8Botulinum toxin type A treatment for Raynaud’s phenomenon and other novel dermatologic therapeutic applications

INTRODUCTION

This chapter will discuss the use of botulinum neurotoxin type A (BoNTA) in dermatology for the treatment of painful conditions including Raynaud’s phenomenon, postherpetic neuralgia, headache, reflex sympathetic dystrophy (or complex regional pain syndrome), and a variety of other conditions. The use of BoNTA to improve upper thoracic posture and thus improve the appearance and presentation of female breasts will be discussed. An approach to the management of acute overdoses of BoNTA will also be described.

Since BoNTA was first reported to be useful for the reduction in the pain of spasmodic torticollis in 1985 (1), the number of references in Medline™ to “botulinum” and “pain” have been growing at an increasing rate, and by the end of 2009 there were over 1,130 references. The list of painful conditions reported to respond well to BoNTA is also growing, and now includes some dermatologic conditions, and other conditions like headache, which are treated by some dermatologists who have expertise in the use of BoNTA (2,3).

It is important to note that the BoNTA used by the authors in the management of these conditions was BOTOX®, and the doses described in this chapter refer to BOTOX®. Because the diffusion characteristics and dosing of other forms of BoNTA differ from BOTOX®, it is not possible to establish a simple ratio for the conversion of BOTOX® doses to other formulations of BoNTA, or to other botulinum neurotoxins serotypes, for example, BoNTB or BoNTE (chapter 1). To reduce the risk of confusion, the recently designated generic instead of the trade name of the BoNTA actually injected will be used throughout this chapter, which is onabotulinumtoxinA for Allergan’s BOTOX®; abobotulinumtoxinA for Medicis’ Dysport®; and incobotulinumtoxinA for Merz’s Xeomin®. The term BoNTA will be used to refer to the general class and serotype of neurotoxin.

BoNTA TREATMENT IN RAYNAUD’S PHENOMENON

Raynaud’s phenomenon is defined as an episodic digital asphyxia caused by vasospasm of the digital arteries triggered by cold exposure or stress. It is either idiopathic and known as Raynaud’s disease, or secondary to diseases such as scleroderma, lupus erythematosus, rheumatoid arthritis, and occlusive arterial disease. Its symptoms include a progression from digital blanching and cyanosis to reactive hyperemia, to pain and dysesthesias, which if prolonged, can result in severe digital vascular compromise, ulceration, digital infarction, and may even necessitate amputation. The etiology of Raynaud’s disease is complex, but both vasospasm and nociception appear to play a major role. The inhibitory effects of BoNTA on somatic and autonomic neurotransmission are well documented. BoNTA inhibits norepinephrine (NE)- mediated sympathetic vasoconstriction, thus improving perfusion of digits by opening up the vasculature and allowing for better oxygenation. It concurrently inhibits pain-mediating neuropeptides, namely substance P (SP), neuropeptide-Y (NPY), vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and glutamate, thus interfering with nociception, both peripheral and central sensitization, and decreasing swelling and inflammation.

BoNTA is successfully used in Raynaud’s phenomenon as a safer and easier alternative to surgical sympathectomy (4). It essentially produces a chemical sympathectomy that lasts for months and effectively improves hand temperature within 1 to 2 days as well as shortens

warm-up time after exposure to cold (5), controls rest pain, shortens and reduces frequency and severity attacks (6) including stiffness, numbness, acute pain, color change, and swelling (7), prevents impending infarction of digits and successfully heals ischemic ulcerations caused by profound vasospasm in the majority of patients (1). These favorable changes of improved perfusion are quantified using visual analogue scale (VAS) and confirmed by digital surface temperature readings (1,2), imaging studies with laser Doppler interferometry (3), intravascular arteriography, or high-resolution digital magnetic resonance angiography (1). The adverse events reported are rare and include mild and temporary hand weakness. Amelioration of pain improves hand function despite occasional muscle weakness (1).

PHYSIOLOGICAL BASIS OF BoNTA FOR RAYNAUD’S PHENOMENON

Autonomic: Vasodilator and Vasoconstrictor

In addition to the widely recognized inhibitory effects on the release of acetylcholine (Ach) from neurons innervating striated muscle and sweat glands, BoNTA has been shown to produce a neuromodulating effect on autonomic nerves (8). Cutaneous vasoconstriction and vasodilation are regulated by modulation of sympathetic and parasympathetic neuronal inputs and the complex actions of released ACh, NE, peptides like NPY, and small molecules such as nitric oxide on vascular smooth muscle.

In an animal model of significantly constricted uterine arteries, BoNTA has been shown to reduce the amplitude of sympathetic NEmediated vasoconstriction by 80% (9). Likewise, isometric contractions of venae cavae mediated by NE acting on alpha-adrenoceptors are substantially reduced by BoNTA administration (10). Concurrently, in parasympathetic neurons, BoNTA is found to significantly reduce the autocrine acetylcholine-mediated inhibition of vascular relaxation and also to reduce the slow component of neurogenic vasodilation mediated by the peptides VIP and CGRP (11). Thus, a differential effect of BoNTA on different classes of neurotransmitters is observed, whereby it may reduce neurotransmitter and neuromodulator release from vasoconstrictor and vasodilator neurons depending on various regulatory mechanisms.

Local BoNTA injection consistently shows an ability to improve perfusion of the injected tissue by both substantial opening of the vascular bed and an increase in aerobic metabolism. BoNTA inhibits the neurogenic contractions of tumor vessels by blocking NE, thus improving tumor perfusion and oxygenation and thus aiding in delivery of cancer therapy (11,12). In inflammatory muscle states due to decreased microcirculation, such as in lateral epicondylitis secondary to low intramuscular blood flow in extensor carpi radialis brevis, BoNTA injection allows for muscle relaxation, a shift toward aerobic metabolism and a decrease in lactate production, restoration in intramuscular blood flow, decreased pain, improved muscle strength, and function (13).

BoNTA Has Anti-Inflammatory and Antinociceptive Effects

BoNTA also acts on the nociceptive portion of the sensory system to reduce pain and neurogenic inflammation by attenuating the peripheral release of neuroactive compounds such as SP and glutamate from C-fibers, as well as reducing central sensitization (6). BoNTA does not directly decrease excitability of nociceptors, but acts by reducing inflammatory pain (14) and thus pathological pain (15).

Substance P

BoNTA inhibits substance P (SP), a peptide released both peripherally and centrally by nociceptive primary afferent C-fibers, thus producing the analgesic effect seen in treating primary headache disorders (16). It markedly inhibits SP secretion in dorsal root ganglia neurons (17) within hours and lasts for at least 2 weeks. Local inflammation sensitizes peripheral nociceptive neurons, and as the increase in peripheral pain input causes increased release of SP in the spinal cord, it induces central sensitization (6). BoNTA thus attenuates both the peripheral and central sensitization by its inhibition of SP.

CGRP

BoNTA inhibits the release of calcitonin gene-related peptide (CGRP), an inflammatory neuropeptide found on its own as well as colocalized with SP in sensory ganglia neurons, when pain stimulus is present, but not basally. It reduces bladder pain response by 62% through inhibition of CGRP release from afferent nerve terminals (18), and in trigeminal nerves (19), explaining the observed efficacy of BoNTA in migraine and cluster headache therapy. Curiously, CGRP released during inflammation causes vasodilation, thus BoNTA’s analgesic effect in migraines may be secondary to vasoconstriction of the meningeal vasculature.

Glutamate

BoNTA dose-dependently inhibits inflammatory pain by decreasing glutamate release. Glutamate is a stimulant of local nociceptive neurons through activation of receptors on primary afferents (20). Peripheral glutamate release results in edema, pain, and inflammation (21), which is abolished by local BoNTA injection at doses below ones that would elicit muscle paralysis (15).

PRACTICAL TIPS

Assessment

Assessment of disability caused by Raynaud’s phenomenon or disease should be performed prior to and after the BoNTA treatment at 1 week, 1 month, and then routine follow-up. This is done by asking patients to evaluate the level of their (a) pain and (b) hand function using the 10-point visual analogue scale (VAS) , as well as the dermatology quality of life scale. If digital ulcerations are present, a photographic record is useful.

Injection Parameters

There is no consensus of how many injection sites should be administered per affected hand, and whether the entire hand should be treated or just the most affected digits. The clinical decision will be based on the extent and severity of the patient’s Raynaud’s phenomenon/disease, with consideration given to the pharmacoeconomics of using BoNTA and also consideration of how best to avoid causing unwanted muscle weakness in the treated hand.

The authors consider that it is reasonable to administer up to 100 units of onabotulinumtoxinA per hand being treated, reconstituted in 3 to 6 cc of normal saline/100 U vial (1,4). This relatively high reconstitution volume is presently preferred as the increased volume may facilitate spread of the injected onabotulinumtoxinA from the injection point to the vessels we wish to relax. The trend is to inject the palm and all fingers at their base, with the exception of thumb unless it is specifically symptomatic (since thumb ischemia is uncommon in Raynaud’s). Targeted anatomy includes the superficial palmar arch, common digital arteries, and proper digital arteries, with injections being just adjacent to the targeted vasculature (in order to avoid injury to vessels) and needle tip perpendicular to the palm and deep to the palmar fascia (Fig. 8.1) (1).

A 30, 31, or 32G needle is used to infiltrate the soft tissues, with 10 to 40 injection sites spaced approximately 1 cm apart, of equally distributed volume of reconstituted 100 U of onabotulinumtoxinA (1,4). This is followed by a massage of the injected tissues to help distribute the medication throughout the region. Due to the discomfort associated with palmar injections, sufficient anesthesia (e.g., ice, vibration, or nerve blocks) is necessary to make the procedure tolerable (see chapter 11). To minimize weakness of the thumb, it is important to avoid injection into the thenar muscle group on the radial side of the proximal part of the palm (flexor, extensor and abductor pollicis longus, and extensor pollicis brevis).

OTHER NOVEL DERMATOLOGIC USES OF BoNTA

Targeting Hypersecretion

Based on the positive results seen with treatment of hyperhydrosis using onabotulinumtoxinA injections, onabotulinumtoxinA has been found to be helpful for other conditions made worse by increased sweating. These conditions include persistent facial flushing with or without localized sweating, gustatory sweating (Frey’s syndrome), localized unilateral hyperhydrosis, Ross’ syndrome (22), familial benign pemphigus (Hailey-Hailey disease), and dishydrotic eczema (23).

Frey’s syndrome is facial hyperhidrosis in the preauricular region from gustatory stimulus, observed commonly after parotidectomy. On average, 40 units of onabotulinumtoxinA effectively alleviates the symptoms within days after injection and remission has been reported to persist for 15 to 18 months (24). Other glandular hypersecretory disorders, including sialorrhea, excessive lacrimation, chronic rhinitis (25,26) and parotid fistulas (27–29) also have been reported to respond to treatment with onabotulinumtoxinA.

Hailey-Hailey disease is an autosomal-dominant acantholytic blistering disease affecting the intertriginous skin and is exacerbated by heat, sweat, moisture, friction, and infection. Intertriginous injections of BoNTA have been reported to induce significant improvement within 2 weeks with onabotulinumtoxinA (30) and improvement can be maintained for many months with abobotulinumtoxinA (31). Dyshidrotic hand eczema (pompholyx) is a chronic, relapsing inflammatory vesiculobullous disease also aggravated by hyperhidrosis (32). The addition of onabotulinumtoxinA injection to topical steroid therapy

has shown significant benefit in managing pompholyx eruptions and the associated symptoms of pruritus (33,34). Inverse psoriasis is exacerbated by maceration, secondary infection, and inflammatory pain; onabotulinumtoxinA injections to affected intertriginous regions also improve the symptoms and eruptions of inverse psoriasis (35).

Targeting Pain

OnabotulinumtoxinA’s antinociceptive properties have been used in the treatment of multiple cutaneous piloleiomyomas, with effective rapid and sustained resolution of pain (36). It has also shown substantial benefit in the treatment of notalgia paresthetica (37).

BoNTA enters neurons by binding to the synaptic vesicle protein SV2 receptor (isoforms A, B, and C) (38). SV2 is transiently exposed when synaptic vesicles fuse with the presynaptic membrane to discharge neurotransmitter into the synaptic junction (Fig. 8.2). This is the physiological basis for the important clinical observation that generally the most effective and efficient way to administer BoNTA for painful conditions is to inject BoNTA in the points and areas of maximum discomfort indicated by the patient, because it is in these areas that there is maximum discharge of pain mediating neurotransmitter and thus maximal exposure of the SV2 protein, which mediates uptake of BoNTA. This method of administration of BoNTA is commonly referred to as the “follow the pain” approach. Clinical trials of onabotulinumtoxinA for painful conditions sometimes use a rigid protocol of doses and injection sites rather than the “follow the pain” approach, which customizes the treatment to the needs of each individual patient, and this difference may explain why some clinical trials (in particular for headache) do not obtain the degree of improvement which is commonly achieved in clinical practice (39–42).

BoNTA for Postherpetic Neuralgia

Perhaps the first to use onabotulinumtoxinA for the treatment of postherpetic neuralgia (PHN) were Dr. Arnold Klein (43) and, later, Drs. Mariusz Sapijaszko and Richard Glogau (personal communication) who used onabotulinumtoxinA to treat PHN on the trunk. Their informal oral reports, together with a consideration of the well-established role of SP in the pathogenesis of PHN, and considering reports that BoNTA blocked the release of SP from vesicles in nerve terminals, provided the rationale

SV2 receptors on neurotransmitter (NT) vesicles are the binding site for

BoNTA

Presynaptic motor nerve terminal or peripheral terminal of nociceptive primary afferent neuron (C-fibre)

NT

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After stimulation of the nerve terminal, vesicles containing NT (for example acetylcholine, substance P, calcitonin generelated peptide, or glutamate) fuse with the neuronal membrane (via the SNARE complex), releasing NT and exposing SV2 receptors to BoNTA.

for additional trials of treatment with BoNTA for severe, intractable PHN (44). One author (KCS) has found onabotulinumtoxinA to be a very reliable treatment for PHN on the face and scalp, but has had only treatment failures when attempting to use onabotulinumtoxinA to treat PHN on the trunk and extremities. The reason for this difference in responses is not known, and additional investigations are warranted.

It is important clinically, for communication with other physicians and with third party payers, and in terms of pharmacoeconomics to objectively quantify a patient’s condition at baseline and in response to therapy. The four tools which are helpful include:

1.Likert pain scale and global assessment (Fig. 8.3).

2.Physician’s global assessment (Fig. 8.4).

3.Number of doses of pain medication taken in the 7 days preceding evaluation, and the number of doses taken since the last visit.

4.Marking and photographing the boundaries of the area or areas of PHN before treatment and then marking and photographing the involved areas at every subsequent visit (Fig. 8.5).

Patients are advised to continue their usual pain medications, and only to reduce the dose of pain medication as they respond to their BoNTA treatment.

The patient identifies the area or areas of involvement. The boundaries of the area(s) of involvement are marked with washable pink fluorescent marker, photographed (Fig. 8.5), then injected with onabotulinumtoxinA intradermally or subdermally at doses ranging from 2.5 to 5 units per injection site, with the injections spaced 2 to 3cm apart. The total dose of onabotulinumtoxinA is generally in the range of 1 to 2 units per cm or cm2.

BoNTA is reconstituted using normal saline with benzyl alcohol preservative (which has local anesthetic properties and reduces injection discomfort). A reconstitution volume of 1ml per 100 units of onabotulinumtoxinA is used by the author (KCS), but the reconstitution volume does not seem to influence efficacy—the only thing that matters is how many units of BoNTA are administered (45). Because there is commonly hyperalgesia

in areas of PHN, it is best to use BD-II 0.3 ml insulin syringes with attached 31G needles (Becton Dickinson, Franklin Lakes, NJ). It is not usually necessary to pretreat patients with a topical anesthetic, but this could be used in cases where there is a likelihood of intolerable injection discomfort.

Patients should be informed that there will very likely be some unwanted relaxation of muscles in the treated area. Injecting BoNTA intradermally can minimize muscle weakness. Injections for the pain of PHN seem to be equally effective whether given intradermally, subdermally, or intramuscularly.

The maximum analgesic effect of BoNTA treatment for PHN often occurs at around 3 to 4 weeks. For this reason, patients are asked to return for reassessment and possibly additional treatment every 3 to 4 weeks until they are pain free.

While the occasional patient will respond in a dramatic manner to a single session of treatment with BoNTA, it is more typical for patients to improve in a stepwise manner. Patients generally need between one and four treatment sessions to become pain-free. Objective quantification of the area of involvement, medication intake, Likert pain score, and patient’s and physician’s global assessment will help both the patient and the physician to determine whether or not additional treatment is justified. The author (KCS) has only had success treating PHN on the face and scalp with BoNTA, and has not found BoNTA useful for the treatment of PHN on the trunk or extremities. The reasons for treatment failure on the trunk and extremities are not known, and further studies are warranted.

Usually, serial photographs of the involved area demonstrate progressive reduction of the surface area (Fig. 8.5). Patients find this encouraging. There is often a paradoxical increase in the patient’s Likert pain score as the total area of involvement shrinks. The reason for this phenomenon is not well understood. It could be that the mildest areas of PHN resolve first, with the result that because of “averaging” by the patient, the pain score in the residual area of involvement

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would tend to rise. When the patient with PHN has been rendered pain-free by treatment with BoNTA, there is usually a long-term drug-free remission of pain.

BoNTA in the Management of Painful Scars

Immunohistochemistry has demonstrated substantial numbers of nerves staining for SP and CGRP in some scars (46). This observation, together with successful experience treating PHN, formed the rationale for offering a trial of treatment with injections of BoNTA to patients suffering from chronic intractable painful scars. Objective quantification of the patient’s pain is of great importance in the management of painful scars. Tools that are useful for this purpose are essentially the same as those used in the assessment of patients who have PHN.

1.Likert pain scale and global assessment (Fig. 8.3).

2.Physician’s global assessment (Fig. 8.4).

3. Marking the boundaries of the area or areas of pain prior to treatment and then marking and photographing the involved areas at every subsequent visit (Figs. 8.5 and 8.6).

Injections are usually performed using a 30G 1-inch needle, or a BD-II 0.3 ml insulin syringe with 31G needle, inserted into the scar. In the case of a thick scar (for example, a keloid on the central chest after thoracotomy (Fig. 8.6), the patient may offer advice about whether the pain is deep or superficial and the injection can be adjusted to take this into account. Application of ice for 30 to 60 seconds, or injection of lidocaine around and below the scar, are generally not necessary but could be used in a very sensitive patient to reduce the pain of injection. The author (KCS) has successfully used injections of onabotulinumtoxinA to treat pain associated with keloid scarring, hypertrophic scarring, and normal scarring.

The author (KCS) uses a reconstitution of 1 ml in 100 units of onabotulinumtoxinA. The amount of onabotulinumtoxinA administered in each treatment has ranged from 10 to 50 units per ml (cubic volume) of scar tissue.

As with the treatment of PHN, the antinociceptive effect of BoNTA for painful scars seems to reach a maximum at around 3 weeks, so it is

advisable to have patients return for reassessment and retreatment every 3 to 4 weeks until the patient is pain-free. The required number of treatments has ranged from one to four. As with PHN, the visual analog or Likert pain score may rise in residual areas of involvement even as the patient globally improves (Fig. 8.7), and patients typically remain pain-free for a long time once they have been rendered pain-free by treatment with BoNTA. In one case, there have been partial relapses at 6 to 12-month intervals, and these have responded within 5 to 10 days to additional injections of BoNTA.

There has been no clinically significant improvement in the appearance (assessed by serial photography) of the scars injected by the author (KCS) with onabotulinumtoxinA, but one hypertrophic scar on the breast (Fig. 8.8) seemed much softer 6 months after two injections with onabotulinumtoxinA. Because SP and CGRP interact with some of the cytokines involved in collagen remodeling and collagen deposition (47–49), it is conceivable that treatment with BoNTA could affect the physical properties of some scars, perhaps with repeated treatments or after longer follow-up.

BoNTA in the Management of Reflex Sympathetic Dystrophy (Complex Regional Pain Syndrome)

Reflex sympathetic dystrophy syndrome (RSDS) is characterized by constant burning pain and hyperesthesia in an extremity. Swelling, sweating, vasomotor instability, and sometimes trophic changes often accompany pain. There is often a history of injury or other trauma. Muscle spasms, myoclonus, or focal dystonia may occur. Diffuse pain, loss of function, and autonomic dysfunction are three main criteria suggested for diagnosis. Successful use of BoNTA for this entity has been reported (50,51).

Over the past five years, the author (KCS) has treated a 41-year-old woman who had an 8-year history of severe, refractory RSDS rendering her right arm and leg useless since injuries in a motor vehicle accident. She also had posttraumatic headaches with muscle spasm pulling her head to the right. The headaches and muscle spasm were also treated with onabotulinumtoxinA. Initially injections were exceptionally painful and anxiety provoking. Anxiety was reduced in subsequent injection

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Painful sternal keloid: visual-analog pain scale

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Week 10 Botox™ 25 units superior 1/3 of scar

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sessions by pretreating this patient with 80 mg of oxyprenolol (a very lipid-soluble beta blocker, which crosses the blood–brain barrier quite well and attenuates the central effects of adrenaline) together with 4 mg of lorazepam, 1 to 2 hours before injection of onabotulinumtoxinA. Over the past several years, fentanyl 100 to 150 mcg administered intravenously 10 minutes before the injection sessions has been very helpful to reduce both anxiety and pain. Gradual improvement in the hyperalgesic component of her RSDS has also contributed to improved tolerance of the BoNTA injections.

The patient characterized her pain as coming predominantly from bone, and deep injections close to bone using a 30G 1-inch needle were

of particular benefit. Subcutaneous and intramuscular injections of onabotulinumtoxinA (a total of 120–400 units per session, about once a month) into the areas of discomfort in the right hand and arm gave substantial pain relief (for which the patient was very grateful) and also normalized skin color and temperature in the right hand and forearm within several minutes, but after one year of treatments there has not been any improvement in her ability to use the right hand. Even though the right hand remains useless, it is less of an impediment. It should be noted that reduction in pain and sensitivity has allowed this patient to take part in a greater range of activities of daily living and to participate more fully and effectively in physiotherapy and in society, so there has

been an overall improvement in general functional ability. Treatment of the involved areas in the right lower leg and foot were also helpful. At times the total dose of onabotulinumtoxinA for treatment of headache and for treatment of RSDS in the right arm and leg reached 1,200 units per month. This was well tolerated. After about four years of treatment, her headaches, neck spasm, and RSDS in the right arm and lower leg improved to the point where onabotulinumtoxinA in those areas was stopped, and the dose of onabotulinumtoxinA declined to about 400 units every 2 to 3 months to control her headaches, neck spasm, and pain in the right shoulder.

This is consistent with the observations of Cordivari et al. (45), who noted that four out of four of their patients with dystonia-complex regional pain syndrome affecting the hand had pain relief after treatment with abobotulinumtoxinA, but only one of the four had functional improvement.

There is less concern now than in the past about the risk that a patient such as this, who was treated with high doses of onabotulinumtoxinA, will develop antibodies against the onabotulinumtoxinA formulation of BoNTA. Jankovic et al. (21) found that blocking antibodies were detected in 4 of 42 (9.5%) cervical dystonia patients treated only with the original onabotulinumtoxinA, but in none of the 119 patients (p < 0.004) treated exclusively with the current onabotulinumtoxinA, which has been on the market since late 1997.

BoNTA for Improvement of Upper Thoracic Posture and “BOTOX® Breast Lift”

BoNTA has a long history of being used to improve posture in a variety of conditions (52,53). The position of the shoulders is determined largely by the balance of forces between the pectoralis minor and pectoralis major muscles (Fig. 8.9), which tend to rotate the shoulders medially and to depress the shoulders and the opposing muscles of the back, for example the rhomboids. The use of onabotulinumtoxinA to improve upper thoracic posture and so improve the presentation of the female breast has been detailed in the previous edition of this textbook (54) by the present author (KCS) and by Dr. Francisco Pérez-Atamoros.

This proposed mechanism of action has been criticized by Dr Otto Wegelin (personal communication, April 2004), who argues that

1.the muscles (pectoralis minor and rhomboid minor) invoked to carry out the postural changes are far too small to do what is expected of them,

2.the muscles do not in fact rotate the shoulder but rather act primarily to stabilize the scapula,an entirely different function,

3.the muscles are not antagonistic in action, as are the frontalis and the orbicularis oculi, but rather synergistic,

4.there is no way to determine how much, if any, of the onabotulinumtoxinA is actually acting on the pectoralis minor as the onabotulinumtoxinA can diffuse widely in a three-dimensional plane unlike the forehead where there is the bony skull limiting diffusion.

Dr. Doris Hexsel (personal communication, July 2004), in a study of six women, was not able to obtain satisfactory results, and in two cases noted that the nipples hung lower.

On the other hand, Pérez-Atamoros has successfully achieved elevation of the breasts when the nipples are projecting downward by injecting three doses of 15 units of onabotulinumtoxinA into the part of the pectoralis major which lies medial and inferior to the pectoralis minor (Fig. 8.10). In a series of 100 female patients between 30 and 55 years of age with different degrees of breast ptosis, elevation of the ptotic breast has been achieved, averaging 1.1 cm with the maximum elevation being 1.8 cm. Each patient was injected with onabotulinumtoxinA on only one side in this pilot study, with the contralateral side as control. Sixty-five of the 100 patients rated the results as good to very good, and 73 of the 100 patients would repeat the procedure. Pérez-Atamoros has noted that the best candidates are physically fit women between the ages of 30 and 55 years, with small or moderate-sized breasts. The dose recommended per breast is three injections ranging from 15 to 30 units of onabotulinumtoxinA each. The total dose in one application is 90 to 180 U. Approximately 89% of the study patients presented with asymmetry of the breasts before the treatment. It is important not to correct naturally occurring breast asymmetry by giving higher doses on one side of the chest or the other, but to inject the same total dose of onabotulinumtoxinA on each side. Five patients had pain lasting longer than a week after treatment. Pérez-Atamoros has suggested that relaxation of the inferior medial portion of the pectoralis major muscle allows the superior portion to lift the ptotic breast (Fig. 8.11). For a comparison of the injection sites used by Pérez-Atamoros and one of the authors (KCS) see Fig. 8.9.

The ideal candidates for this treatment seem to be non-obese women with slightly rounded shoulders or who are slightly stooped forward, with breasts of cup-size A or B. Older women, and those with larger breasts, tend to respond more slowly and to a lesser extent (Fig. 8.10).

The benefits of onabotulinumtoxinA treatment usually develop over a period of 1 to 2 weeks, and persist for 3 to 4 months (Fig. 8.12). The duration of effect is somewhat longer than might be expected considering the

relatively low doses of onabotulinumtoxinA in proportion to the size of the muscles. It may be that improvements in shoulder posture persist for a while once posture has been improved by onabotulinumtoxinA, altering the balance of forces between the pectoralis minor and/or major muscles and the opposing muscles in the back (Fig. 8.11).

Some women have noted that not only are the breasts and nipples elevated by their more erect posture with shoulders back, but also that there is a pleasing outward projection of the nipples which develops about a week after the onabotulinumtoxinA treatment and persists for 3 to 4 months. The reasons for this are not known. Perhaps projection

of the breasts as a result of improved shoulder posture leads to increased mechanical stimulation of the nipples under some circumstances. Another more speculative hypothesis is as follows: SP and CGRP have been demonstrated in neurovascular structures related to the nipple– areolar complex in animals (55) and in humans (56). BoNTA has been shown to block the release of SP and CGRP from nerve terminals. If some of the injected onabotulinumtoxinA makes its way from the injection sites to the nipple–areolar complex, it might affect smooth muscle in the nipples by way of its effect on the release of SP and CGRP.

OnabotulinumtoxinA is administered using a 30G 1-inch needle. Pneumothorax or bleeding has not been seen, and would not be expected with a 30G needle. The risk of entering the pleural space can be reduced by limiting needle insertion depth to less than 2 cm.

Recently it has been reported that the combination of BoNTA to relax muscles in the chest, when combined with a program of stretching to relax the chest muscles and exercises to strengthen muscles in the back, can produce a higher response rate and a greater duration of effect on upper thoracic posture than treatment with BoNTA alone (57–59).

Issues which remain to be resolved include optimization of patient selection, onabotulinumtoxinA dosing, injection placement, the issue of placebo effect versus biomechanical effect, and elucidation of the mechanism of action if indeed there is a biomechanical effect from onabotulinum toxin A treatment of the pectoralis minor and/or pectoralis major muscles with onabotulinum toxin A (60,61). It is our position that until these issues have been addressed, the “BOTOX® breast lift” will not be ready for commercialization as a medical procedure (62). T-2-weighted magnetic resonance imaging (MRI) before and immediately after exercise is being evaluated as a technique to visualize and perhaps partially quantify the degree of flaccid paralysis induced by onabotulinumtoxinA treatment (63).

Management of BoNTA Overdose

Overdoses of BoNTA are most commonly the result of accidental injection of small quantities of BoNTA, causing unintended localized muscle weakness. In some cases this will be annoying for the patient, but will resolve in a matter of weeks or months without treatment. Resolution in such cases may be accelerated if the patient tries to exercise the affected muscle as hard as possible for 5 minutes, five times a day.

If the local overdose is more serious (e.g., if an extraocular muscle has been injected) and if the mistake was immediately recognized, it might be possible to limit the uptake of BoNTA into the affected neurons by flooding the area with lidocaine. This might both dilute and wash away the injected BoNTA, and would also reduce or stop depolarization of the affected motor neurons, and so greatly reduces the exposure of the SV2 receptors that BoNTA binds to.

Because the uptake of BoNTA into motor neurons is an energydependent process, and considering that the rate of metabolic processes drops by about 50% for every 10°C reduction in temperature, it can also be useful in some circumstances to apply ice immediately after flooding the injected area with lidocaine, and to keep the injected area iced for a couple of hours. Pretreatment with lidocaine can directly reduce uptake of BoNTA as discussed above, and also reduces the discomfort that can result from the application of ice. Icing may reduce the temperature of the affected tissue from about 37°C to around 7°C, resulting in perhaps an eightfold reduction in the metabolic rate in the treated area (KCS, D Schachter, R Schachter, unpublished observations).

In a severe systemic intoxication with BoNTA, if the exposure was recognized almost immediately (e.g., in a laboratory or industrial accident), it might be beneficial to paralyze the patient temporarily in an intensive care unit setting using a medication like Pavulon®, and perhaps also to reduce the patient’s body temperature as much as possible while the BoNTA was being flushed out of the patient’s

system and while awaiting delivery of immunoglobin directed against BoNTA.

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35.Zanchi M, Favot F, Bizzarini M, et al. Botulinum toxin type-A for the treatment of inverse psoriasis. J Eur Acad Dermatol Venereol 2008; 22(4): 431–6.

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37.Weinfeld PK. Successful treatment of notalgia paresthetica with botulinum toxin type A. Arch Dermatol. 2007;143(8):980–2.

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be an effective treatment for chronic tension-type headache? J Headache Pain 2009; 10: 27–34.

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51.Saenz A, Avellanet M, Garreta R. Use of botulinum toxin type A on orthopedics: a case report. Arch Phys Med Rehabil 2003; 84(7): 1085–6.

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Botulinum toxin (BoNT) has evolved from the “most poisonous of all poisons” (1) to one of the most widely applied medical drugs within the last 60 years (2). The muscle-paralyzing activity of BoNT was first noticed in 1817 and subsequently has led to the hypothesis that small doses of BoNT could be beneficial in therapeutic uses. By now, several commercial preparations of botulinum toxin serotype A (BoNT-A) products are widely used for the treatment of strabismus, blepharospasm, cervical dystonia, and other conditions of excessive muscle contraction. In recent years, the aesthetic uses have expanded remarkably since the Carruthers first investigated the usefulness of BoNT-A for glabellar frown lines (3).

Onabotulinum toxin (BOTOX®, Allergan, Irvine, California) was first approved by the Food and Drug Administration (FDA) in 2002 for glabellar lines, but since then it has been applied off-label for other facial dynamic wrinkles and other aesthetic indications (4).

Abobotulinum toxin (Dysport®; Ipsen, Medicis US and Azzalure, Galderma, Europe) was first licensed for medical usage in Europe in 1990 (5). Clinical studies for esthetic indications were first performed in Europe 2002 and 2003, followed by U.S. FDA studies until 2009. FDA approval for treatment of glabellar frown lines occurred in May 2009.

Other BoNTA preparations now under consideration for aesthetic, usage include NT-201, now oncobotulinumtoxinA (Xeomin, Merz), Purtox (Mentor, California) and a topical BoNTA (Revance, California).

All of the preparations are BoNTA molecules, but there are some technical differences in the formulations. Most clinical properties seem to act the same. There may be some subtle differences the clinician must understand. It is thus important to review the science of the molecule, its formulations, and its physiologic action to use each of the preparations correctly.

To use the new products correctly, it is necessary to understand the following points:

1.The science of the BoNTA molecule and its differences

2.The clinical studies demonstrating efficacy and safety

3.Differences in the two products

4.Experience in world wide usage

SCIENCE OF BOTULINUM TOXIN A

The BoNTA molecule is a polypeptide with a light and a heavy chain actuated by “nicking” at the junction of the disulfide bond. This activates the molecule to irreversibly bind to the presynaptic terminal of the neuromuscular junction, cleaving specific membrane proteins, thus blocking the exocytosis of acetylcholine. The BoNTA cleaves the SNAP-25 protein blocking the neuromuscular junction (6).

The toxin exists as a complex with a surrounding coat of protective proteins: the hemagglutinin and nontoxic nonhemagglutinin proteins. The surrounding complex protein can serve to protect the neurotoxin from its potential destruction by the low pH of stomach acid. On absorption as the pH becomes physiological the outer protein coat releases the neurotoxin (7). Similarly, the full complex found in the vial prior to injection (750 or 900 kDa) and upon injection dissociates to the naked 150 kDa neurotoxin molecule (8).

Though both the BOTOX® and Dysport® neurotoxin molecules are the same weight (150 kDa), the complexes are different sizes due to variations in production. BOTOX® is 900 kDa and Dysport® is

750 kDa (9). The influence of the complexes once injected is really unknown, especially since dissociation occurs at physiologic pH. Questions concerning field of effect, diffusion and onset of action of each toxin are not fully answered. We do know that each has different units of potency (BOTOX® units versus Dysport® units) and this has a major impact on its clinical significance.

Technical differences in the two products are less than the similarities. The complex size is as follows:

1.BOTOX® (onabotulinumtoxinA): 900 kDa

2.Dysport® (abobotulinumtoxinA): 500 to 700 kDa

3.Xeomin (oncobotulinumtoxinA): 150 kDa-naked neurotoxin

4.Purtox: 150 kDa-naked neurotoxin

Other differences are in the composition of the product, which is summarized in Table 8A.1. Protein content is slightly greater in onabotulinumtoxinA with more serum albumin, but the carriers—NaCl and lactose—do differ; whether or not this makes a clinical difference is unknown.

THE CLINICAL STUDIES

AbobotulinumtoxinA (i.e., Dysport®) was first studied for aesthetic usage in Europe by Ascher in the later 1990s and again by Ascher and Rzany in 2004 and 2006 (10). Ascher performed a multicenter, randomized double-blind placebo controlled study of efficacy and safety of each dilutional doses of abobotulinumtoxinA for the treatment of glabellar lines. The 119 patients were from 18 to 70 years of age, with moderate to severe glabellar frown lines and no prior aesthetic treatment. The dosages used were placebo, 25, 50, and 75 units in a double-blind control. They were injected in five controlled glabellar sites targeting the obicularis oculi pars frontalis, the corrugators and the procerus muscle, each with appropriate divided units. Outcome measurements were assessed from blinded standardized photographs, investigator assessments, and patient evaluation. These were compared to a rating scale 0 to 4 of glabellar lines as follows: 0 = no lines; 1 = mild lines; 2 = moderate lines; 3 = severe lines. A responder was defined as 0:1 on the rating scale. The results indicated that all groups except placebo showed a response at 1 month and at 3 months. At 6 months, approximately two-thirds of the abobotulinumtoxinA-treated patients were still responders. Though the primary statistical analysis was performed at rest, the assessment at maximal frown was similar up to 3 months confirming the activity of abobotulinumtoxinA on the glabellar musculature.

The safety protocol was favorable with a 7.0% rate of adverse events, all mild and reversible. Headache was the most common with all resolving within 2 to 10 days. There were no reported cases of blepharoptosis or diplopia. The conclusions indicated the abobotulinumtoxinA was an effective cosmetic treatment for glabellar lines as evaluated by independent photographic analysis and investigator assessment. The result suggested that 50 units was the optimal dosage for the glabella and with 10 units injected into each of five glabellar sites. Most interesting was the long-term result indicating that one-third of the patients treated were still responders at 6 months (11). Other studies by Asher have indicated similar results of efficacy and safety for abobotulinumtoxinA in other locations including the forehead and crow’s feet (12).

This was followed by the U.S. studies beginning in 2003 extending to the present. The Inamed, Ipsen, and Medicis studies included phase II, phase III single, and repeat dosage studies with at total of 2,300 patients assessed for efficacy and safety. All studies evaluate efficacy and safety of

glabellar frown lines with rating scales at rest and at maximal frown. The U.S. studies used the same injection points as the U.S. onabotulinumtoxinA trials and were evaluated at maximal frown as its end points. In Europe, end points for response were determined at rest for efficacy and the lateral corrugator injection points were placed 0.5 cm more medial. The results though for efficacy and safety for both studies were similar.

Phase II trials were a dosage ranging study including placebo, 20 units, 50 units, and 75 units. There was a 90% responder rate at both 50 and 75 U. All doses were well tolerated with only minor side effects including headache, needle pricks, and bruising but blepharoptosis was observed in only three patients. Of those reported cases, only one demonstrated a true clinical ptosis to the investigator. Ptosis had been reported in other product studies but not in other studies involving abobotulinumtoxinA (13).

Antibody production has always been of concern with clinical usage of BoNTA, but studied only with cervical dystonia (14). None of the patients in this study showed any evidence of neutralizing antibodies either at baseline or on follow-up evaluations. From these observations, the 50-U dosage was recommended as the optimal dose for safety and efficacy. The lower dosage of 50 U was chosen for all of the phase III trials (15).

The initial single dosage, placebo-controlled, double-blinded, randomized trial of glabellar frown lines included over 400 subjects followed for 150 days (16). The patients were then enrolled in a repeat dosage trial for 23 months including four cycles of repeat dosage when the patient’s frown lines returned to baseline. The patients were evaluated for efficacy (i.e., number of responders at 30 days and duration of response) and safety. Over 90% responder rate was recorded at 30 days with duration at 4 months of 40% responders and at 5 months; 25% were still full responders (17). This produced a very similar efficacy case for responders and duration as onabotulinumtoxinA.

One factor reported by the subjects was an onset of action within 1 to 2 days. Subsequent studies have included a diary that the patient recorded when an onset of effect was first noted. In three of the studies the onset was recorded. Fifty percent of subjects noted an onset within 2 days and 80% noted it within 3 days (18). Though this was felt to be different from prior neurotoxins, true onset studies were not performed

Table 9.1 Constituent of Botulinum Toxin A

aBOTOX® Cosmetic is also available in a 50 U vial. The 100 U vial is referenced in this comparison.

Dysport® [package insert]. Scottsdale, AZ: Medicis Aesthetics Inc. 2009. BOTOX® Cosmetic [package insert]. Irvine, CA: Allergan, Inc. 2002.

to date with onabotulinumtoxinA. Reinjection treatment studies were performed to ensure that repeated exposure to the toxin did not influence efficacy or duration.

The repeat administration studies involved 768 individuals from phase III clinical trials who received up to six repeated treatments over 17 months. A patient was reinjected when glabellar wrinkle lines returned to baseline. The patients were followed for efficacy and safety including adverse effects and assessment of serum-neutralizing antibodies to abobotulinumtoxinA. Results confirmed continued effectiveness throughout the study with no increase of active events and no patients developed neutralizing antibodies.

The possibility of blocking antibodies influencing efficacy and toxin action has been noted with large therapeutic doses given over years for treatment of spastic torticolis and cerebral palsy. Antibody blocking effect, as of this time, has not been recorded with the cosmetic use of abobotulinumtoxinA (19).

As the data of these initial trials were reviewed, it was noted that efficacy and duration of action for men was less than that for women on a 50-U dosage for treating the glabella. This observation stimulated a variable dose study, which stratified patients by race/ethnicity, sex, and randomized by muscle mass. The muscle mass groups were to receive a single treatment of various doses of abobotulinumtoxinA. AbobotulinumtoxinA was administered as a single dose of 50, 60 or 70 U for women and 60, 70, or 80 U for men. This is based on procerus/corrugator muscle mass, small, medium, or large. Efficacy and duration was evaluated during a 5-month period. The results indicated that 87% of men and women had full efficacy at 30 days with a mean duration of 109 days for both men and women with no difference in ethnicity or gender (20).

Though clinicians have individualized abobotulinumtoxinA glabellar treatment as to sex, ethnicity, and muscle mass in clinical practice, this is the first controlled clinical study to verify this common practice.

DIFFERENCES IN THE BoNTA PRODUCTS

As the science of BoNTA and the clinical studies are very similar, what are the differences? The real differences have to do with manufacturing, dosage measurement, and what is in the vial.

The first real difference is in how treatment units are measured. The Dysport® units (DU) are measured differently from the BOTOX® units (BU) and are not interchangeable. Because these are proprietary measurements, a unit-to-unit measurement is an estimate. The current assessment is 2.5 DU versus 1.0 BU with a range of 2 or 3 to 1. This can give some guidance to the novice user but one should learn to think and treat using individual units—as one learns a foreign language— and not convert for usage.

The vial of each product is slightly different (Table 9.1). The major difference is the number of units in each. AbobotulinumtoxinA has 300 DUs in the United States and 500 U throughout the rest of the world, while onabotulinumtoxinA has 100 BUs. Both have albumin while abobotulinumtoxinA has lactose as a carrier and onabotulinumtoxinA has NaCl.

Most other differences found with treatment have to do with the clinicians’ injection technique when utilizing the product in individual patients. This produces variability as to dosage, dilution, and technique of injection. These variables are pertinent to both products.

Questions still asked concern a direct unit to unit ratio and differences of effect with similar units injected. As of this time, there are no direct comparisons of the units of biologic activity. Because of this the “head to head” studies performed for duration, efficacy and “diffusion” are imperfect and results are difficult to interpret. The anhidrotic halo study by De Almeida was a 3 to1 ratio giving a greater field of effect for abobotulinumtoxinA (21) while a similar study by Hexsel using a 2.5 to 1 ratio revealed similar fields of effect (22). The answer probably lies in the fact

that spread in field of effect is related more to dosage, dilution, and technique rather than intrinsic differences in the toxin or its preparation.

PRODUCT EXPERIENCE

AbobotulinumtoxinA has been used world wide for aesthetic needs for over 10 years. Those clinicians who have the greatest experience have defined injection points, minimal dosage, and a range of doses for each of the facial areas.

Both glabella and crow’s feet have been well studied by Asher with results comparable to onabotulinumtoxinA (23). Forehead, eyebrows, and full upper face are successfully treated with abobotulinumtoxinA in a similar fashion to onabotulinumtoxinA.

Volume injected is an important variable and varies as to physician preference. Common dilutions for 1 vial, 300 U of abobotulinumtoxinA are 1.5 ml or 2.5 ml, though some physicians prefer 3.0 ml. A 1.5 ml dilution will give 20 units on the 0.1 ml scale of a 1.0 ml tuberculin syringe, while a 3.0 ml dilution yields 10 units on the 0.1 ml scale, similar to onabotulinumtoxinA. It is recommended that the physician beginning abobotulinumtoxinA treatment use the 1.5 ml dilution, the most concentrated form to limit field of effect until he is familiar with the product. Experienced practitioners though use many off-label dilutions from 1.5 to 3.0 ml successfully. It is best for the physician to keep dilution a constant and vary the dosage as to patient needs.

AbobotulinumtoxinA has been used in clinical cosmetic practice worldwide over the last 10 years with similar injection points and techniques as onabotulinumtoxinA, but with different dosages. A full understanding of anatomy and product effect on distinctive facial muscles is essential for ensuring optimal treatment results and should be acquired through proper training. Since there are only a few clinical studies concerning off-label indications, an international consensus conference was held in Paris in January 2009, which provided general guidelines for effective and safe use of abobotulinumtoxinA on the generally useful yet off-label sites for injection. These have included the common upper face sites: the glabella, forehead, brow, crow’s feet and eyelid; and other less common facial sites including bunny lines, depressor angularis oris, obicularis oris, mentalis, and platysma. These recommendations gave guidelines to beginning dosage and range for each site as well as injection points and technique. Those physicians attending the summit include the following:

International Board of Botulinum Toxin

January 12–13, 2009

Paris, France

1.Benjamin Ascher: Chairman, France

2.Sergio Talarico: Co-Chairman, Brazil

3.Daniel Cassuto: Italy

4.Sergio Escobar: Argentina

5.Doris Hexsel: Brazil

6.Pedro Jaen Olasolo: Spain

7.Gary Monheit: United States

8.Berthold Rzany: Germany

9.Maurizio Viel: London

10.Alexandre Kaoukhov: France/Galderma Research

Sponsoring: Galderma

Ipsen

Conversion ratio and dilution should be a constant for a physician’s practice and dosage adjusted to individual needs. Dilution for a 300 U vial of abobotulinumtoxinA has been 1.5 cc of nonpreserved saline for the clinical trials. Other dilutions have been 2.5 and 3.0 cc, depending

on practice experience of the physician using onabotulinumtoxinA. The author has preferred the more concentrated dilution as experience with U.S. clinical trials has used the 1.5 cc dilution. Table 9.2 lists the dosages recommended for upper face with injection points described in the figures (Figs. 9.1–9.5).

The forehead is best treated through five injection sites located at midforehead at a distance of at least 2.5 cm above the brow. A dosage of 40 to 60 DU of abobotulinumtoxinA is effective for forehead wrinkle relaxation. The lateral forehead injection site should be above the highest point of the outer one-third of the brow. This will prevent an undesirable lateral brow elevation, the “Mephisto look” (24).

Laugh lines or crow’s feet are treated with 30 abobotulinumtoxinA injected lateral to each orbital rim, but not inferior to the orbital rim. The injection sites are 1.0 cm lateral to the orbital rim in the three positions, representing the muscle bulges, superior, mid, and inferior. Care must be taken not to inject below the orbital rim as lip ptosis or asymmetry may result from the zygomaticus muscle.

Lower eyelid wrinkles formed from an overactive or hypertrophic orbicularis oculi can be treated judiciously with 3 to 4 DU of abotulinumtoxinA injected in the lower lid at the mid papillary line 2 to 3 mm below the tarsal plate. This will flatten the bulging muscle and create an image of “open eye.” Overaggressive treatment may, though, create an unwanted ectropion (24).

Treatment of the lower face should be performed with more precaution as overdosage leads to significant dysfunction of obicularis oris creating an asymmetric smile and oral aperture. I would also recommend the more concentrated dilution of 1.5 cc saline per 300 unit vial to titrate, the toxin for contouring within appropriated muscles. Dosage recommendations in the lower face are given in Table 9.3.

As with onabotulinumtoxinA treatment, the physician must have a thorough understanding of facial musculature and the balance between elevator and depressor muscles. It is especially important in the lower face to be familiar with the anatomy and function of the facial muscles. Injections in or near many perioral muscles can cause facial asymmetry with expression. Because the field of effect is influenced by volume, the 1.5 cc dilution is recommended to limit abobotulinumtoxinA effect to the muscles injected.

AbobotulinumtoxinA can be used for elevation of the oral commissure by injecting the depressor angularis oris (DAO) with 10 DU of abobotulinumtoxinA (Fig. 9.6). The mentalis can be treated with 10 U to suppress chin dimpling (Fig. 9.7). Care is taken to keep both of these injections away form the depressor labialis inferioris. Platysma injections for bands use 5 DUs of abobotulinumtoxinA per injection with a total of 20 DU per band. This is a superficial injection spaced out at 1 cm intervals along the platysmal band (Fig. 9.8).

As aesthetic physicians become familiar with this second botulinum toxin product in the United States, new innovations and techniques will evolve and new data beyond the clinical trials will emerge. It is said the real clinical trial for a drug or device occurs in the first 2 years after release. It is with the large usage numbers that we gain a further understanding of both efficacy and safety.

Table 9.2 Recommended Dysport® Dosage for Upper Face

= 5–10 DUs

DU = Dysport® units

Figure 9.6 Injection sites for depressor angularis oris.

= 5–10 DUs

= 10 DUs

DU = Dysport® units

Figure 9.7 Injection sites for mentalis, (either the two blue sites or the one red site would be used).

= 5–10 DUs

DU = Dysport® units

Figure 9.8 Injection sites for platysma.

NON-COMPLEXED (NAKED) AND TOPICAL BOTULINUM TOXIN

Other BoNTA products under development include Xeomin/NT-201 (Merz Pharmaceuticals, Frankfurt, Germany) and Purtox (Mentor, Santa Barbara, California). Both products are naked 150 kDa molecules without accessory proteins. Advantages may be the lack of accessory proteins, which may be antigenic. Immune response to the proteins can lead to a lack of clinical response, thus the use of the “pure” 150 kDa molecules may prevent this.

OncobotulinumtoxinA has been studied in Europe with clinical trials and now has been released for cosmetic usage in Germany and England. It is undergoing phase II trial in the United States. Trials in Europe have found oncobotulinumtoxinA similar in units, dosage, and potency as onabotulinumtoxinA. It has an onset within 2 days and a duration of 110 days and there was very little difference in adverse events compared to onabotulinumtoxinA and abobotulinumtoxinA.

Purtox also is a 150 kDa pure neurotoxin without accessory proteins. It has undergone Phase I and Phase II clinical trials in the United States and found to have a 1- to 2-day onset with similar duration, efficacy, and safety record similar to the other toxins discussed. It is now undergoing phase III clinical trials.

A topically applied botulinum toxin without accessory proteins is currently under development by Revance Therapeutics Company. The botulinum molecule is transported through the skin by a proprietary, noncovalently bonded transport peptide. This molecular biologybased approach to topical drug delivery utilized a positively charged peptide combined with protein transduction domains (PTD). Through an active cellular transport mechanism, the peptide/PTD complex facilitates the transdermal flux of the naked BoNTA molecule across epidermis and then passively through dermis to muscle (25).

The very first studies were performed in 2007 by Dr. Richard Glogau using crow’s feet or lateral canthal wrinkle lines. The in-patient study of 12 subjects using the opposing side as a control demonstrated an active decrease in muscle activity by 65%.

The Phase II study for facial aesthetics comprised 532 subjects (377 with the active compound-RT001 and 155 subjects as control) evaluated for efficacy and safety. The FDA study demonstrated 70% 1-point improvement on the wrinkle severity scale at rest 4 weeks post treatment with a 30% 2-point improvement at therapeutic dosages. The safety profile revealed no significant adverse events (26). The Phase III trials are now underway.

Though the topical approach may not be applicable for dynamic wrinkles controlled by deeper muscles such as glabella, the superficial muscle penetration alone may play a significant role in treating eyelids, forehead, and lips without muscular side-effects from deeper penetration. In addition, its usage for hyperhidrosis, skin texture from pores and acne control all are uses the topical preparation may correct.

Within the last year, there are now two neurotoxins available for the aesthetic physician in the United States to treat cosmetic patients. Two additional toxins will be available within the next five years. Physicians will have a choice of products to use in specific facial areas.

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