Botox 101: Everything you want to know about Botox (& other Neuromodulators)
Introduction
This is a fairly scientific article that will be most helpful for healthcare professionals in the industry interested in injecting or receiving Botox injections. It may also be helpful for other professionals and consumers that want a more thorough explanation of the different neurotoxins.
If you are looking for a simple explanation of Botox and what it does, check out the following articles:
What is Botox?
Botox, which is the brand name for onabotulinumtoxinA (onaA), is a commonly known neuromodulator used to prevent and treat facial rhytids (wrinkles).
It is derived from botulinum toxin and is an injectable medication that can decrease wrinkles by stopping communication between the nerve and the muscle, temporarily leaving the muscle weakened or paralyzed. By inhibiting muscle movement, dynamic wrinkles (wrinkles that occur during expression) become less apparent or completely disappear. Static wrinkles (wrinkles at rest) become less obvious and may also diminish over time as the decreased movement gives the area time to heal.
Botox is made by a pharmaceutical company called Allergan and comes in a 50-100 unit vial containing preservative free, vacuum dried powder of botulinum A toxin, human albumin and sodium chloride. Price varies per unit with the average being $10-14/unit, with an extreme low of $8/unit and high of $20/unit.
Botox/onabotA is one of 7 serotypes of botulinum toxin and has been studied most extensively. It has the most FDA approved indications for cosmetics including the glabellar region (forehead frown/scowl lines), the forehead lines and crow’s feet but is also commonly used off label in the lower face and neck as well as for medical purposes such as migraine.
Please note that terms such as neuromodulators, toxin, & botulinum toxin will all be used interchangeably throughout this article
What are the other types of neuromodulators besides Botox?
As mentioned above, 7 different strains of botulinum toxin have been discovered (A, B, C1, D, E, F and G). Only A and B are currently available for clinical use and A is the most common for aesthetics/cosmetic use. Other forms of type A include AbobotulinumtoxinA (Dysport) and Incobotulinumtoxin (Xeomin). RimabotulinumtoxinB (Myobloc or NeuroBloc) is a type B form typically used for medical purposes and not studied much in cosmetics.
This article will focus on the 3 most commonly used toxins: Botox, Dysport and Xeomin
Dysport
Dysport (aboA) is another form of botulinum toxin used for cosmetics. It was first available in Europe before coming to the United States in 2009. The ingredients in each vial of Dysport are 300-500 units of lyophilized aboA, serum albumin, and lactose. It is FDA approved for the treatment of glabellar lines but is commonly used off-label in other areas of the face and neck. The pharmaceutical company Galderma makes this product.
The dose conversion when comparing Dysport to Botox is about 2-3:1 so many providers will give 2.5 units of Dysport to equal 1 unit of Botox. For example, when treating the glabellar region 11’s lines/scowl lines), if a patient would require 20 units of botox they would require 40-60 units of Dysport for the same area. Dysport is typically priced lower per unit than Botox with an average of $4-8/unit.
Xeomin
Xeomin, a newer formulation of botulinum toxin, is FDA approved for cosmetic treatment of the glabellar region (forehead frown/scowl lines) but is commonly used in other areas of the face and neck. It comes in 50-100 unit vials that consist of a lyophilized powder containing botulinum toxin A, human albumin and sucrose. This product is manufactured by the pharmaceutical company Merz.
It is considered to be equally as potent as Botox and is a 1:1 ratio for treatment, i.e. 20 units of Botox in the glabellar region equals 20 units of Xeomin in the glabellar region. It is thus priced similarly to Botox with an average of $9-13/unit.
Xeomin is also sometimes considered a more pure form of botulinum toxin A because it does not contain complexing proteins (more below).
Can you become resistant to Botox, Dysport and Xeomin?
The short answer is that though it is possible, it is very rare and a suboptimal response is more likely related to concentration, dosage and injection technique. We’ll still dig into the science a bit though.
OnaA (Botox) and aboA (Dysport) both consist of a form of botulinum toxin A that is comprised of a surrounding protein molecule. This protein complex is also present in the original toxin, only larger, as a safeguard to protect it in it’s natural habitat. It is possible that when injected the human immune system might notice this foreign protein and mount an immune response, leading to antibody production and potential resistance.
Much of the literature, mainly with medical treatment, has pointed to larger protein molecule sizes being related to larger resistance. Because of this research, the current makers of Botox and similar Ona forms of botulinum toxin A have markedly decreased the size of the protein complex from around 25ng/100u toxin to 5ng/100units.
Resistance is also much more rare when the medication is used for cosmetic indications as it is injected in much smaller dosages. Uptodate reveals that a meta-analysis that comprised of randomized trials involving 2,240 patients from 1999-2007 only found 11 patients developed detectable antibodies to the toxin and of those only 3 developed true resistance; that is a rate of 0.0049% and 0.0013% respectively.
Xeomin does not contain the protein complex and thus in theory much lower risk for resistance or immune reaction. To visualize the protein complex we’re going to talk candy. So if you think of the 3 different medications as M&Ms, the Botox and Dysport would each be a different colored candy with a hard coating and the Xeomin would simply be a little ball of naked chocolate, with no coating.
Starting with the lowest treatment dose to be effective and waiting at least 3 months between injections can also minimize risk for resistance. If resistance, or tolerance, occurs consider talking to your injector about Xeomin. Also ask them how taking Zinc may improve your results. Read more on that HERE.
Can botulinum toxin spread to other areas?
Knowledge of facial anatomy is crucial to target the correct muscle and prevent spread of toxin.
The spread of injected botulinum toxin is commonly referred to as diffusion. Each of the 3 drugs mentioned: Botox, Xeomin, and Dysport each have different molecular weights that in theory should determine how far they can travel in the tissues. Xeomin is the lightest molecule, followed by Dysport and then Botox. Based on this data researchers have theorized that Xeomin should diffuse the easiest followed by Dysport then Botox. However, this has not been the case.
Most studies have found that neither molecular weight nor protein complexes affect the rate or distance of diffusion. More likely the concentration of medication, dosage, and technique (muscle targeting) contribute to the spread of the drug. For instance, Dysport requires more units per injection to equal Botox or Xeomin, i.e. 10units/0.5ml for one injection of Dysport versus 4 units/0.01 ml of Botox or Xeomin for the same treatment. So despite being a lighter medication than Botox, there has been some evidence that Dysport may spread more extensively than it’s related counterpart. However, more high quality research is needed on humans to prove this.
Do Botox injections hurt?
Pain associated with botulinum toxin injections for cosmetic purposes is fairly mild. Typically there is a poke sensation and then sometimes a burn when the medication is injected. Depending on how the medication was reconstituted, the size of the needle used, the technique of the injector and the amount of toxin injected will all determine pain experienced. Individual pain tolerance is also a factor among others as below.
Whether the medication is injected sub-dermally (just below the skin) or intramuscularly (into the muscle) also contribute to comfort level. Some areas must be injected intramuscularly, for instance in the glabellar region, but the forehead and the crow’s feet can be either. New research that has compared intramuscular vs sub-dermal injections into the forehead region found that patients had less discomfort and equal clinical results with sub-dermal injections. This technique can also be used in the crows feet area to reduce bruising in this highly vascular area.
Reconstituting the toxin with preservative free vs preserved saline also impacts pain levels during injection. The manufacturers typically recommend the preservative free form but research, and personal experience in practice, has shown that this is more painful for the patient. Studies have not found any difference in efficacy of the medication when using either saline. Patients with allergy to benzyl alcohol should request preservative free saline.
Using a smaller needle size can also aid in comfort, a 30-32 gauge needle is ideal. Hand-held vibration or tapping on the face during injection can distract from the pain as well. If a patient is particularly sensitive to pain, or simply nervous, ice or numbing cream can be used prior to the procedure.
Are cosmetic botulinum toxin injections safe?
Cosmetic botulinum toxin injections, when used appropriately, have been proven to be overwhelmingly safe in the correction of wrinkles and other cosmetic defects worsened from muscle contraction.
It is important that providers screen patients and not inject on patients that are not good candidates for this treatment. The patient should also screen the provider to ensure that the injecting individual is well educated, experienced and willing to answer any questions they may have.
Side effects are typically mild and commonly include discomfort during injection, redness or bruising at the injection site, and headache. Other side effects include, but are not limited to: uneven or asymmetric results, spreading of medication, brow or eyelid drooping, swelling and cold/flu like symptoms. For a complete list of drug facts and side effects for Botox go here.
How long does botox last?
How long Botox, Xeomin or Dysport will last varies but the average is 2-4 months. Onset is typically 3-4 days with full results at 10-14 days and peak effect at 4 weeks; movement slowly coming back from 4-weeks to several months.
High movement areas such as around the mouth and eyes will typically not last as long (6-12 weeks) and lower movement areas such as the forehead region will last longer (3-6 months). The more consistent, and longer duration, of receiving injections the better the result.
For optimal treatment of deep wrinkles, where filler might be needed, botulinum toxin is recommended 7 days prior to or during the time of filler placement for the best result. Studies suggest that best results are obtained using these products together versus either one alone.
Regardless of product or region injected the effect of botulinum toxin is always temporary and muscle movement will eventually return. There are other more permanent solutions, such as surgery, but they come at much higher risk.
When started early these injections are also great to prevent future wrinkles. Though they are not medically necessary, neuromodulator injections to wrinkles can be compared to brushing teeth and regular trips to the dentist to prevent cavities.
Who should not get botulinum toxin injections?
For safety, all medical history, surgery/radiation history and medications should be discussed with your provider prior to injections.
Individuals with active infections at the site of injection or with known hypersensitivity reaction to the toxin, or any of it’s components, should absolutely not have injections. Individuals with allergies to cow’s milk proteins should not receive Dysport.
Relative contraindications, for those who should discuss risk versus benefit with their primary care provider (PCP) prior to receiving cosmetic injections, include: anyone with a nerve or muscle disorder that could potentiate the effect of the toxin, such as myasthenia gravis (MS), amyotrophic lateral sclerosis (ALS), Eaton-Lambert syndrome, or any other neuromuscular disease.
Caution should also be used in patients that have history of guillan barre syndrome or reaction to vaccines.
An allergy to eggs should also be discussed with your provider prior to receiving Botox or Xeomin as both of these contain human albumin which is similar in composition to egg. Despite that we all have albumin in our own bodies, it is possible to react to albumin from a donor source.
Prescription blood thinning medications, over the counter NSAIDs, antibiotics, allergy medications or any other medication or supplement should be discussed with your injecting provider.
Other considerations:
If you are pregnant or breast feeding: you should make your provider aware and discuss risk versus benefit. Brin et al. (2016) reviewed 24 years of data from Allergan on women that received Botox before and during pregnancy and found that fetal defects were comparable to the general population that did not have injections. Epocrates (Botox Cosmetic, 2018) also notes that Botox Cosmetic may be used during pregnancy as fetal harm is not expected based on limited human data and low systemic absorption.
Data is limited and more studies should be done before determining that this is a safe practice. Typically it is recommended to heir on the side of not receiving injections during pregnancy if the use is strictly cosmetic and not for medical reasons (i.e. severe migraine).
If you are vegan: From an ingredient standpoint all of the cosmetic botulinum toxin injectables available in the United States are made from purified bacteria but most also contain human albumin, a donated human blood protein. Dysport contains lactose from dairy and is therefore not Vegan.
Most were also tested on animals for FDA approval, other than Xeomin. Merz, the maker’s of Xeomin, were reportedly approved for alternatives to animal testing for cosmetic Xeomin.
So if you follow a vegan diet for health or religious purpose and cannot use any animal products, including receiving human blood products, you would not be able to receive these cosmetic injections.
If you are vegan because or moral or ethical issues, i.e. for the humane treatment of animals, but would be willing to receive human blood products that were donated voluntarily; one might consider using Xeomin. This is a personal choice and risk vs benefit should always be weighed.
Provider’s opinion
Each medication has pros and cons and there are many others out there that have barely been explored. But with all of the research I have done, as well as personal experience injecting and receiving injections myself, I currently offer Botox and Xeomin with an overall preference for Xeomin.
Rationale:
Why I offer Xeomin- No resistance is possible because of it’s pure form and no protein complex, as above. It is convenient as it does not have to be refrigerated prior to use and studies suggest that it is equal in dosing and efficacy when compared to botox. It kicks in faster and lasts just as long as Botox. There are no preservatives in Xeomin. Lastly, Xeomin also earns extra points because Merz pharmaceuticals has started a movement to not test this product, or any of their other products, on animals.
Why I offer Botox- it is the most well researched form of botulinum toxin out there and has the most FDA approved indications. It is also a well known brand name and clients ask for it. However, some feel that there is more inactive toxin in Botox than in some of it’s counterparts and I’m interested to see more studies on this in the future.
Why I don’t offer Dysport- In theory if a patient reacts to or has “resistance” to Botox they will likely have the same effect with Dysport (due to complexing proteins as above). Dysport is also most likely to diffuse to the surrounding tissue/muscles and create unwanted side effects when compared to Botox or Xeomin.
Summary
- Botox, Xeomin and Dysport are all made from the type A strain of botulin toxin, each with slightly different compositions.
- Botox costs on average $10-14/unit, Xeomin $9-13/unit and Dysport $4-8/unit
- For treatment, 1 unit of Botox and 1 unit of Xeomin provides the same treatment. Dysport typically requires 2.5 units of medication for every 1 unit of the 2 former drugs.
- The average treatment for Botox or Xeomin is around 30-60 units but varies depending on desired results and treatment areas.
- Proteins present in Botox and Dysport have potential to cause resistance and diminished results but this is rare. More likely dosage, concentration and muscle targeting affect treatment results.
- Each drug has a different molecular weight but more than likely dilution and quantity injected contribute to spreading of the medication outside of target which leads to adverse effects.
- Results typically last 2-4 months and consistency of treatment can lead to longer lasting results.
- Botulinum toxin injections can be therapeutic or preventative and the best result is when used 7 days prior to filler treatment (if filler is needed or desired).
- Pain with injection can be reduced by using smaller needles, preserved saline, and sub-dermal injection technique (when/where indicated)
- All medical history and medications should be discussed with your injecting provider.
- Caution with use during pregnancy as data is limited
- No botulinum toxin available in the U.S. is considered vegan due to the human albumin ingredient but Xeomin would be considered the most humane
References
Botox Cosmetic (2018). In Epocrates Essentials for Apple iOS (Version 11.4.1)[Mobile Application Software] Retrieved from http://www.epocrates.com/mobile/iphone/essentials
Brin, M. F., Kirby, R. S., Slavotinek, A., Miller‐Messana, M. A., Parker, L., Yushmanova, I., & Yang, H. (2016). Pregnancy outcomes following exposure to onabotulinumtoxinA . Pharmacoepidemiology and Drug Safety, 25(2), 179–187. http://doi.org/10.1002/pds.3920
Brodsky, M. A., Swope, D. M., & Grimes, D. (2012). Diffusion of Botulinum Toxins. Tremor and Other Hyperkinetic Movements, 2, tre–02–85–417–1.
Carruthers, J. & Carruthers, A. (2018). Overview of Botulinum Toxin for Cosmetic Indications. In UpToDate. Retrieved Septemper 6, 2018, from https://www.uptodate.com
Frevert, J. (2010). Content of Botulinum Neurotoxin in Botox®/Vistabel®, Dysport®/Azzalure®, and Xeomin®/Bocouture®. Drugs in R&D, 10(2), 67–73. http://doi.org/10.2165/11584780-000000000-00000
Lorenc, P. Z, Kenkel, J., Fagien, S., Hirmand, H., Nestor, M., Sclafani, A., Sykes, J., Waldorf,H. (2013). IncobotulinumtoxinA (Xeomin): Background, Mechanism of Action, and Manufacturing. Aesthetic surgery journal / the American Society for Aesthetic Plastic surgery. 33. 18S-22S. 10.1177/1090820X12474633.
Scaglione, F. (2016). Conversion Ratio between Botox®, Dysport®, and Xeomin® in Clinical Practice. Toxins, 8(3), 65. http://doi.org/10.3390/toxins8030065
Sapra, P., Demay, S., Sapra, S., Khanna, J., Mraud, K., & Bonadonna, J. (2017). A Single-blind, Split-face, Randomized, Pilot Study Comparing the Effects of Intradermal and Intramuscular Injection of Two Commercially Available Botulinum Toxin A Formulas to Reduce Signs of Facial Aging. The Journal of Clinical and Aesthetic Dermatology, 10(2), 34–44.
