Abstract
N
Pharmacology
BoNTs are a metabolic waste product of the bacteria Clostridium botulinum. In large quantities, BoNTs cause botulism, a rare but potentially lethal illness resulting from muscle paralysis. In minute quantities, the toxin can be therapeutic for overactive muscle conditions through reversible inhibition of presynaptic acetylcholine release at the neuromuscular junction. They are also known to inhibit gland secretion through parasympathetic effects. At least one of the seven antigenically different serotypes (A) may have direct analgesic effects. 1
Practical Aspects
Treatment with BoNTs involves direct, localized injection of a saline solution containing the diluted toxin at the site of intended action (intramuscular or subcutaneous). It is usually an office-based procedure. Procedural specialists often provide this service, but other clinicians could become certified after training and demonstrating proficiency, depending on individual institutional regulations. Onset of action is generally within three to four days. The toxins' effects can last three to four months for striated muscle and six to nine months for autonomic neurons.
Specific Palliative Indications
Spasticity
Controlled studies suggest that BoNTs can be particularly useful for short-lived spasmodic pain that may be difficult to target with systemic analgesics. Serotype A is FDA approved to treat spasticity of the upper and lower extremities in adults. In children, different BoNT formulations are used off label to treat many muscle groups; the only FDA-approved pediatric indication is cervical dystonia in patients older than age 16. Available data suggest that a BoNT is safe and improves function, self-worth, and parental/caregiver perception of care for cerebral palsy (CP)-related spasticity in children when used as an adjunct to traditional therapies. 2 Other evidence suggests that BoNTs may have a role in:
Neuropathic pain syndromes
Case reports and case series suggest that BoNTs may reduce neuropathic pain and reduce opioid use from postmastectomy and post-thoracotomy pain syndromes.10–12 A randomized controlled trial (RCT) suggested that BoNT reduces pain severity and attack frequency in trigeminal neuralgia 13 and should be considered for patients who cannot tolerate other standard treatments because of toxicities. RCTs also show that BoNTs can improve pain scores, reduce recovery time, and decrease opioid use in postherpetic neuralgia.14,15
Sialorrhea
Randomized trials show that BoNT injections into salivary glands are beneficial for sialorrhea from many neurological conditions (CP, amyotrophic lateral sclerosis, Parkinson's disease, multiple system atrophy, and corticobasal degeneration), with results lasting several months.16–18
Depression
Psychotherapy and antidepressant medications remain the mainstay of depression treatment (see Fast Fact #309), but BoNTs show promise in patients with limited prognoses. Single glabellar region BoNT injections show antidepressant effects within two weeks and lasting four months, as demonstrated by several RCTs.19–21
Other uses
Anecdotally, BoNTs have been used for radiation proctitis pain, chronic pelvic pain, phantom limb pain, chronic regional pain syndrome, multiple sclerosis tremors or spasticity, chronic low back pain, neurogenic bladder, diabetic neuropathy, and speech failure after laryngectomy.
Financial Issues
Cost and insurance coverage can be significant barriers. Medicare often covers BoNTs for noncosmetic indications with a small copayment. Private insurance coverage can be variable, leading some patients to require prior authorization and others to pay entirely out of pocket. Depending on the supplier and pharmacy, a single vial of BoNT can cost more than $800, which may limit its use in hospice patients.
Risks and Limitations
The diminishing effect of BoNT over months can require repeat injections over time. Depending on injection site, patient age, and tolerance of the procedure, sedation or even general anesthesia may be required, introducing additional risks. Furthermore, there is a lack of large RCTs for many indications. Although the side effect profile is felt to be low if injected correctly, clinicians should be aware of the following potential adverse reactions, most of which occur within hours to days of the injection, and usually subside after several days22–24
:
• Anaphylaxis or botulism-like systemic reactions: most have occurred in off-label use in children; consequently, the FDA issued a black box warning for all BoNT products in 2009. • Bruising, edema, or pain at the injection site (2%–3%). • Flu-like symptoms (1.7%–20%). • Ptosis or diplopia (2%–13%). • Dry mouth, dysarthria, or dysphagia (2%–10%).