Updated review on neuromodulators
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Abstract
As botulinum toxin is increasingly used cosmetically and medically, it is important to understand the differences between each formulation of this product. While the active molecule in each is a 150 kDa protein that prevents neurotransmitter release, there are currently five products FDA-approved for clinical use, with a sixth currently in its Phase 3 trial and a seventh applied under FDA review, each with different nontoxic accessory proteins and varying amounts of human serum albumin. These properties affect diffusion rates and storage methods, which are outlined in this review. Common complications and recommendations to avoid them are discussed.
Keywords
INTRODUCTION
The history of botox
Botox injection has become the most common nonsurgical cosmetic procedure performed in the United States, with an annual estimate of 4.4 million injections of botulinum toxin type A administered by plastic surgeons in 2020, solely for nonsurgical cosmetic use[1]. The earliest reporting of botulinum toxin, however, dates back to the Napoleonic War in the late 1700s. Due to unsanitary conditions during the war, there were many deaths associated with eating smoked sausage, which was later discovered to be caused by botulinum toxin-related food poisoning. Several decades later, Justinus Kerner, a German physician and poet, began conducting experiments to better understand the effects of this toxin. He also conducted experiments on himself where he would ingest small amounts of toxin and record his own symptoms including intestinal spasms, ptosis, strabismus, and even respiratory failure. He later published the first case of botulism, and importantly, he hypothesized that this toxin could be used in treating medical conditions such as movement disorders[2].
Botulinum toxin was first used in humans to treat strabismus medically in 1980 by Dr. Alan Scott, an ophthalmologist in California, USA, who sought to find an alternative treatment to the existing surgical treatment for strabismus. He was the first to report the positive therapeutic effects of this toxin. Dr. Scott named his original product Oculinum, and it was first approved as a treatment for strabismus and blepharospasm associated with dystonia by the FDA in 1989. Once an ophthalmologist, Jean Carruthers, used this medication to treat a blepharospasm patient and received feedback from the patient that it made her wrinkles disappear, she and her husband, a dermatologist Alastair Carruthers, started to experiment for the first time with the cosmetic use of botox. They published the first paper on this topic in 1992 in The Journal of Dermatologic Surgery and Oncology, which led to the widespread use of botulinum toxin in aesthetic medicine[3]. The familiar name, Botox (OnabotulinumtoxinA), was given to the product in 1991 by Allergan, the first manufacturer of botulinum toxin for cosmetic use. From this point on, various companies created and received FDA approval for several types of botulinum toxin type A, and one formulation of type B (Myobloc) for different aesthetic and medical uses [Table 1] and additional approvals are continually being sought[4]. The constant addition of products and indications requires a continual amendment to the current literature to maintain an updated and accurate summary[5-8].
Formulations of botulinum toxin A with FDA-approved use, preparation and storage specifications[4,10,11]
| Generic name | OnabotulinumtoxinA | AbobotulinumtoxinA | IncobotulinumtoxinA | PrabotulinumtoxinA | DaxibotulinumtoxinA-lanm |
| Brand Name | Botox | Dysport | Xeomin | Jeuveau | Daxxify |
| Manufacturer | Allergan | Galderma | Merz | Evolus | Revance |
| Packaging (U/Vial) | 50, 100 | 300 | 500 | 100 | 100 |
| Molecular weight (kDa) | 900 | 500 | 150 | 900 | 150 |
| Preparation | Vacuum-drying | Lyophilized | Lyophilized | Vacuum-drying | Lyophilized |
| Storage prior to reconstitution | 2-8 °C | 2-8 °C | Room temperature | 2-8 °C | Room temperature |
| Shelf life post-reconstitution | 36 h | 24 h | 36 h | 24 h | 72 h |
| Contains accessory proteins | Yes | Yes | No | Yes | No |
| Contains HSA | Yes; 500 µg | Yes; 125 µg | Yes; 1 mg | Yes | No |
| Excipients | Sodium chloride, HSA | Lactose, HSA | Sucrose, HSA | Sodium chloride, HSA | PS20, sugar, buffer, excipient peptide (RTP004) |
| FDA-approved medical use | Overactive bladder, urinary incontinence from detrusor overactivity (adult), neurogenic detrusor overactivity (5+), prophylaxis of headaches from chronic migraine (adult), cervical dystonia (adult), severe axillary hyperhidrosis, dystonia-associated blepharospasm (12+), strabismus (12+) (Botox) | Cervical dystonia (adult), spasticity (2+) | Chronic sialorrhea (2+), upper limb spasticity (2+), cervical dystonia (adult), blepharospasm (adult) | Cervical dystonia (adult) | |
| FDA-Approved cosmetic use | moderate to severe glabellar lines, moderate to severe lateral canthal lines, moderate to severe forehead lines (Botox Cosmetic) | moderate to severe glabellar lines | moderate to severe glabellar lines | moderate to severe glabellar lines | moderate to severe glabellar lines |
PHARMACOLOGY
Botulinum toxin is produced by the bacteria Clostridium. There are seven known serotypes of botulinum neurotoxin (A-G), five of which the human nervous system is susceptible to (A, B, E, F, G), and two of which (A and B) have been approved by the FDA and are commercially produced for clinical use. The active subunit of botulinum toxin type A (BoNT-A) neurotoxin is a 150 kDa protein. This 150 kDa protein binds to cholinergic nerve terminals to enter the cell through receptor-mediated endocytosis enabled by the C-terminal of the 100-kD heavy chain. Once internalized, a disulfide bond is cleaved, creating a 100 kDa heavy chain and a 50 kDa light chain. The light chain cleaves and inactivates SNAP-25, a SNARE protein that is required for the fusion of the synaptic vesicle with the presynaptic membrane and subsequent neurotransmitter release (inhibits acetylcholine exocytosis)[4,5]. Without the release of acetylcholine into the synapse, muscle fibers do not depolarize or contract.
Serotype A botulinum toxins have a longer onset of action but also a longer duration of effect. Their duration of action, measured by how long they inhibit neurotransmitter release, varies based on the half-life of the light chain and how long it takes the neuron to restore SNARE proteins[9].
INDICATIONS
The FDA-approved uses of botulinum toxin are described in Table 1, with approved age ranges of use specified in parentheses.
OFF-LABEL USE OF NEUROMODULATORS
Off-label use of neuromodulators spans both medical and cosmetic indications[6]. BoNT-A has been used for many dermatological conditions such as scar prevention, burns, keloids, wound healing[10], of psoriasis, rosacea, bullous skin disease, Darier disease, eccrine nevus hyperhidrosis, chromhidrosis, bromhidrosis, pompholyx, hidradenitis suppurativa[7], lichen simplex chronicus, lichen planus, pachyonychia congenita, aquagenic keratoderma, and alopecia[8]. Neurological conditions include facial palsy, spasm, post-herpetic neuralgia[8], trigeminal neuralgia, diabetic neuropathy, tremor, tics, post-stroke pain, spinal cord injury, myofascial pain, and bladder pain[6,12,13]. Muscular and fascial conditions include temporomandibular joint dysfunction, plantar fasciitis[10], and anal fissures, while skeletal and vascular conditions include epicondylitis, thoracic outlet syndrome, and Raynaud phenomenon.
Cosmetic off-label uses include treatment for decreased sebum production in oily skin[14], facial flushing[8], nasal tip ptosis[15], gummy smile[16], drooping oral commissures[12,17], dimpled chin[18], mental crease[18], platysma[19], neck elongation[19], bunny lines on the nose[20], pretarsal orbicularis hypertrophy[21], perioral lines[22], lip ptosis[23], and masseter[24], shoulder[25] and calf contouring[26,27]. In addition, once one of the Botulinum toxin A brands is FDA-approved for an indication, all other brands are often used off label despite not having that specific indication[13,14].
FORMULATIONS
There are five variations of botulinum toxin A that are FDA-approved for clinical use, with a sixth currently in its Phase 3 trial and a seventh applied under FDA review. Table 1 provides the preparation and storage specifications of each formulation. Botox, Dysport, and Xeomin have been in circulation for much longer compared to Jeuveau which was initially approved in 2019 and Daxxify in 2022. A new product, RelabotulinumtoxinA, developed by Galderma, is in Phase 3 trials for the use of improving glabellar and lateral canthal lines[28]. In addition, Hugel is currently seeking FDA approval for LetibotulinumtoxinA (Letybo).
Clostridium botulinum is a bacteria that produces botulinum neurotoxin. The neurotoxin is produced from a culture and purified by a series of steps and then excipients are added to minimize product inactivation before the product is either freeze-dried (lyophilized) or vacuum-dried. All formulations except Daxxify contain human serum albumin (HSA), a protein component of human blood. BoNT-A is a protein complex comprised of nontoxic accessory proteins (NAPs) bonded to the 150 kDa neurotoxin. The molecular weight of the formulation depends on the composition of the NAPs and the manufacturing process. Xeomin has the complexing proteins removed during the manufacturing process, yielding a solution of just the 150 kDa toxin[29]. The purpose and effects of complexing proteins in botulinum toxin A may include stabilization of the neurotoxin and delay of diffusion into adjacent tissues[30], but can also cause the formation of neutralizing antibodies against the toxin[31]. This lack of complexing proteins may decrease the immune response, as was shown in a meta-analysis that revealed the lowest rate of neutralizing antibody formation[32].
Daxxify is the first to be formulated with the positively charged, proprietary stabilizing excipient peptide, RTP004. This peptide has demonstrated enhanced binding of the neurotoxin to negatively charged extracellular structures such as neuronal surfaces and extracellular matrix proteins. It is hypothesized that the enhanced binding may increase the likelihood of internalization of the neurotoxin, correlating with the clinically observed longer duration of effect[33].
While the active unit of all formulations of BoNT-A is the 150 kDA protein, there are still significant differences in the quantity of neurotoxin in each potency unit, and therefore, units cannot be compared and the units for different BoNTA preparations are not equal. In cosmetic practice, the dose ratio of Dysport:Botox:Xeomin has been shown to be approximately 2.5:1:1[9]. When comparing Dysport, Botox, and Xeomin, they were all shown to have equivalent light chain (LC) activities per quantity of BoNT-A, which disputed findings from a previous paper published by Frevert[34] that stated the difference in specific activity could be attributed to varying light chain activities. However, there are significant differences in the quantity of neurotoxin in each potency unit of these three BoNT-A products. Dysport was found to have greater amounts of active neurotoxin per vial compared to Botox and Xeomin[34]. The higher quantity of neurotoxin in Dysport could explain not only its possible longer duration of action, but also the possibility of increased adverse effects outside the target region compared to Botox[35].
COMMON PREPARATION AND DILUTION
Botox is the oldest commercially available product and therefore the most studied botulinum neurotoxin. Most manufacturers recommend that botulinum toxins be reconstituted with unpreserved saline, but preserved saline (which contains 9 mg of sodium chloride and 9 mg of benzyl alcohol) has been shown to not affect the potency of the neurotoxin[36] while making the injections less painful[37]. In addition, reconstitution using lidocaine with epinephrine reconstitution also reduced patient discomfort while not decreasing the efficacy or safety of botulinum toxin A[38].
Yen et al. demonstrated a synergistic effect among Botox and bupivacaine, where patients experienced less pain with this combination compared to Botox with unpreserved saline as well as greater muscle weakness in the experimental side compared to the control at one week. This could be due to the greater myotoxicity of the combined formulation, but no difference was noted between the control and experimental sides at one and three months[39].
DIFFUSION
Several studies have examined the diffusion potential of botulinum toxin in both animals and humans. Neither molecular weight nor the presence of complexing proteins seems to affect diffusion, with one possible exception being Daxibotulinum toxin, in which the complexing proteins impart a positive charge. Instead, modifiable factors such as the type of reconstitution solution, the volume, concentration, and dose all influence this property[39]. In animals, Borodic et al. demonstrated that with high enough doses, diffusion of botulinum toxin could reach up to 45 mm from the site of injection and only 15-30 mm with the use of lower doses. Patients who were treated with botulinum A for idiopathic spasmodic torticollis for a mean of 1.1 years with 150 vs. 100 units had a significantly greater incidence of dysphagia (P = 0.026). This was due to the spread of botulinum toxin to pharyngeal muscles from the site of injection in the sternocleidomastoid when high doses are administered[39,40]. Arezzo and Yaraskavitch et al. also showed that it spread to other muscles that were not injected in a dose-dependent manner[41,42]. In addition, a human study showed an effect of botulinum toxin on untreated muscles, which the investigators hypothesized to be due to local diffusion[43].
In a study by Hsu et al., diffusion was shown to be affected by fluid volume. Patients had one side of their forehead treated with 5U of toxin in 0.25 mL of preserved saline and the other side with 5U in 0.05 mL of preserved saline. The side injected with a fivefold increase in volume had a 50% increase in the affected area[44]. In addition, in a review paper, Ramirez-Castaneda writes that “the spread of [botulinum toxin] is dependent on a number of factors, one of the most important is the volume”[45].
However, there are other studies that do not show any effect on diffusion to nearby muscles. This difference in outcomes is likely related to many possible variables such as the concentration, volume, and dose of the botulinum toxin, the concentration of receptors and distance to the target area, muscle activity, and the technique used to inject (speed of injection, size of needle, placement, and number of injections).
COMPLICATIONS AND HOW TO AVOID THEM
Overall, the use of botulinum toxin A is very safe; however, there are certain common side effects including bleeding, edema, erythema, and pain at injection site[46]. All side effects will resolve and there have been no reported serious permanent side effects from the on-label use of botox for cosmetic indications[12]. While there is a potential risk of spreading viral diseases such as Creutzfeldt-Jakob Disease (CJD) in those products containing human albumin, it is extremely rare, and there have been no reported cases of any transmission to date[47].
Bruising, especially around the lateral canthus region, can be limited by using a small gauge needle and being attentive to the superficial vessels[48]. While more rare, nausea, malaise, influenza-like symptoms, brow or lid ptosis, ectropion, or strabismus may occur[46].
Contraindications
The prescribing information advises caution when administering to patients with pre-existing cardiovascular disease, neuromuscular disorders (myasthenia gravis, multiple sclerosis, and Eaton Lambert Syndrome), and those with compromised respiratory function or dysphagia. In addition, caution is recommended for those on aminoglycosides, anticholinergic agents, cyclosporin, D-penicillamine, and muscle relaxants. There are no studies or adequate data on the risk associated with the use of BoNTA in those who are pregnant or breastfeeding, and therefore, it should not be used in such cases. The safety and effectiveness of BoNTA in patients under 18 have not been studied. BoNTA is contraindicated in those with known hypersensitivity or allergy to either BoNTA or any components such as human albumin and those with an infection at the injection site.
Injection site reactions
Side effects can occur at local injection sites, including pain, skin dryness, and infection. Localized pain can occur from the needle puncturing skin. This pain can be attenuated using topical anesthetic, adjusting the needle to puncture with bevel side up, injecting slowly, using smaller gauge needles, or diluting the botulinum toxin with saline containing preservative. Local skin can become dry from decreased sweat gland activity. Additionally, the injection site can develop an infection. This rare side effect can be prevented with proper antiseptic solution application prior to the procedure, aseptic technique during the procedure, and post-operative care to not touch the area for 6 h until the injection site has closed[49].
Ecchymosis and purpura could possibly be decreased with cold application to injection sites before and after treatment[50]. However, there are also publications showing the uptake of neuromodulator is temperature dependent[51] with decreased uptake at lower temperatures. In addition pressure on the injection site after treatment for at least 10 seconds may decrease post-injection bruising[52]. Finally, there are many conflicting studies regarding the use of arnica, bromelain, and vitamin K in reducing bruising and increasing the rate of reabsorption. A systematic review of oral bromelain and arnica treatments for bruising reported insufficient data to determine their efficacy and additional research is needed[53].
Two short-term side effects are headache and allergic reactions. Headaches occur commonly after treating rosacea, and the severity depends on which nerve branch is affected. These usually resolve by themselves within a few days of the treatment. Otherwise, they can be treated with nonsteroidal anti-inflammatory drugs or opioids. Allergic reactions can also vary in severity and symptoms, including edema, erythema, urticaria, and anaphylactic shock. Antihistamines can be used for erythema lasting over 24 h, and anaphylactic shock is treated as a medical emergency[49].
Ptosis, diplopia & assymetry
One of the most dreaded aesthetic complications that arises is brow or lid ptosis. Brow ptosis occurs when horizontal forehead lines are treated by injecting the frontalis muscle. This complication can be avoided by injecting at least 2-3 cm above the supraorbital margin or 1.5-2 cm above the eyebrow. This allows the inferior frontalis muscle fibers to be spared and therefore can prevent ptosis[54,55]. To assist in preventing lid ptosis, which occurs from affecting the levator palpebrae muscle, placing fingers on the orbital ridge to prevent the toxin from diffusing into the orbit can be done and avoiding deep injections above the midpupillary line where the toxin could enter the supraorbital notch or foramen is important[56,57].
Injection of botulinum toxin close to the orbital ridge near the lateral canthus can cause diffusion through the orbital septum, leading to diplopia and strabismus by weakening the lateral rectus and extraocular muscles[29,34,35]. In addition, injecting toxin too deeply into the upper lateral aspect of the periocular area can affect lacrimal gland secretions, leading to xerophthalmia, while diffusion of toxin into the palpebral portion of the orbicularis oculi can lead to lagophthalmos[54,55]. Staying 1-2 cm away from the lateral orbital rim and injecting superficially can aid in decreasing the likelihood of these side effects[55].
Rare complications seen when injecting toxin below the superior zygomatic arch or too low along the nasal side walls are asymmetry and lip ptosis. Diffusion into the upper lip elevators, levator labii superioris alaeque nasi, the zygomaticus muscles, and levator labii superioris can even result in difficulty with speaking, smiling, and eating[58]. An asymmetric smile can also occur when treating the masseter too medially or too superiorly by affecting the risorius, or by hitting the depressor labii inferioris when treating either the depressor anguli oris too medially or the mentalis too laterally, and finally, when not treating the orbicularis oris equally[59,60].
While it can be safe to treat the platysma, diffusion to underlying muscles due to improper technique can precipitate complications. These cholinergic muscles are responsible for deglutition, phonation, and neck flexion, and higher doses of botulinum toxin or deeper injection can result in xerostomia, dysphagia, and neck weakness[61,62].
CONCLUSION
In summary, the active subunit of botulinum neurotoxin is composed of a 150 kDa protein that binds to cholinergic nerve terminals, enters, and inactivates SNAP-25, preventing neurotransmitter release, disabling muscle fiber contraction. On-label cosmetic use of BoNTA has been found to be a very safe and effective medication with no long-term side effects when used correctly. It has been studied for a wide variety of indications, from wrinkle treatment to dystonia, as well as for a myriad of off-label indications. While each indication carries its own risk of side effects, a thorough understanding of the anatomy of each area will decrease the risk of potential side effects.
Increasing formulations with different onset of action and duration are continually emerging in the market. As more companies seek approval for newer products, additional research will be required to compare those with existing ones. There are also newer indications being studied with current products that may lead to a better understanding of botulinum toxin and all its capabilities.
With botulinum toxin’s various cosmetic and medical applications, it is important to understand the differences in properties and clinical implications of each formulation. This article provides a comprehensive review of established and more recent products and both their on-label and off-label indications and can serve as a guide to understanding the uses and complications associated with each. In addition, while we understand the basic mechanism of action of botulinum neurotoxin, there is still a lot yet to be discovered.
DECLARATIONS
Authors’ contributions
Background research, writing, and editing: Gupta S, Sudharshan R, Shen A, Zhang-Nunes S, Siperstein R
Availability of data and materials
Not applicable.
Financial support and sponsorship
None.
Conflicts of interest
Dr. Robyn Siperstein is a primary investigator, consultant, speaker, and trainer for Allergan and Galderma. All other authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2024.
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Gupta, S.; Sudharshan, R.; Shen, A.; Zhang-Nunes, S.; Siperstein, R. Updated review on neuromodulators. Plast. Aesthet. Res. 2024, 11, 16. http://dx.doi.org/10.20517/2347-9264.2023.90
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