The glabellar frown lines (between the eyebrows) are a top target for Botox injections. They are what the initial studies for FDA approval was based on and continue to be the number one wrinkle area treated by injection. Other than an occasional bruise or temporary soreness in the injected area there are few other adverse problems that happen with injections in this part of the face. The typical effective dose of Botox is in the range of 16 to 24 units by most injectors.
In the September issue of the journal Plastic and Reconstructive Surgery, an article was published entitled ‘Efficacy and Safety of Botulinum Toxin Type A in the Treatment of Glabellar Lines: A Meta-Analysis of Randomized, Placebo-Controlled, Double Blind Trials’. In this paper the authors looked at seven studies comprising nearly 1500 patients to assess the safety and effective endpoint (dose) of botulinum toxin type A for treating glabellar lines. The seven studies included were all randomized, placebo-controlled and double blind trials that used an injection dose of 20 units. Their findings show the the botulinum toxin injected patients had much better improvement in their glabellar wrinkles than the placebo group but, interestingly, the same rate of adverse events.
The incredible popularity and use of neuromuscular modulators in the face using botulinum toxin injections over the past nearly two decades is a statement in and out itself. It is a testament alone that they must be fairly effective and incredibly safe. This study, which amassed well conducted other studies supports what widespread clinical use has shown.
Botox is the undisputed king of aesthetic neurotoxins since it was officially FDA approved in 2002. While newer neurotoxins from different manufacturers have since emerged (Dysport, Xeomin), they have not and likely never will topple the market share that Botox currently has. Most likely it will waver with modest changes back and forth very similar to what goes on the soda market battle of Coke vs. Pepsi.
But just because these other neurotoxins have a much smaller piece of aesthetic neurotoxin pie, does that mean they are inferior products? It is generally believed that all three neurotoxins are equivalent in terms of effectiveness and in how long they last. Botox is much better known, not only because they were the first neurotoxin FDA-approved and revolutionized the aesthetic facial industry, but because its manufacturer Allergan has done an outstanding job with its branding efforts.
As the last of the neurotoxin three to enter the market, the comparative effectiveness of Xeomin has not been backed up by any good comparative science. A recent study, however, may finally put that issue to rest. In a recently reported prospective double-blinded study Xeomin and Botox went head to-head in the treatment of glabellar frown lines in several hundred women using 20 units of each drug. The study showed equivalence in terms of time of onset, peak effect, number of complications and patient satisfaction levels. Such study information is critical as doctors had to rely on their own experience and word of mouth as to the merits of Xeomin.
Despite its equivalence to Botox, the use of Xeomin is going to be highly influenced by the practice behavior of the injector. Some practices use all three neurotoxins while others may only use one exclusively. Personal preference, brand familiarity, practice behavior and cost all lead to preferences of neurotoxin use. The cost issue is what aspect where Xeomin excels over Botox. It comes at a lower acquisition cost and these savings can be passed onto the patient.
Change is difficult and for this reason many patients may not be willing to leave Botox for a different neurotoxin. But because of clinical equivalency neurotoxin experimentation is possible with no downside.
Aesthetic facial neuromodulation, aka ‘Botoxing one’s face’, is a long proven method for reducing the development of certain facial wrinkles and unwanted facial expressions. It has been done for so long and with such success that the original facial neurotoxin and still the most popular, Botox, has worked its way into the cosmetic procedure lexicon as a verb.
But Botox is not the only player in the injectable neurotoxin market as two ‘younger’ products have appeared in the scene in the last five years, that being Xeomin and Dysport. While all three advertise, promote whatever subtle differences that may exist between them and physicians have their preferences between them for their own reasons, but it is not really clear whether one is more or less effective than the other.
In the May 2015 issue of Plastic and Reconstructive Surgery journal, the article entitled ‘A Prospective Split-Face, Randomized, Double-Blind Study Comparing OnubotulinumtoxinA to IncobotulinumtoxinA for Upper Facial Wrinkles’ was published . In this paper a clinical study was published on 45 patients (41 women and 5 men) who had three types of facial wrinkles treated using a 1:1 dose ratio of Botox and Xeomin. A total of 50 units of each drug was administered to the upper face in three areas. (glabella, forehead and crow’s feet) and evaluated over a four month period. The effect on the wrinkles was assessed by a scale amongst blinded physicians. For toxin comparison, the researchers calculated differences in the degree of wrinkle scale at each period compared with pre-treatment and performed statistical analyses. They analyzed wrinkle types both individually and combined.
Their results showed that at identical doses, both Botox and Xeomin are safe and effective in the treatment of upper facial wrinkles. However, Botox had statistically greater effectiveness in dynamic wrinkle reduction at each point in the study out to four months. This would suggest. although does not prove, that Xeomin may need higher doses to be equally effective.
Botox injection therapy is the single greatest pharmacologic agent in use today for non-surgical facial rejuvenation. It has been become so popular and used that patients talk about getting ‘Botoxed’…reminiscent of days when copying was known as ‘Xeroxing’. That is how you know your product has worked its way into the national lexicon when its name becomes used as a verb.
With such treatment popularity, competition is inevitable (which is good) but imitators may also emerge. (which for a drug can be very bad) Known as ‘Black Market Botox’ drugs that appears as the real Botox or try to be passed off as such have been known to occur. The FDA reports today that such compounds have been found in the U.S. and may be being used in some doctor’s office and clinics. This occurs when an unlicensed supplier who is not permitted by FDA regulations to ship or distribute products into the U.S. does so. Offering seemingly similar effectiveness but at lower prices is the inducement for physicians to purchase and use it. Patients would have no idea that an unlicensed drug may be given to them during their treatments.
Since these compounds have not been manufactured according to FDA standards, there is no assurance that they are safe or effective. How can one tell if their ‘Botox’ is real? For physicians it can be determined by the packaging and the actual vial that contains the compound. On real Botox as manufactured by Allergan the active ingredient known as onabotulinum toxin A is listed on the outer carton as well as on the glass bottle. With the fake compound, the active ingredient is listed as botulinum toxin type A is listed on the outer carton and glass bottle. Also on the fake product the glass bottle may be missing any lot numbers.
For patients determining that they be given a counterfeit product may be impossible to tell. Very low advertised prices per unit or extraordinary specials may be a clue. Injections done in non-medical settings by dubiously qualified injectors may be another tip off. Any change in the effectiveness of one’s ‘traditional’ Botox treatment may also raise some suspicion.
Botox can be used for a wide variety of facial deanimation purposes that has aesthetic benefits. By far the most common facial area that is treated by Botox injections because of its undesireable wrinkles and furrows created by excessive muscle activity is the forehead. A far less common area is that on the south side of the face around the mouth.\
One of the features that makes for an aged or unhappy appearance is that of drooping or downturned corners of the mouth. This is partially contributed to by the weight of falling midfacial tissues, but an overactive depressor anguli oris (DAO) muscle can also play a major role. This muscle originates from the lower jawline and comes upward and inserts into the modiolus muscle as well as interconnects with other adjacent facial muscles as well. (risorius, zygomaticus and depressor labii inferiorus) The action of the DAO muscle pulls the corner of the downward.
Botox injections into the DAO muscle can help lift and level out a downturned corner of the mouth. But to be effective, its injection must be precise due to numerous muscular interconnections. In the November 2014 issue of the journal Plastic and Reconstructive Surgery, on this topic entitled ‘Anatomical Considerations Regarding the Location an Boundary of the Depressor Anguli Oris Muscle with Reference to Botulinum Toxin Injection’ was published. Using cadavers for study, they found that the modiolus was located about 1 cm to the side of the mouth corner and slightly less than 1 cm below this lateral point. The DAO muscle fans oout below the modiolus and is located less than 45 degrees lateral and less than 30 degrees medial to the modiolus down to the jawline. The authors suggest that this fan-shaped area is the safest and most effective Botox injection site.
The modiolus is the intersection of all muscles that act on the corner of the mouth. Since the DAO muscle pulls down on the modiolus, its hyperactivity can lead to drooping of the corner of the mouth. Injection of Botox into the DAO will allow for its weakening and allow its antagonists (levator anguli oris and zygomaticus major muscles) to lift up the mouth corner.
The announcement this month that Johnson & Johnson (J & J) has pulled any further development of their aesthetic neuromuscular modulator PurTox was a surprise. It was certain several years ago that a fourth injectable drug would soon be on the market to compete with the big three, Botox, Dysport and Xeomin. But it now appears that these three cosmetic drugs will only have only to compete amongst themselves for some time into the foreseeable future.
It has now been three years since the last of the big three (Xeomin) was approved. And while there has been some minor new FDA approvals for indications that were already widely done off-label anyway (crow’s feet), the number of men and women seeking this injectable cosmetic treatment continues to grow. Having multiple products to treat unwanted facial lines and wrinkles has helped create awareness and grow the market. These drugs today are as accepted as capuccinos and are done almost just as much. To some degree, Botox and his competitors have very much become commodities where the lowest cost per unit often sways what provider/location that a patient will go to.
This raises the question of how do these drugs differ and, what advantages if any, do any of them offer over the others? What all three drugs share is that they are FDA-approved Type A botulinum toxins. They work exactly the same through the same mechanism of molecular action and all have the same type of heavy chain receptor. While Dysport and Xeomin have a little shorter onset (1 to 2 days), they last the same amount of time as Botox having a duration of action of between 3 and 4 months after injection.
They do differ significantly, however, in their dosing and methods of storage. The dosing of Dysport is very different from that of Botox or Xeomin. This makes it difficult to compare Dysport to the other two in clinical studies. While the biologic activity is the same for Botox and Xeomin, it is quite different for Dysport and there is no standard dose conversion. While all three must be reconstituted on the day of administration, Xeomin does not require refrigeration which makes it more portable and not prone to be accidentally left out of cold storage after a treatment.
From a marketing and public awareness standpoint, Botox is the dominant force occupying close to 80% of the market. It is the ‘Coke’ of the injectable neuromuscular modulators, the most studied and also the most expensive. Dysport and Xeomin are the ‘Pepsi’ and ‘Seven-Up’ by comparison and are still trying to gain market share. As a result they are priced under that of Botox and is there only real method of improving their small market share given that they have no other advantages.
Some small claimed advantages over Botox for Dysport is that it has wider zone of diffusion from the injection site. This may be an advantage in the bigger muscles areas of the frontalis muscle of the forehead and the orbicularis muscle of the crow’s feet area. But would be a disadvantage in a discrete muscular area like the glabella which is also the number one area for all aesthetic neuromuscular injections. Xeomin claims a less risk of allergic reaction than with Botox because it does not contain hemagglutin and non-hemagglutin complexing proteins. While this may be theoretically true, the incidence of allergic reactions to Botox is so insignificant after over twenty years of clinical use that this advantage is meaningless.
While there are other aesthetic injectable neuromuscular drugs under development, none of them seem to have any major advantages over the big three that are available now. Every patient would like them to last longer (or be permanent) and cost less but that does not appear to be likely for as far as one can see into the future. The one promising approach is that of a topical botulinum type A gel of which several companies have ongoing clinical trials. Avoiding needle sticks could be the one advantage a new product could have that would help shakeup the market as we know it now.
Botox is the most common method of forehead rejuvenation used today. Literally billions of injections has been done in various locations around the brows and upper forehead over the past two decades around the world. Its effectiveness is unquestioned and there is no indication that the number of treatments provided in the foreseeable future will be any less.
While there are variables in the administration of Botox, including dose and forehead injection locations, injecting into the forehead tissues seems straightforward. But to those who have ever done Botox injections, the forehead tissues are thick and there are a number of different tissue planes where it can be deposited. From just under the skin to all the way down to the bone, the deposition of the neuromuscular toxin can be done. But what is the correct tissue level and does it matter?
In the March/April 2014 issue of JAMA Facial Plastic Surgery an article appeared entitled ‘Subcutaneous vs Intramuscular Botulinum Toxin – A Split-Face Randomized Study’. In this paper, a study was done to determine the difference between subcutaneous (SC) and intramuscular (IM) injection location. In nineteen patients, Botox injections were done on a randomized basis so that each patient received SC injections on one side of the forehead and IM injections on the other side. At two weeks and two and four weeks after injection, the degree of eyebrow elevation by measurements was assessed. These measurements showed no differences between the SC and IM injections. IM injections were rated as having greater discomfort than SC injections.
This study showed that the SC injection of Botox is equally effective in achieving denervation of the forehead muscles as IM injections. And what is known from my experience is that the deeper the injections are placed the more uncomfortable it can be for some patients. And with no benefit for effectiveness, there is no reason to place the needle any deeper than just under the skin.
Keloids represent the extreme of scar problems. As a tissue overgrowth response to an injury, and often progressive and unremitting, keloids are a true pathologic scar problem. Besides being an overly obvious scar problem, it is also highly refractory to conventional scar therapies. While many strategies have been used for difficult keloids after excision (e.g., steroid injections, radiation treatments), there still remains a very high recurrence rate. There remains a need to for new and novel approaches to see if lower recurrence can be achieved.
In the Summer 2013 issue of the Canadian Journal of Plastic Surgery, an article was published entitled ‘Eradication of Keloids: Surgical Excision Followed By A Single Injection of Intralesional 5-Fluorouracil and Botulinum Toxin’. This study involved eighty (80) patients with keloids of at least one-years’ duration. Following total surgical excision of the keloid, a single dose of 5-fluorouracil (5FU) was injected into the edges of the healing wound on postoperative day nine (9) together with botulinum toxin.
The concentration of 5-fluorouracil used was 50 mg/mL and approximately 0.4 mL was infiltrated per cm of wound tissue, with the total dose <500 mg. The concentration of botulinum toxin was 50 IU/mL with the total dose <140 IU. Patients were followed-up to two years and a recurrence rate of 3.75% was found.
The present study shows a very low recurrence rate by keloid scar standards that is comparable to other studies with post-excision radiation treatments. One has to assume that it is the Botox that has a significant pharmacologic effect as 5FU injections alone would not have such a low recurrence rate.
Since Botox has a known effect as a muscle weakener/paralyzer, how then does it work on scars? Several clinical studies and reviews have been done on the effects of Botox injections on scars. Besides the obvious benefit of preventing muscle pulling on the edges of a fresh wound or scar (which is really only a consideration in certain types of facial scars), its potential benefits are largely conjecture. Some have hypothesized that it inhibits fibroblast proliferation or the action of myofibroblasts, which makes theoretical sense, but that has never been scientifically proven or verified.
This is a fairly large clinical series of keloid treatments and would thus indicate that there is merit to the injection of Botox after their excision. The mechanism of action remains speculative but its use is certainly more convenient and less costly than post-excision radiation treatments.
Botox is the trade name of the first commercially available preparation of botulinum toxin A (BTN-A). It is the miracle drug in aesthetic medicine, plastic surgery and neurology. Botox is so popular in aesthetic medicine because it predictably works each and every time. It is a medication in the real pharmacological sense of the word. Like a blood pressure pill which lowers the blood pressure if taken as directed by the doctor, Botox decreases facial wrinkling if injected correctly by an experienced practitioner. Like any other medication, Botox has to be reapplied at certain intervals to maintain its anti-aging and facial rejuvenation effects.
Botulinum toxin A (BTN-A), the pharmacologically active substance in Botox, is a very potent neurotoxin. It is naturally produced by spores of the bacterium Clostridium botulinum and results in severe poisoning if ingested in high doses. Clostridium botulinum produces a range of neurotoxins, which were named very creatively Botulinum Toxin A to F. They bind to the junction of the nerve endings with muscle fibers and prevent those nerve endings from secreting the neurotransmitter acetylcholine in response to electrical impulses. Without acetylcholine the muscle fiber at the downstream end of the junction does not contract.
Botox Is Both A Poison And A Cure. Swiss physician Paracelsus in the 1500s stated that the main difference between poison and medication is the dose. This statement is no better illustrated than in the use of Botox. When used in minute doses as a Botox preparation and injected directly into the relatively small target muscles in the face then activity of those muscles and formation of wrinkles at right angles to the course of the muscle fibers are reduced without any systemic toxicity. How different is the dose between the treatment of wrinkles and systemic toxicity? Try the difference between 20 units and 35,000 units.
The Use Of Botox Is Not New. It has been used since 1989 to treat painful spasticity in the context of various neurological diseases. One of the first applications in the face was in the treatment of spasticity of the eyelids, so-called blepharospasm, which subsequently led to its use for facial wrinkles. Use of Botox for cosmetic purposes was not approved by the FDA for the longest time, although large quantities were used off label for wrinkles since the early 1990s. Only in 2002 was it officially approved for treatment of forehead wrinkles and glabellar wrinkles and frown lines. Although used to treat the small radial wrinkles around the eyes, the so called crow’s feet, for decades, it was not formally FDA-approved until much later in 2013.
Botox Wears Off By Nerve Sprouting. Why does the effect of Botox not last indefinitely? The reduced but still present activity of muscle fibers represents a stimulus for the sprouting of new nerve endings secreting acetylcholine without impediment of previously applied Botox. Thus the activity of muscle fibers is again increased. This process takes three to four months on a molecular level. One can picture it like a potato forming sprouts if left in darkened storage. Additionally, nerve endings replace the entire blocked mechanism of acetylcholine secretion.
Botox Is No Longer Alone. Botox was originally manufactured by the US company Allergan under the trademark Botox and marketed worldwide. Until fairly recently, Allergan owned a patent which conferred a monopoly on the market. The latter was lost when alternative preparations of botulinum toxin were approved in the form of Dysport and Xeomin. From a patient perspective and clinical effectiveness standpoint, there is hardly any difference between them. They differ mainly in their pharmaceutical preparation, dose equivalents, necessity of an intact cooling chain, and activity after reconstitution, all concerns for the manufacturers and injectors but not things patients need to worry about.
The Applications for Botox Continue To Grow. Being a true miracle drug, the areas of application for Botox are far from over. One of the milestones in the Botox success story was undoubtedly the recent approval of Botox in the treatment of migraine headaches, which are caused by certain hyperactive muscle of the face which compress sensory nerves running through them causing a migraine.
The use of botulinum toxin A, otherwise known as Botox, has become a common aesthetic practice around the world. It is used daily as a treatment to soften wrinkles, helping to prevent and correct tired and aging appearances. In today’s society looking as young on the exterior as people are feeling on the inside is becoming more and more important. Botox is allowing this to happen in a quick, safe and effective manner.
There are, however, undesired aesthetic consequences from Botox that prove that facial expressions are complex and can easily be imbalanced to create peculiar aesthetic appearances that many find unattractive and want to avoid. At the least they are the telltale signs of having had Botox injections.
Spock Eyebrow The famous “Spock eyebrow,” also referred to as the evil eyebrow, leaves people with a consistent angry look on their face. It is the result of glabellar injections or treating the 11s. The glabellar creases are formed because of the actions made by both the procerus and corrugator muscles, pulling the eyebrows inward. If the frontalis muscle is also injected directly above the procerus, this will paralyze the entire central forehead and brows, causing the medial brows to drop and the lateral brows to remain high. In addition, there may be residual small horizontal wrinkles left above the lateral brows. Treatment for the “Spock eyebrow” can be done by injecting the frontalis muscle laterally above the eyebrows to help lower them to the same level as the medial brows. This treatment will also eliminate the small horizontal wrinkles above the lateral brows as well.
Frozen Face A heavy forehead and brows is also another unaesthetic sequelae from Botox injections. This is also commonly referred to as a “frozen face” or being left with the feeling an elephant is sitting on one’s forehead. This can occur when many areas of the forehead are injected from the glabellar creases, horizontal forehead lines and the crow’s feet. When all three areas are treated, people are often left with the appearance of a “frozen face” because all that appears to move is the mouth. Although this is the look some people are after with Botox treatments, often times it is not. This proves that it is possible to have too much of a good thing.
Heavy Brows When injecting the glabellar creases in addition to the forehead it is important not to block the frontalis muscle directly above the procerus as well as not to over inject (use too many units) in the frontalis muscle as a whole. When too many units are used, the muscles become so relaxed that the brows become heavy and sag lower. In a patient who already has some degree of hooding, it doesn’t take much Botox to potentially tip the balance towards further brow ptosis. of It is important to assess a patient prior to injection, paying close attention to the amount of hooding that may or may not already be present in the upper eyelids. The administration of too many units can easily make this hooding worse, and leave the patient feeling they have heavy brows.
The only treatment for heavy brows or the frozen face is time. While Botox normally takes a full three to four months to wear off, fortunately these adverse effects seem to improve more quickly often being much better by six to eight weeks after the initial injections.
Dr. Barry Eppley is an extensively trained plastic and cosmetic surgeon with more than 20 years of surgical experience. He is both a licensed physician and dentist as well as double board-certified in both Plastic and Reconstructive Surgery and Oral and Maxillofacial Surgery. This training allows him to perform the most complex surgical procedures from cosmetic changes to the face and body to craniofacial surgery. Dr. Eppley has made extensive contributions to plastic surgery starting with the development of several advanced surgical techniques. He is a revered author, lecturer and educator in the field of plastic and cosmetic surgery.