Continuing Education Activity

Botulinum toxin is a medication used in the management and treatment of therapeutic and cosmetic purposes. Therapeutic uses include chronic migraine, spastic disorders, cervical dystonia, and detrusor hyperactivity. It is in the neurotoxin class of medications. This activity reviews the indications, action, and contraindications for Botulinum toxin therapy as a valuable agent for therapeutic and cosmetic treatment in the clinical setting. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to members of the healthcare team in the management of patients with spastic muscle disorders and related conditions.

Objectives:

• Identify the mechanism of action of Botulinum toxin.
• Describe the possible adverse effects of Botulinum toxin.
• Summarize the indications for Botulinum toxin.
• Review interprofessional team strategies for improving care coordination and communication to advance Botulinum toxin and improve outcomes.

Indications

Botulinum toxin is a highly potent neurotoxin that is produced from the bacteria Clostridium botulinum.[1] Clinicians have used this neurotoxin in practice since late 1970.[2] Clostridium botulinum is a spore-forming, gram-positive, anaerobic bacterium.[1] Botulinum neurotoxins are a group of seven serotypes A-G and are prepared in four types for practical use.[3][4] Serotype A is of three sorts; serotype B is one.[4] There are three forms of serotype A and one form of serotype B.[4] All four types are approved globally for treating spasmodic torticollis, a condition that can cause fixed head posturing or abnormal head movements. The three serotype A products have approval for focal dystonia that can affect the eye, causing abnormal eyelid twitching or closure.[4] Botulinum toxin is FDA-approved to treat migraines, which to date is the only chronic condition approved for its use. The therapeutic effect derives from the ability to minimize muscle tension and enhance muscle relaxation.[5] The neurotoxin formulation onabotulinumtoxin A is amongst the popular cosmetic procedures practiced in America.[5] Aesthetically, all three serotypes A forms are used for wrinkles and facial lines.[4] The toxin has also shown effectiveness in other medical conditions, such as strabismus and hypersalivation.[2][1][6] The neurotoxin is a beneficial and useful alternative pain remedy and should be considered for those that do not yield desirable results to opioid treatment.[5]

FDA-approved Use[5][7][8][4]:

• Chronic migraine
• Cervical Dystonia
• Blepharospasm
• Strabismus
• Hyperhidrosis
• Cosmetics
• Urinary incontinence from detrusor overactivity
• Hemifacial Spasms

Off-label Use[9][6][10]:

• Neurogenic thoracic outlet syndrome 
• Epicondylitis
• Post-stroke pain
• Post-herpetic neuralgia
• Diabetic neuropathy
• Trigeminal neuralgia
• Neuropathic pain
• Spinal cord injury
• Myofascial pain
• Bladder pain

Mechanism of Action

The potent zinc proteinase neurotoxin binds to extracellular receptors on cholinergic nerve terminals, cleaving one of the three (SNARE) soluble N-ethylmaleimide-sensitive factor attachment receptor proteins. This action causes reversible inhibition of the release of acetylcholine by presynaptic vesicles intracellularly, leading to a transient restraint of neurotransmitter release at the neuromuscular junction.[2][11][3][12][8] SNARE proteins also play an identified role in neurons recognized to release glutamate and substance R. Their actions are to release bradykinin, prostaglandins, histamine, and serotonin, which are proinflammatory mediators. The inhibition of these constituents may account for its possible treatment in chronic pain disorders, migraines, and neuralgias.[8]

Administration

Botulinum toxin has a longer duration of its action once administered. It takes approximately two weeks to thoroughly develop efficacy and the last three to five months in cosmetic practice.[13][5] Botulinum toxin's therapeutic uses on autonomic neurons for hyperhidrosis or overactive bladder have a significantly more notable effect, ranging from six to nine months[8]. 

FDA-approved Preparations[14]:

• OnabotulinumtoxinA 
• AbobotulinumtoxinA
• IncobotulinumtoxinA 
• RimabotulinumtoxinB

Dilution[8]:

OnabotulinumtoxinA suggested dilution:

• 100 U of powder form in 1 to 8 mL of saline.

AbobotulinumtoxinA suggested dilution:

• 300 U of powder form in 0.6 to 2.5 mL of saline.

The pharmaceutical form is packaged and distributed in powder form for all four preparations.[8] Numerous practitioners consider that when diluting the powder pharmaceutical form of botulinum toxin, it requires caution if more significant dilution with saline is desired. This dilution may cause spread to unwanted regions and yield suboptimal results; it can also cause unwanted adverse effects, such as eyelid ptosis.[8] 

FDA-approved Dose for Aesthetic Glabellar Lines[15]:

• AbobotulinumtoxinA 50 U
• OnabotulinumtoxinA cosmetic 20 U
• IncobotulinumtoxinA 20 U

FDA-approved labels advise against performing potency conversions.[14] The injection of botulinum toxin into distinct muscles causes flaccid paralysis and muscle relaxation.[10] Aesthetically this can diminish wrinkles by confined muscle relaxation and smoothing the overlying dermis.[13]

Adverse Effects

Adverse effects are frequently moderate and self-limited.[8] Therapeutic use of botulinum toxin reported more pressing adverse effects over the cosmetic practice; this may be due to the higher dosing required for therapeutic applications and possible complicated underlying conditions.[7] Among the more minor complications, bruising, edema, or pain at the injection site can develop during aesthetic use.[8][13] Flu-like symptoms can also occur. More uncommon complications include blepharoptosis and eyebrow ptosis, which is dependent on the injector.[13] Eyelid ptosis transpires with the introduction of botulinum toxin is introduced into the glabella, procerus, and corrugator muscles with unintended dispersion into the levator orbicularis muscle.[8] These unfavorable effects can serve up to three months.[8] As the technique and skill for injections improve, the incidence of complications decreases.[13] Allergic reactions are amongst the rare reported adverse effects. Symptoms may range from trivial to more severe rashes, and systemic anaphylaxis may also occur.[8]

Other complications include[8]:

• Headache
• Infection
• Cocked eyebrow
• Ectropion
• Decreased strength of eye closure
• Xerophthalmia

Contraindications

Botulinum toxin contraindications include[13][16]:

• Keloidal scarring
• Neuromuscular disorders 
• Botulinum toxin allergies
• Body dysmorphic disorder
• Pregnancy
• Breastfeeding
• Amyotrophic lateralizing sclerosis myopathies

Monitoring

The continuation of the paralysis and muscle relaxation effect is based on the temporary restraint of neurotransmitter release. The half-life differs among the serotypes and relies on when the SNARE protein regains function and releases neurotransmitter acetylcholine. Studies suggest that botulinum neurotoxin serotype A has the most prolonged half-life.[8]

Toxicity

The human LD50 for inhalation botulism is 1 to 3 ng/kg body mass.[17] LD50 is a lethal dose that would cause fatality in 50% of people receiving an application of the drug. As a bioweapon, botulinum toxin can be transmitted in airborne or foodborne methods. Toxicity will induce symptoms 12hrs to 3 days following exposure. Presenting symptoms include difficulty swallowing, hoarseness in voice, slurred or slow speech, double vision, and descending flaccid paralysis.[18][12]

Toxicity Treatment[17][19]:

• Antitoxin
• Vaccine
• F(ab')2 immune fragment therapies

These treatments are in addition to supportive therapy.[17]

Enhancing Healthcare Team Outcomes

Botulinum toxin is an FDA-approved medication indicated for therapeutic and cosmetic treatments. Managing the care of patients prescribed botulinum toxin for therapeutic purposes requires excellent communication between the patient and an interprofessional team of healthcare providers. These providers include a primary care clinician, a neurologist, a gynecologist, a urologist, and a nurse with their respective therapeutic uses for chronic migraine, post-stroke pain, cervical dystonia, and urinary incontinence from detrusor overactivity. Meanwhile, cosmetic treatments require technique and skill for facial injections, which can be administered in an outpatient clinic setting by a highly skilled nurse or clinician. The recommendation is that site injections are under the clinician's guidance to assure patient safety in case complications do arise. The primary care, specialist, and nurses should be familiar with botulinum toxin, its implications, and adverse effects. The clinicians and nurses require excellent patient rapport, and the patient needs thorough education on the treatment and symptoms of adverse effects. Botulinum toxin injections require routine checkups every three to five months to keep desired outcomes in an optimal range.[20][21][22][23] The interprofessional team approach, customized to the particular indication, will enhance patient outcomes with Botulinum toxin while mitigating potential adverse events. [Level 5]