).  The botulinum toxin was isolated in the 1940’s.  Very controlled amounts were used to treat some specific medical conditions leading to an FDA approval for Botox in 1989 for blepharospasm and strabismus, conditions relating to muscles around the eye.  In 2002 (Botox just had it’s 20th anniversary in April 2022) the medicine was approved for cosmetic treatments of wrinkles between the eyebrows.  Subsequent approvals of Botox for hyperhydrosis (2010), migraines (2013) and other medical applications have occurred.  New botulinum toxin A products have also been approved Dysport (2009), Xeomin (20110, and Jeuveau as the 4th.

These medications act at the nerve endings where vesicles of acetylcholine are released and dumped into the space between the nerve endings and muscle fibers causing the muscle to contract.  Botulinum toxin A  binds irreversibly to the SNAP25 receptor on the acetyl choline vesicles preventing them from releasing.  This leaves the muscle unable to contract until new vesicles are generated which takes several months.  Depending on dosing, the muscle relaxes partially or totally.

Treatment Experience

Treatments include carefully assessing the dynamic component of any feature which is caused by muscle contraction and the resting tension in the muscle.  Fixed wrinkling resulting from aging changes in the skin is not well treated by relaxers.  Careful assessment must also be made of where the muscle is active which requires good anatomic knowledge and an observant provider.  This tells us where the medicine needs to be placed.  The treatment targets the muscle not the wrinkle itself.    Numbing gel, topically applied cooling or vibrating devices are used to blunt the sensation of injecting.  The medicine is dotted in with small injections in several areas over the targeted muscle.  This only takes a few minutes after which you can return to work or routine social activities.  Every provider has different rules, but I ask my patients to avoid bending lifting and sports for the next four hours.  Over a few days the effect begins to show, peaking after a couple of weeks and lasting a few months.  This varies from person to person depending on their muscle dynamics and the dosing and injection scheme used.

Cosmetic Uses for Relaxers

The most common uses for relaxers, often performed simultaneously, include:

  • 11’s –the vertical lines formed between the eyebrows
  • Forehead lines –the horizontal lines across the forehead at rest or with animation
  • Crow’s feet –wrinkling at the corner of the eye, if dynamic, made worse on smiling

Other commonly treated areas:

  • Bunny lines –little wrinkling by the side of the nose
  • Chin –for cobblestone like dimpling during animation
  • Lip stick bleed lines –if there is a dynamic component
  • Marionette lines –if there is a dynamic component
  • Platysmal bands –vertical bands in the neck if visible and no significant loose skin

Newer uses:

  • Lip flip –helps to roll up the upper lip, providing more vermillion show (pink lip)
  • Masseter –to soften a square jaw to a more oval facial shape
  • Nefertiti lift –jawline injection to float up and sharpen mild laxity

Acetyl choline blocking also affects sweat production and sebum production.  Microinjections to modulate oiliness of skin, pore size and potentially acne are being tried.  Injections for hypertrophic scars also sometimes include small doses of relaxers.

Role of Neuromodulators/Takeaways:

  • Not for laxity prevention or treatment
  • Not for volume loss
  • Excellent for dynamic rhytids, the dynamic component of some folds
  • The future may include really different relaxer products with longer durability or topical application. Impossible to say when or if they will be approved.
  • Neuromodulators (relaxers) are the #1 cosmetic treatment with 65 million injections in 2020 according to statistics from The Aesthetic Society.  By comparison, fillers are the #2 treatment with 1.3million injections and liposuction, the most common surgical cosmetic treatment was performed 296,000 times in the same year.

Why are neuromodulators the most popular treatment?  Reason include the easy experience, speed, lack of downtime but most important the effect is exceptionally pleasing to most people, leaving them looking rested and natural in a way that really resonates and makes them love their appearance.


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Doreen Wu (00:00):
Welcome to another episode of Park Avenue Plastic Surgery Class, the podcast where we explore controversies and breaking issues in plastic surgery. I’m your cohost Doreen Wu. I’m excited to be here with Dr. Lawrence Bass Park Avenue plastic surgeon, educator, and technology innovator. The title of today’s episode is some relaxing news exploring how the neuromodulator landscape is evolving from Botox to this episode is focused on neuromodulators. I hear that term often used interchangeably with neurotoxins. Are they the same thing? Do they both refer to Botox Dr. Bass?

Dr. Lawrence Bass (00:39):
Yes. There are all kinds of different names for these medicines. Neuromodulators is the most popular. I also like the phrase relaxer because it explains what it does. Uh, but these are all medicines that are botulinum toxin A.There are four products on the market in the United States, all of which are type A, there used to be a type B product. There, there are several stereotypes for this particular toxin, but only type A is on the market currently as Botox, which was the original product. And then several others, which we’ll discuss going forward.

Doreen Wu (01:24):
It’s interesting to know that there are several neuromodulator brands available on the market. Can you give us a history lesson of how neuromodulators came to be used for cosmetic purposes?

Dr. Lawrence Bass (01:35):
So the medication is distinctly different from the illness. Botulism is an illness that’s caused by bacteria and food. The bacteria multiply in your body and in the food and produce the toxin, which poisons you. Many medicines are in fact, metabolic blockers. They block or poison a specific metabolic pathway, but if it does it very specifically and is dosed correctly, that can be therapeutic instead of dangerous. And that’s exactly what happens with Botox and the other medicines like it, the particular chemical substance that does this, that the bacteria was eventually identified and isolated in the 1940s, very controlled amounts of this were then studied for treatment of various muscle spasm disorders. And while they were doing this, they noticed that wrinkling in the area would be reduced as well. In 1989, the FDA approved, uh, Botox for blepharospasm and strabismus problems with involuntary blinking of the eyelids and trouble with some of the muscles that control the position of the eye. In 2000 muscle spasm problems in the neck were approved.

Dr. Lawrence Bass (03:09):
And then in 2002, it was approved for wrinkles in between the eyebrows. What’s become termed the elevens and other approvals followed that in reconstructive areas as well as cosmetic approvals. So 2004 excessive sweating, or hyperhydrosis 2010 migraines, in 2013 an approval for lateral canthal wrinkles or the crows feet wrinkles at the side of the eye. Um, and also we’ve had multiple approvals of new products. So in 2009, Dysport became the second neuromodulator approved in the United States. Um, Xeomin in 2011, became the third and Jeuveau the fourth of these type A botulinum toxin medications.

Doreen Wu (04:12):
How do these neuromodulators work? You mentioned that they’re made from the botulinum toxin type A, but how exactly do they relax our muscles and treat the wrinkles?

Dr. Lawrence Bass (04:23):
So the medication acts actually at the nerve ending where normally little vesicles of acetylcholine are released open up and dump acetylcholine into the synapse or the space between the nerve and the muscle. And that stimulates the muscle to fire these medications bind to a specific receptor called snap 25 that prevents the vesicles from opening up and releasing the neurotransmitter acetylcholine that leaves the muscle unable to contract and it relaxes. So that depending on the dosing takes some role of the activity out of the muscle.

Doreen Wu (05:14):
The science behind how these medicines work makes a lot of sense. Can you talk me through what a treatment is like

Dr. Lawrence Bass (05:21):
A typical cosmetic treatment on the face involves looking at the features assessing, is there mostly a dynamic component? Is there a fixed wrinkle or fold component? And that’s going to be treated in a different way, not with a neuromodulator, but the dynamic component is going to be treated with the neuromodulator seeing exactly where the muscle is active because the treatment targets the muscle, not the wrinkle, in other words where the medicine needs to be placed. Most of us will apply numbing gel or cool, or sometimes a vibrating element. All of which blunt the sensation of injecting the medicine under the skin and the medicine will be dotted in, in several areas over the course of the muscle that’s being targeted. This treatment’s done in just a few minutes. And at the end of the treatment, you can resume most of your normal activities. Although everyone has different rules. I ask patients not to have bending, lifting or sports for a few hours over a few days, the muscle starts relaxing. And after a week or two, the medicine is at peak effect. And this persists for several months, the package insert or what’s called the information for use says the effect is three to four months. Although many patients may go as long as six months before they need retreatment.

Doreen Wu (07:01):
So far, we’ve mostly focused on the muscle relaxing effect of neuromodulators, but I’ve heard of Botox being used for other purposes. Can you talk about some of these?

Dr. Lawrence Bass (07:11):
So this blocking of acetylcholine release has effect on a number of other factors, such as sweat production, and again, a specific FDA indication for hyperhydrosis sebum production, uh, which is oil produced on the skin and may be related to how oily the skin looks or how much acne is taking place in the skin. Other characteristics of skin, character or scars may be treated, and some people believe can be treated with micro amounts of, of neuromodulators. And these are all off-label kinds of applications currently, except the hyperhydrosis. And there’s some discussion about mood elevation with Botox and other neuromodulators. And whether that’s because we’re happier, because we look better. Whether not frowning makes us feel better, or if there’s some direct biological effect, nobody knows, but this is something that’s being investigated.

Doreen Wu (08:21):
Let’s shift gears and talk about how the neuromodulator landscape is evolving. What are some of the new developments?

Dr. Lawrence Bass (08:28):
There are always new approvals and new indications coming, uh, for cosmetic applications. The original approval, as we said was the 11 lines, the, the vertical lines in between the eyebrows, but there are approvals being sought for all three areas together with, with each of the individual neuromodulator products. There are approvals for new medical conditions being sawed and, and a number of treatments for off-label indications. We treat the vertical lines, but bunny lines in the nose are commonly treated lines going side to side across the forehead, the crows feet, as we mentioned. And in addition, there are a number of areas low down in the face that are treated, things like cobblestoning in the chin lipstick bleed lines, sometimes marionette lines have a significant dynamic component or more of a dynamic component on one side of the face and neuromodulators can be used to help that vertical banding in the neck is commonly treated. And some people like to do something called the nefertiti lift, which involves injecting under the jaw line to help relax that portion of the platysma muscle and float up some of the skin in a face that’s beginning to sag.

Doreen Wu (09:55):
That leads me to my final question, Dr. Bass, what is the role of neuromodulators overall and what are some takeaways for our listeners from this episode?

Dr. Lawrence Bass (10:05):
So each modality has its own application. So neuromodulators are not for laxity prevention or treatment. They’re not for volume loss prevention, which is fillers, but they’re excellent at treating dynamic rids and or wrinkles. And as an adjunctive treatment for the dynamic component of some folds, for example, the marionette lines or cobblestoning in the chin. There are new products coming that are under investigation. At least two companies have spent time investigating topically applied products that can be transmitted through the skin using proprietary vehicles. These are not FDA approved and no way of knowing if they ever will be, but there are certainly significant clinical data suggesting that there’s progress in these areas. So we may see products that are really different from what has happened previously with the existing four. Uh, this is a primary treatment for dynamic rids. That’s the number one cosmetic treatment in the US, surgical or nonsurgical. There were 2.6, 5 million injections in 2020, which again is the last year that statistics were available from the aesthetic society. Fillers are number two with 1.3 million treatments. And just to give you an example, the number one surgical treatment is liposuction with 296,000 in 2020. Why is it the most popular treatment? Because it’s quick, it’s easy to do. There’s no downtime. And there’s something about the effect that patients seem to find exceptionally pleasing, just a rested smoother look. That’s natural that resonates with patients as looking like themselves, but looking good.

Doreen Wu (12:05):
Thank you for joining us today and sharing the quote unquote relaxing news about neuromodulators. It has been fascinating to learn more about the myriad of ways in which neuromodulators can be used for aesthetic purposes. If you think of other exciting developments in plastic surgery that you would like us to discuss in an upcoming episode, please reach out. This is Doreen Wu, thanking you for joining Dr. Bass and me for this discussion of neuromodulators Botox and the like be sure to join us next time. And don’t forget to subscribe to our podcast so that you don’t miss out on all of the exciting content that is coming soon.

Speaker 3 (12:40):
Thank you for joining us in this episode of the Park Avenue Plastic Surgery Class podcast with Dr. Lawrence Bass Park Avenue plastic surgeon, educator, and technology innovator. The commentary in this podcast represents opinion. This podcast does not present medical advice, but rather general information about plastic surgery that does not necessarily relate to the specific conditions of any individual patient. No doctor-patient relationship is established by listening to or participating in this podcast, consult your physician to advise you about your individual healthcare. If you enjoyed this episode, please share it with your friends and be sure to subscribe to our podcast on Apple Podcasts, Google, Spotify, Stitcher, or wherever you listen to podcasts.

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