Update on Botulinum Toxin

A. Carruthers, MD, FRCPC

Division of Dermatology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Botulinum toxin type-A (BTX-A) is a neurotoxin which blocks presynaptic release of acetylcholine. It interferes with neuromuscular transmission¹, temporarily paralyzing the affected muscle⁶. Of special interest for dermatologists is the unlabelled cosmetic applications, for conditions such as wrinkles and hyperhidrosis. Labelled indications in Europe are for cervical dystonia and cerebral palsy. In the US, it is approved for treatment of strabismus, blepharospasm and hemifacial spasm in adults². After repeated use of high doses, antibodies can develop in some individuals, making further treatment ineffective indefinitely. Even when used in high doses for neurological conditions, the development of antibodies occurs in < 5% of patients. In 1997, the US FDA approved a new bulk toxin source for use in the manufacture of BTX-A. It has a higher specific potency than original BTX-A formulations, reducing the amount of utilized neurotoxin protein, and thereby reducing antibody production⁹. Another form of this neurotoxin (type B) also appears to be effective in patients who have developed antibodies to BTX-A. It is awaiting US FDA approval for treatment of cervical dystonia.

Key Words:
Botulinum toxin, type-A, Hyperhidrosis

PHARMACOLOGY

Botulinum toxin type-A (BTX-A) is a neurotoxin produced by C. botulinum which blocks presynaptic release of acetylcholine. When a minute amount is injected into a muscle, it prevents neuromuscular transmission¹ temporarily paralysing the affected muscle, and can provide symptomatic relief for up to three months or more after a single injection⁶. This can be useful for a wide variety of conditions.

Cosmetic Uses

BTX-A has had a lot of publicity recently for its off-label cosmetic use in facial wrinkles¹¹. It is currently in widespread use for the treatment of glabellar frown lines, crow’s feet, and horizontal forehead lines¹. Other more recent uses include more extended management of cosmetic problems, including platysmal bands and horizontal neck lines as well as lines in the lower part of the face. The nasolabial fold, mental crease, and upper lip wrinkling have all been successfully treated using BTX-A although these indications are not without controversy³.

Hyperhidrosis

Hyperhidrosis is another condition that has been managed successfully using BTX-A intracutaneously^4,5, though some researchers report some associated muscle weakness5.

Refractory Pain Associated with Spasticity

BTX-A offers an alternative for patients with refractory pain associated with spasticity. This includes dystonia due to abnormal posture, sustained muscle spasm and tremor. Investigators are looking at a wide range of disorders characterized by chronic soft tissue pain. These include fibromyalgia, chronic fatigue syndrome and temporal mandibular joint pain. Headache that is secondary to pericranial muscle tension may also respond to injection of BTX-A^7,10.

LABELLED INDICATIONS

In Europe, BTX-A is approved for cervical dystonia and cerebral palsy, but in the US, the only approved indication is treatment of blepharospasm and strabismus associated with dystonia, although a supplemental NDA for cervical dystonia is pending. It is in late stage development in Europe and the US for upper limb spasticity, and in early phase development for headache/migraine and lower back spasm/pain¹¹.

A NEW GENERATION OF BOTULINUM TOXIN

While this drug is gaining popularity, it’s effect is temporary and most patients require repeat treatments. In some, BTX-A given in doses greater than 100u can induce the development of antibodies that make further treatment ineffective for an indefinite period⁸. However, even when used in high doses for neurological conditions, the development of antibodies occurs in < 5% of patients.

In 1997, the US Food & Drug Administration approved a new bulk toxin source for use in the manufacture of BTX-A. The new product, called current BOTOX®, is comparable in clinical efficacy to the original BOTOX®, but the higher specific potency reduces the amount of neurotoxin protein utilized, which in turn, leads to a reduction in the production of antibodies⁹.

NeuroBloc®, produced by Elan in Dublin, Ireland, is new and contains one of the other subtypes of botulinum toxin, type B. In clinical trials, this product has also been shown to be effective in patients who have developed antibodies and have stopped responding to BTX-A. It is currently awaiting US approval for use in the treatment of cervical dystonia¹¹.

Conclusion

BTX-A has had a lot of publicity recently for its off-label cosmetic use in facial wrinkles¹¹. These unlabelled cosmetic applications are of special interest for dermatologists. However, repeated use of this product can induce the development of antibodies in some individuals, making further treatment ineffective for an indefinite period. Treating patients with a preparation of botulinum toxin (type A or B) that minimizes exposure to neurotoxin complex proteins may be preferable for reducing the risk of antibody formation^9,11.

References

1. Carruthers A, Kiene K, Carruthers J. Botulinum A exotoxin use in clinical dermatology. J Am Acad Dermatol 34(5):788–797 (1996 May).
2. Carruthers JDA, Carruthers A. Botulinum A exotoxin in clinical ophthalmology. Can J Ophthalmol 31(7):389–400 (1996).
3. Carruthers A, Carruthers J. The Adjunctive usage of botulinum toxin. Dermatol Surg 24:1244-7 (1998).
4. Naumann M, Hofmann U, Bergmann I, Hamm H, Toyka KV, Karlheinz R. Focal Hyperhidrosis: Effective treatment with Intracutaneous botulinum toxin. Arch Dermatol 134(3):301-4 (1998 Mar).
5. Odderson IR. Hyperhidrosis treated by botulinum A exotoxin. Dermatol Surg 24(11):1237-41 (1998 Nov).
6. Girdler NM. Uses of botulinum toxin [letter]. Lancet 349(9056):953 (1997 Mar 29).
7. Schulte-Mattler WJ, Weiser T, Zierz S. Treatment of tension-type headache with botulinum toxin: A pilot study. Eur J Med Res 4(5):183-6 (1999 May 26).
8. Goschel H, Wohlfarth K, Frevert J, Dengler R, Bigalke H. Botulinum A toxin therapy: Neutralizing and nonneutralizing antibodies—therapeutic consequences. Exp Neurol 147(1):96–102 (1997 Sep).
9. Considerations in selecting a botulinum toxin: Relationship between specific potency, protein load and immunogenicity. The Botulinun Toxin Express™ Report discusses data from the poster presentation: Aoki KR, Merlino G, Spanoyannis A, Wheeler L. BOTOX (Botulinum Toxin Type A) purified neurotoxin complex prepared from the new bulk toxin retains the same preclinical efficacy as the original but with reduced immunogenicity. Poster 06.109, at the 51st Annual Meeting of the American Academy of Neurology, April 17–24, 1999, in Toronto, Ontario, Canada.
10. Wheeler AH. Botulinum toxin A, adjunctive therapy for refractory headaches associated with pericranial muscle tension. Headache 38(6):468-71 (1998 June).
11. Chustecka Z. New uses for Allergan’s Botox. Scrip World Pharmaceutical News No 2439:26 (1999 May 21).

FORMS OF BOTULINUM TOXIN — TYPES A & B

NeuroBloc®
(Elan)

Botulinum toxin — type B

Awaiting US FDA approval.