Fast Fact #324 Non-cosmetic uses of botulinum neurotoxin (BoNT) have been FDA-approved for a growing number of spastic neuromuscular conditions, headaches, and secretory conditions (see Fast Fact #299).  While supporting evidence is limited for many indications and expense can be a barrier, this Fast Fact will review potential BoNT uses for seriously ill patients when traditional treatment modalities have failed.

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 via reversible inhibition of presynaptic acetylcholine release at the neuromuscular junction.  They are also known to inhibit gland secretion via parasympathetic effects.  At least one of the seven antigenically different serotypes (A) may have direct analgesic effects (1).

Practical aspects   Treatment with BoNT 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 3-4 days. The toxins’ effects can last 3-4 months for striated muscle and 6-9 months for autonomic neurons.

Specific palliative indications 

Spasticity   Controlled studies suggest 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 over age 16.  Available data suggests BoNT A 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 BoNTs may have a role in:  

• Stroke-related spasticity and pain (3-5).
• Non-malignant chronic neck pain (6).
• Pain and spasticity in cancer related pain (7-9).
• Dysphagia, esophageal strictures related to advanced cancer (7).

Neuropathic pain syndromes   Case reports and case series suggest BoNTs may reduce refractory neuropathic pain and opioid use (10-13). A randomized controlled trial (RCT) suggested that BoNT reduces pain severity and attack frequency in trigeminal neuralgia (14) and should be considered for patients who cannot tolerate other standard treatments due to toxicities.  RCTs also show BoNT can improve pain scores, reduce recovery time, and decrease opioid use in post-herpetic neuralgia (15).

Sialorrhea   Randomized trials show BoNT injections into salivary glands are beneficial for sialorrhea from many neurologic conditions (CP, amyotrophic lateral sclerosis, Parkinson’s disease, multiple system atrophy, corticobasal degeneration), with results lasting several months (16-18).

Depression   Psychotherapy and anti-depressant 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 anti-depressant effects within 2 weeks and lasting 4 months, as demonstrated by several RCTs (19-22).

Other Uses   Anecdotally, BoNTs have been used for radiation proctitis pain, chronic pelvic pain, phantom limb pain, chronic regional pain syndrome, tremors, chronic low back pain, neurogenic bladder, diabetic neuropathy, and speech failure following laryngectomy.

Financial Issues   Cost and insurance coverage can be significant barriers.  Medicare often covers BoNTs for non-cosmetic indications with a small co-payment.  Private insurance coverage can be variable, prior authorization and/or out of pocket costs may be necessary. Depending on the supplier and pharmacy, a single vial of BoNT can cost over $800, which may limit its use in hospice patients.

Risks and limitations   The diminishing effect of BoTN 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. 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 days (23-25): 

• Anaphylaxis or botulism-like systemic reactions:  most have occurred in off-label use in children; consequently, the FDA issued a black box warning for BoTNs.
• 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%).

References: 

1. Guo B, Zheng C, Sui B, Li Y, Wang Y, Yang Y. A closer look to botulinum neurotoxin type A-induced analgesia. Toxicon 2013; 71:134-9.
2. Hoare B, Wallen M, Imms C, Villanueva E, Rawicki H, Carey L. Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy (UPDATE).  Cochrane Database Syst Rev 2010; (1): CD003469.
3. Kaji R, Osako Y, Suyama K, Maeda T, Uechi Y, Iwasaki M. Botulinum toxin type A in post-stroke lower limb spasticity: a multicenter, double-blind, placebo-controlled trial. J Neuro 2010; 257(8):1330-7.
4. Lim J, Koh J, Paik N. Intramuscular botulinum toxin-A reduces hemiplegic shoulder pain: a randomized, double-blind, comparative study versus intraarticular triamcinolone acetonide. Stroke 2008; 39(1):126-31.
5. Wissel J, Ganapathy V, Ward A, Borg J, Ertzgaard P, Herrmann C, Haggstrom A, Sakel M, Ma J, Dimitrova R, Fulford-Smith A, Gillard P. OnabotulinumtoxinA improves pain in patients with post-stroke spasticity: findings from a randomized, double-blind, placebo-controlled trial. J Pain Symptom Manage. 2016;52(1):17-26.
6. Miller D, Richardson D, Eisa M, Bajwa RJ, Jabbari B.  Botulinum neurotoxin-A for treatment of refractory neck pain: a randomized, double-blind study. Pain Med 2009; 10(6):1012-17.
7. Lippi L, de Sire A, Turco A, et al.  Botulinum toxin for pain relief in cancer patients: a systematic review of randomized controlled trials.  Toxins 2024; 16(3):153.
8. Bach C, Wagner I, Lachiver X, Baujat B, Chabolle F.  Botulinum toxin in the treatment of post-radiosurgical neck contracture in head and neck cancer: a novel approach.  Eur Ann Otorhinolaryngol Head Neck Dis 2012; 129(1):6-10.
9. Mittal S, Machado D, Jabbari B. OnabotulinumtoxinA for treatment of focal cancer pain after surgery and/or radiation. Pain Med 2012; 13(8):1029-33.
10. O’Donnell C. Pectoral muscle spasms after mastectomy successfully treated with botulinum toxin injections. PM R 2011; 3(8):781-2.
11. Dessy L, Maruccia M, Mazzocchi M, Scuderi N. Treatment of post mastectomy pain syndrome after mastopexy with botulinum toxin. J Plast Reconstr Aesthet Surg 2014; 67(6):873-4.
12. Fabregat G, Asensio-Samper J, Palmisani S, Villanueva-Pérez V, De Andrés J. Subcutaneous botulinum toxin for chronic post-thoracotomy pain. Pain Pract 2013; 13(3):231-4.
13. Mercado MD, Olea MS, Rodrigues AT, et al. Intraneural injection of botulinum toxin-A in palliative care and unresponsive neuropathic pain. Asia Pacific Journal of Pain. 2023 Feb 13;1:1.
14. Wu C, Lian Y, Zheng Y, Zhang H, Chen Y, Xie N, Wang L. Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. Cephalalgia 2012; 32(6):443-50.
15. Apalla Z, Sotiriou E, Lallas A, Lazaridou E, Ioannides D. Botulinum toxin A in postherpetic neuralgia: a parallel, randomized, double-blind, single-dose, placebo-controlled trial. Clin J Pain 2013; 29(10):857-64.
16. Ondo W, Hunter C, Moore W. A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson’s disease. Neurology 2004; 62(1):37-40.
17. Jackson C, Gronseth G, Rosenfeld J, Barohn R, Dubinsky R, Simpson C, McVey A, Kittrell P, King R, Herbelin L. Randomized double-blind study of botulinum toxin type B for sialorrhea in ALS patients. Muscle Nerve 2009; 39(2):137-43.
18. Young C, Ellis C, Johnson J, Sathasivam S, Pih N.  Treatment for sialorrhea (excessive saliva) in people with motor neuron disease/amyotrophic lateral sclerosis. Cochrane Database Syst Rev 2011; (5):CD006981.
19. Wollmer M, de Boer C, Kalak N, et al. Facing depression with botulinum toxin: a randomized controlled trial. J Psychiatr Res 2012;46(5):574-81.
20. Finzi, E, Rosenthal, E. Treatment of depression with onabotulinumtoxinA: A randomized, double-blind, placebo controlled trial.  J Psychiatric Res 2014; 52:1-6.
21. Magid M, Reichenberg J, Poth P, Robertson H, LaViolette A, Kruger T, Wollmer M. Treatment of major depressive disorder using botulinum toxin A: a 24-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2014;75(8):837-44.
22. Schulze J, Neumann I, Magid M, et al. Botulinum toxin for the management of depression: An updated review of the evidence and meta-analysis. Journal of psychiatric research. 2021 Mar 1;135:332-40.
23. Cavallini M, Cirillo P, Fundarò S, Quartucci S, Sciuto C, Sito G, Tonini D, Trocchi G, Signorini M. Safety of botulinum toxin A in aesthetic treatments: a systematic review of clinical studies. Dermatol Surg 2014; 40(5):525-36.
24. Keuhn, B.  FDA Requires Black Box Warnings on Labeling for Botulinum Toxin Products. JAMA 2009; 301(22):2316.
25. Naumann, M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis.  Current Medical Research and Opinion 2004; 20(7): 981-990. 

 Authors’ Affiliations:  Massachusetts General Hospital; Harvard Medical School.
Conflicts of Interest: None.
Version History: Originally edited by Sean Marks MD; first electronically published in November 2016; reviewed and updated in June 2025.