Botulinum Toxin

Updated: Jun 02, 2016
  • Author: Divakara Kedlaya, MBBS; Chief Editor: Elizabeth A Moberg-Wolff, MD  more...
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Overview

Overview

Botulinum toxin (abbreviated either as BTX or BoNT) is produced by Clostridium botulinum, a gram-positive anaerobic bacterium. [1] The clinical syndrome of botulism can occur following ingestion of contaminated food, from colonization of the infant gastrointestinal tract, or from a wound infection.

BoNT is broken into 7 neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, and G), which are antigenically and serologically distinct but structurally similar. Human botulism is caused mainly by types A, B, E, and (rarely) F. Types C and D cause toxicity only in animals.

The various botulinum toxins possess individual potencies, and care is required to assure proper use and avoid medication errors. Recent changes to the established drug names by the FDA were intended to reinforce these differences and prevent medication errors. The products and their approved indications include the following:

  • OnabotulinumtoxinA (Botox®, Botox Cosmetic®)
    • Botox® - Cervical dystonia, severe primary axillary hyperhidrosis, strabismus, blepharospasm, neurogenic detrusor overactivity, chronic migraine, upper limb spasticity
    • Botox Cosmetic® - Moderate to severe glabellar lines, moderate to severe lateral canthal lines, known as crow’s feet
  • AbobotulinumtoxinA (Dysport®) - Upper limb spasticity, cervical dystonia, moderate to severe glabellar lines.
  • IncobotulinumtoxinA (Xeomin®) - Upper limb spasticity, cervical dystonia, blepharospasm, moderate to severe glabellar lines.
  • RimabotulinumtoxinB (Myobloc®) - Cervical dystonia

The BoNT molecule is synthesized as a single chain (150 kD) and then cleaved to form the dichain molecule with a disulfide bridge (see image below).

Botulinum toxin structure (schematic diagram). Botulinum toxin structure (schematic diagram).

The light chain (~50 kD - amino acids 1-448) acts as a zinc (Zn2+) endopeptidase similar to tetanus toxin with proteolytic activity located at the N-terminal end (see image below). The heavy chain (~100 kD - amino acids 449-1280) provides cholinergic specificity and is responsible for binding the toxin to presynaptic receptors; it also promotes light-chain translocation across the endosomal membrane.

Proteolytic activity is located at the N-terminal Proteolytic activity is located at the N-terminal end of the light chain of botulinum toxin type A.

For patient education resources, see the Procedures Center, as well as BOTOX® Injections.

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History

The German physician and poet Justinus Kerner (1786-1862) first developed the idea of a possible therapeutic use of botulinum toxin, which he called "sausage poison." [2]

  • In 1870, Muller (another German physician) coined the name botulism. The Latin form is botulus, which means sausage.
  • In 1895, Professor Emile Van Ermengem, of Belgium, first isolated the bacterium Clostridium botulinum.
  • In 1928, Dr. Herman Sommer, at the University of California, San Francisco, first isolated in purified form botulinum toxin type A (BoNT-A) as a stable acid precipitate.
  • In 1946, Dr. Edward J Schantz succeeded in purifying BoNT-A in crystalline form–cultured Clostridium botulinum and isolated the toxin.
  • In 1949, Dr. Burgen's ASV group discovered that botulinum toxin blocks neuromuscular transmission.
  • In the 1950s, Dr. Vernon Brooks discovered that when BoNT-A is injected into a hyperactive muscle, it blocks the release of acetylcholine from motor nerve endings.
  • In 1973, Dr. Alan B. Scott, of Smith-Kettlewell Eye Research Institute, used BoNT-A in monkey experiments; in 1980, he used BoNT-A for the first time in humans to treat strabismus.
  • In December 1989, BoNT-A (BOTOX®) was approved by the US Food and Drug Administration (US FDA) for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients aged younger than 12 years.
  • On December 21, 2000, BoNT-A received US FDA approval for treatment of cervical dystonia.
  • In 2001, the United Kingdom approved BOTOX®, synthesized by Allergan, for axillary hyperhidrosis (excessive sweating). Canada approved BOTOX® for axillary hyperhidrosis, focal muscle spasticity, and cosmetic treatment of wrinkles at the brow line.
  • On April 15, 2002, the US FDA announced the approval of BOTOX® Cosmetic to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines). On July 21, 2011, the US FDA approved incobotulinumtoxinA (Xeomin) for temporary improvement in the appearance of moderate-to-severe glabellar lines, or frown lines between the eyebrows, in adult patients.
  • In July 2004, the US FDA approved BOTOX® to treat severe underarm sweating, known as primary axillary hyperhidrosis that cannot be managed by topical agents, such as prescription antiperspirants.
  • The acceptance of BoNT-A use for the treatment of different chronic pain disorders is growing. However, it has not been approved by the US FDA for any chronic pain conditions except for chronic migraine.
  • The clinical use of BoNT-B has been studied, and several products currently are available commercially (eg, MyoBloc, in the United States; NeuroBloc, in Europe). MyoBloc was approved by the US FDA on December 8, 2000, for treatment of cervical dystonia, to reduce the severity of abnormal head position and neck pain.
  • Use of BoNT-F also is under investigation in patients who have become immunologically resistant to serotypes A and B.
  • On April 29, 2009, abobotulinumtoxinA (Dysport) was approved by the US FDA for the treatment of adults with cervical dystonia to reduce the severity of abnormal head position and neck pain in both toxin-naïve and previously treated patients.
  • On March 9, 2010, the US FDA approved onabotulinumtoxinA (BOTOX®) to treat spasticity in the flexor muscles of the elbow, wrist, and fingers in adults with stroke, traumatic brain injury, or the progression of multiple sclerosis.
  • On August 2, 2010, the US FDA announced the approval of incobotulinumtoxinA (Xeomin®) for the treatment of adults with cervical dystonia, to decrease the severity of abnormal head position and neck pain in both botulinum toxin-naïve and previously treated patients and for blepharospasm in adults previously treated with BOTOX®.
  • On October 15, 2010, the US FDA approved onabotulinumtoxinA (BOTOX®) injection to prevent headaches in adult patients with chronic migraine. Chronic migraine is defined as having a history of migraine and experiencing a headache on most days of the month.
  • On August 24, 2011, the US FDA approved onabotulinumtoxinA (BOTOX®) injection for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (eg, spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant of an anticholinergic medication.
  • On September 11, 2013, the US FDA approved onabotulinumtoxinA (BOTOX®) for the temporary improvement in the appearance of moderate to severe lateral canthal lines, known as crow’s feet. This is the only FDA-approved drug treatment option for lateral canthal lines.
  • On July 16, 2015, the US FDA approved Dysport® (abobotulinumtoxinA) for the treatment of upper limb spasticity (ULS) in adult patients to decrease the severity of increased muscle tone in elbow flexors, wrist flexors and finger flexors.
  • On December 23, 2015, the US FDA approved Xeomin® (incobotulinumtoxinA) for the treatment of upper limb spasticity (ULS) in adult patients.
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Mechanism of Action

Botulinum toxin acts by binding presynaptically to high-affinity recognition sites on the cholinergic nerve terminals and decreasing the release of acetylcholine, causing a neuromuscular blocking effect. This mechanism laid the foundation for the development of the toxin as a therapeutic tool.

Recovery occurs through proximal axonal sprouting and muscle re-innervation by formation of a new neuromuscular junction. De Paiva and colleagues suggest that eventually the original neuromuscular junction regenerates. [3]

  • BoNT-A and BoNT-E cleave synaptosome-associated protein (SNAP-25), a presynaptic membrane protein required for fusion of neurotransmitter-containing vesicles. [4]
  • BoNT-B, BoNT-D, and BoNT-F cleave a vesicle-associated membrane protein (VAMP), also known as synaptobrevin.
  • BoNT-C acts by cleaving syntaxin, a target membrane protein.

Table 1. Botulinum Toxin Types, Target Sites, Discoverers, and Year Discovered (Open Table in a new window)

Type Target Discoverer Year
A SNAP-25 Landman 1904
B VAMP Ermengem 1897
C1 Syntaxin Bengston and Seldon 1922
D VAMP Robinson 1929
E SNAP-25 Gunnison 1936
F VAMP Moller and Scheibel 1960
G VAMP Gimenez and Ciccarelli 1970

 

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Preparations

The different preparations of BoNT-A, onabotulinumtoxinA (BOTOX®; Allergan; Irvine, Calif), abobotulinumtoxinA (Dysport®; Ipsen; Paris, France), incobotulinumtoxinA (Xeomin®; Merz Pharmaceuticals, Frankfurt, Germany), CS-BOT (Chiba Serum Institute; Chiba, Japan), and Chinese BTX-A (Prosigne ®; Lanzhou Biological Products Institute, China) differ in potency. [5]

  • BoNT-A is prepared by laboratory fermentation of C botulinum cultures. Crude botulinum toxin is a protein with a molecular weight of about 190,000 Daltons. After purification, the toxin is diluted with human serum albumin, bottled in vials, lyophilized (freeze-dried), and sealed.
  • Each freeze-dried vial containing 100 units (U) of BoNT-A is reconstituted with preservative-free normal saline (1-5 mL) just before use. The manufacturer recommends that the toxin be used within 4 hours of reconstitution.
  • The potency of BoNT-A is measured in mouse units (MU). One MU of BoNT-A is equivalent to the amount of toxin that kills 50% of a group of 20 g Swiss-Webster mice within 3 days of intraperitoneal injection (LD50).
  • According to one report, 1 nanogram of toxin contains approximately 20 U of BOTOX® (ie, 1 U of BOTOX® is equal to approximately 0.05 nanogram of the toxin).
  • According to another report comparing the 3 different preparations of BoNT-A, 1 nanogram of Dysport contains approximately 40 MU, whereas 1 nanogram of the BOTOX® contains approximately 4 MU, and 1 nanogram of CS-BOT contains approximately 15.2 MU.
  • Median paralysis unit (MPU) is thought to be a more pharmacologically relevant unit of biologic activity. Comparison of the potency ratio based on the MPU values for Dysport and BOTOX ® revealed a 2.44-fold difference in potency between these formulations. [6]
  • LD50 of BoNT-A for a 70-kg adult male has been calculated to be 2500-3000 U (35-40 U/kg).
  • Minimum lethal dose of BoNT-B in monkeys is 2400 U/kg.
  • Clinically, 1 U of BoNT-A (BOTOX ®) is approximately equivalent to 3 U of Dysport ®. [7]
  • Studies of Xeomin ® and Prosigne ® use unit dosing comparable (1:1) with BOTOX ®. [8, 9]
  • An animal study that found that Xeomin® contains the highest specific neurotoxin activity, followed by Dysport®, with BOTOX ® having the lowest specific activity. [10]
  • Standardization efforts are underway using measurements of the toxin's pharmacologically relevant actions (eg, median paralysis unit).
  • BOTOX® vials contain sodium chloride (0.9 mg) and human albumin (0.5 mg), and the protein load is 5 ng/100 units; Prosigne® vials contain porcine gelatin (5 mg), dextran (25 mg), and sucrose (25 mg), and the protein load is 4-5 ng/100 units of BoNT-A. [11] BOTOX® is thought to be about 1.5 times more potent than Prosigne®.
  • BoNT-B is marketed in the United States as RimaBotulinumB (MyoBloc®). This preparation is a ready-to-use solution that does not require reconstitution; it is available in 3 vial sizes (ie, 2500 U, 5000 U, and 10,000 U) and is stable for up to 21 months in refrigerator storage.
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Therapeutic Uses

Therapeutic uses of botulinum toxin injection  [12]   [13]

  • Focal dystonias - Involuntary, sustained, or spasmodic patterned muscle activity
    • Cervical dystonia (spasmodic torticollis) [14, 15, 16, 17, 18]
    • Blepharospasm (eyelid closure) [19]
    • Laryngeal dystonia (spasmodic dysphonia) [20]
    • Limb dystonia (writer's cramp)
    • Oromandibular dystonia [19]
    • Orolingual dystonia
    • Truncal dystonia
  • Spasticity - Velocity-dependent increase in muscle tone [21, 22]
  • Nondystonic disorders of involuntary muscle activity
    • Hemifacial spasm [26]
    • Tremor [27]
    • Tics [28]
    • Myokymia and synkinesis
    • Tinnitus (due to myoclonus of stapedius muscle [29] & tensor veli palatini muscle [30] )
    • Hereditary muscle cramps
    • Nocturnal bruxism [31]
    • Trismus [32]
    • Anismus [33]
  • Strabismus (disorder of conjugate eye movement) [34, 35] and nystagmus
  • Chronic pain and disorders of localized muscle spasms
  • Smooth muscle hyperactive disorders
    • Neurogenic bladder – Detrusor hyperreflexia [54, 55, 56, 57]
    • Detrusor-sphincter dyssynergia [58, 59, 60, 61]
    • Benign prostatic hypertrophy [62, 63, 64]
    • Achalasia cardia [65, 66]
    • Hirschsprung disease [67]
    • Sphincter of Oddi dysfunctions [68, 69]
    • Hemorrhoids [70, 71]
    • Chronic anal fissures [72, 73]
    • Raynaud's Phenomenon [74]
  • Cosmetic use
    • Hyperkinetic facial lines (glabellar frown lines, crow's feet) [75]
    • Hypertrophic platysma muscle bands [76, 77]
  • Sweating, salivary, and allergy disorders
    • Axillary and palmar hyperhidrosis [78]
    • Frey syndrome, also known as auriculotemporal syndrome (gustatory sweating of the cheek after parotid surgery) [79]
    • Drooling in cerebral palsy and other neurological disorders [80, 81, 82, 83, 84]
    • Nasal allergy and allergic rhinitis [85, 86]
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Botulinum Toxin Use in Dystonia

Use of BoNT-A in different types of focal dystonias has been well studied and has proven to be very effective. Botulinum toxin injection is the treatment of choice for cervical dystonia (spasmodic torticollis). [14, 15, 87] . A Cochrane review concluded that a single injection of BoNT-B was effective and safe for treating cervical dystonia. [88] This injection benefits the highest percentage of patients in the shortest time and has been proven effective in many double-blind, placebo-controlled trials.

BoNT has fewer side effects than do other pharmacologic treatments. The efficacy and safety of BoNT injections for the treatment of certain movement disorders, including blepharospasm, hemifacial spasm, oromandibular dystonia, cervical dystonia, focal limb dystonias, laryngeal dystonia, tics, and essential tremor is ongoing. [89]

In a double-blind, placebo-controlled trial by Greene and colleagues, 55 patients who previously had failed to find relief in 2 trials of medication received either BoNT or placebo in a double-blinded fashion and were tracked for 12 weeks. [90] Four weeks of open phase then followed when all patients received BoNT. By 6 weeks, 61% of patients showed improvement in head posture, and 39.5% reported reduction of pain. Both measures significantly improved (P < .05) compared to controls. During the open phase, patients who previously received placebo exhibited a similar response. Overall, 74% of patients improved by the end of the study.

A study by Brans and colleagues showed that in 64 patients with cervical dystonia, 84% reported long-term benefits in terms of impairment, disability, handicap, and quality of life (QOL). [91] Mezaki et all described their experience with a Japanese type A toxin for the treatment of cervical and axial dystonias. [92] Injections were given repeatedly at intervals of 28-30 days to carefully chosen muscles with increased activities, with a maximum dose per session of 300 units. The maximum improvements in subjective and objective ratings were obtained only after repeated injections.

Procedure

Treatment dosages of BoNT-A in the United States have been reported to range from 100-300 U per patient. In a double-blind, placebo-controlled study, Poewe and colleagues demonstrated that magnitude and duration of improvement were greatest after injections of 1000 U of Dysport, but the injections caused significantly more adverse effects. [93] The researchers recommended a lower starting dose of 500 U of Dysport (1 U of BoNT-A = 3 U of Dysport). One hundred U of toxin per mL of preservative-free normal saline are commonly used.

Injections are performed with a Teflon-coated, 24-gauge needle connected to an electromyographic (EMG) machine. Those muscles with highest clinical and EMG activity are injected. Usually, 2-4 separate muscles are injected in 1 session and, in larger muscles, 2-4 sites per muscle are injected.

No general consensus exists among users of BoNT regarding the need for EMG guidance while injecting the compound for cervical dystonia. EMG guidance, however, is helpful, particularly in obese patients whose neck muscles cannot adequately be palpated.

Identifying the specific muscles involved in cervical dystonia prior to the injection is important. Those most commonly injected are the sternocleidomastoid, trapezius, splenius capitis, and levator scapulae muscles. An EMG study of 100 patients found that 2 or 3 muscles commonly are abnormal. Eighty-nine percent of patients with rotating torticollis had involvement of the ipsilateral splenius capitis and contralateral sternocleidomastoid with or without the additional involvement of the contralateral splenius capitis. Patients with laterocollis had ipsilateral sternocleidomastoid, splenius capitis, and trapezius involvement, while retrocollis was produced by bilateral splenius capitis activity.

Beneficial effect from toxin injection usually is apparent in 7-10 days. Maximum response from the toxin is reached in approximately 4-6 weeks and lasts for an average of 12 weeks. Injections usually are repeated every 3-4 months.

Complications

Neck weakness, dysphagia, and local pain at the injection site are the most commonly reported side effects. Other adverse effects (eg, local hematoma, generalized fatigue, lethargy, dizziness, dry mouth, dysphonia, flulike syndrome, pain in neighboring muscles) also have been reported.

Most studies have reported side effects in 20-30% of patients per treatment cycle. The incidence of adverse effects varies based on the dosage used (ie, the higher the dose, the more frequent the adverse effects); however, Jankovic and Schwartz reported that incidence of complications was not related to the total dose of BoNT used. [94] Women and patients who received injections into the sternocleidomastoid muscles had significantly higher rates of complications.

Dysphagia has been the most prevalent significant complication and most probably is related to diffusion of the toxin into nearby pharyngeal muscles. In the study by Comella and colleagues, 33% of patients receiving their first dose of botulinum toxin experienced dysphagia. [95] This complication most commonly occurs with injections of the sternocleidomastoid and can be reduced significantly when the dose of toxin administered is 100 U or less.

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Botulinum Toxin Use in Spasticity

Spasticity is defined as a velocity-dependent increase in muscle tone. Intramuscular injections of BoNT have been studied and found to be useful in the treatment of spasticity in multiple sclerosis (MS), cerebral palsy (CP), stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). Different studies have shown the effectiveness of BoNT-A injection in the management of spasticity. [23]

Table 2. Studies of Botulinum Toxin in the Treatment of Spasticity in Different Disorders (Open Table in a new window)

Clinical Diagnosis Author Study Design
Multiple Sclerosis Benecke



Borg-Stein et al [96]



Snow et al [97]



Hyman et al [98]



Open-label



Open-label



Double-blind, placebo-controlled, randomized, crossover



Double-blind, placebo-controlled, randomized, dose-ranging



Spinal Cord Injury Bohlega et al



Takenaga et al



Open-label



Open-label



Cerebral Palsy Koman et al [99] Koman et al [100]



Cosgrove et al [101]



Chutorian and Root



Chutorian, Root, and the BTA study group



Corry et al [102]



Fehlings et al [103]



Wissel et al [104]



Baker et al [105]



Edwards et al [106]



Open-label



Double-blind, placebo-controlled



Open-label



Open-label



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled



Single-blind, randomized, controlled



Double-blind, randomized, placebo-controlled



Double-blind, randomized, placebo-controlled



Double-blind, randomized, placebo-controlled



Stroke Das and Park Memin et al



Grazko et al



Dengler et al



Jabbari et al



Simpson et al



Bhaktha et al [107]



Smith et al [108]



Childers et al [109]



Pittock et al [110]



Brashear et al [111]



Bakheit et al [112]



Open-label



Open-label



Double-blind, placebo-controlled, crossover



Open-label



Double-blind, placebo-controlled, crossover



Double-blind, placebo-controlled



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Double-blind, placebo-controlled, randomized



Traumatic Brain Injury Yablon et al [113]



Pavesi et al [114]



Open-label



Open-label



 

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Pain Management

Use of BoNT-A in the management of different pain disorders is being studied. [115] At this time, indications for the use of BoNT in managing muscle pain disorders still are controversial. The exact mechanism of action behind BoNT's analgesic effect is not known; however, a study by Purkiss and colleagues showed that BoNT inhibits calcium-dependent release of substance P in embryonic dorsal root ganglia. [116] Hence, BoNT may, by blocking the release of substance P, produce an analgesic effect through peripheral inhibition of C and A delta fibers. Based on the research with animal models, BoNT-A in peripheral nociceptive neurons plays a direct role in its peripheral analgesic effect and an indirect role in its central analgesic effect because of retrograde transport. [117]

In a double-blind, randomized, placebo-controlled study, Foster and colleagues showed the efficacy of 200 U of BoNT-A injection, using 40 U per site at 5 lumbar paravertebral levels on the side of maximum discomfort, in chronic low back pain patients. [118]

A Cochrane review regarding the use of BoNT-A injection for chronic low back pain has concluded evidence that BoNT injections improved pain, function, or both better than saline injections was limited, as was evidence this was better than acupuncture or steroid injections. [119] They recommend further high quality randomized controlled studies.

BoNT-A injection has also been studied for chronic neck pain, cervicogenic headache, and whiplash-associated neck pain; however, a Cochrane review and systematic review and meta-analysis by Langevin et al concluded that current evidence fails to confirm either a clinically important or a statistically significant benefit of BoNT-A injection for whiplash-associated neck pain and chronic neck pain associated with or without cervicogenic headache. [120, 121]

BoNT-A has been studied to treat different neuropathic pain disorders such as postherpetic neuralgia, [122] trigeminal neuralgia, [123, 124] and diabetic peripheral neuropathic pain, [125] and has shown to be effective in managing pain in these conditions.

Different studies on the use of BoNT in the management of different pain disorders are listed in Table 3.

Table 3. Studies on the Use of Botulinum Toxin in Pain Management (Open Table in a new window)

Author(s) (Year) Clinical Condition Study Type N Results
Zwart et al (1994) [126] Tension headache Open-label 6 Unilateral temporal injection not effective
Sherman et al (1995) [127] Chronic pancreatitis Open-label 7 Not effective
Paulson et al (1996) [128] Fibromyalgia Randomized, controlled 5 Not effective
Wheeler et al (1998) [129] Myofascial pain [130] Randomized, double-blind, controlled 33 No significant difference, second injection effective?
Wheeler (1998) [131] Tension headache Open-label 4 Effective in 4 patients
Schulte-Mattler et al (1999) [132] Tension headache Open-label 9 Effective in 8 of 9 patients
Freund et al (1999) [133] Temporomandibular disorders Open-label 15 Effective
Freund et al (2000) [134] Temporomandibular disorders Open-label 46 Effective
Silberstein et al (2000) [135] Migraine headache Double-blind, vehicle-controlled 123 Effective prophylaxis
Rollnik et al (2000) [136] Tension headache Double-blind, placebo-controlled 21 Not effective
Freund et al (2000) [137] Cervicogenic Headache Randomized, double-blind, placebo-controlled 26 Effective
Freund et al (2000) [138] Whiplash associated with neck pain Randomized, double-blind, placebo-controlled 26 Effective
Barwood et al (2000) [139] Severe postoperative pain and spasm in cerebral palsy Randomized, double-blind, placebo-controlled 16 Effective prophylaxis
Porta (2000) [140] Chronic myofascial pain syndrome Randomized, controlled, comparative 40 BOTOX® better than methylprednisolone

 

For more information, see Medscape Reference article Botulinum Toxin in Pain Management.

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Adverse Events

Adverse events due to therapeutic and cosmetic injection of BoNT reported to the FDA include respiratory problems, dysphagia, seizure, flulike syndrome, facial and other muscle weakness, ptosis, and skin and injection site reactions. [141] Of the 406 reports related to therapeutic use, 217 met the FDA's definition of serious, with 28 deaths and 17 seizures reported. Clinical characteristics submitted to the FDA for therapeutic cases differed from those of cosmetic BoNT cases, which were usually less serious. Most of the adverse effects linked to local tissue diffusion of BoNT. Careful attention to drug dose, dilution, handling, storage, and site of injection are required for optimal treatment outcome and to minimize adverse effects.

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