Update on the Botulinum Neurotoxins

A. Carruthers, MD, FRCPC¹, J. Carruthers, MD, FRCPC²

1. Division of Dermatology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
2. Department of Ophthamology, Faculty of Medicine, University of British Columbia, Canada

ABSTRACT
The botulinum neurotoxins (BTX) are an exciting group of therapeutic agents with dramatically expanding clinical indications. The US FDA has approved BOTOX® (BTX-A, Allergan) and Myobloc™ (BTX-B, Elan Pharmaceuticals) for the treatment of cervical dystonia. TPP Canada has also approved BOTOX® for the treatment of glabellar frown lines. The US FDA is expected to approve this new indication before the end of 2002. These changes will dramatically expand the marketing of BTXs. Concerns about risks and side effects diminish as clinical experience increases with this “most poisonous of poisons”.² In particular, the incidence of secondary resistance to the toxin’s effect has been dramatically diminished with the reduction of the non-toxic protein in current batches of BOTOX®.³

Key Words:
botulinum toxin, cervical dystonia, glabellar frown lines, hyperhidrosis

Pharmacology

The botulinum toxins are produced by different serotypes of the bacterium, Clostridium botulinum. They act to block presynaptic release of acetylcholine,³ which in turn blocks neuromuscular transmission, causing weakening of the treated muscle or even flaccid paralysis. Reversal of the blockade occurs after approximately 3-4 months. The typical clinical response is in the same time range although much longer responses can be seen.

Drug interactions and contraindications⁴

Theoretical interactions with aminoglycoside antibiotics and calcium channel blockers have not proven to be of clinical significance. Of much greater importance is the possibility of exacerbating preexisting neurological disease. A myasthenic crisis was precipitated in a patient who developed unrecognized myasthenia gravis in between regular BTX injections for blepharospasm.⁵ Amyotrophic lateral sclerosis and Eaton-Lambert syndrome can also be worsened by BTX injection.⁴

The safety of BTX injections in pregnant and nursing women has not been established, though there is evidence that BTX does not cross the placenta.^6,7 Whether it is secreted in breast milk has not been substantiated. However, so little gets into the circulation that the tiny amounts to which a healthy breast-fed infant might be exposed would not pose any likely risk.^6,7

Commercially available preparations

BTX-A

BOTOX® was the first of the BTXs to be produced and used clinically, and experience with this toxin is far greater than with any of the other toxins. Early use of the BTXs caused a significant problem with secondary resistance to the toxin’s effect resulting from the induction of blocking antibody formation. Gradually, Allergan changed, worldwide, the supply of the toxin to a new, purer product. Secondary resistance has not been reported since this change.²

BOTOX® is approved in the US and Canada for the treatment of strabismus, blepharospasm, hemifacial spasm and cervical dystonia (CD) in adults. It was recently approved in Canada for the treatment of glabellar frown lines and approval for this indication in the US is anticipated in 2002. As well, TPP Canada approved this product for the treatment of hyperhidrosis in August 2001, and for the treatment of adult spasticity in November 2001. The European Commission of the European Union passed a positive opinion in October 2001, for the treatment of adult spasticity.

Dysport® was introduced in Europe soon after BOTOX® was launched in North America. It is also BTX-A, however, the Dysport® unit does not appear to be as effective as the BOTOX® unit. Studies suggest a 3-5 fold difference in potency,⁸ which is thought to be due to differences in product formulation (see Table 1). Dysport® has a similar incidence of secondary resistance in CD patients, to the original batch of BOTOX® (3-5%).⁹

BTX-B

Myobloc™ (Elan Pharmaceuticals) was the first available form of BTX-B (called NeuroBloc® outside North America) to be approved for the treatment of CD by the US FDA in December 2000. In studies published so far, the clinical effectiveness and the duration of response in CD appear to be similar to BOTOX® although the dose is dramatically higher.¹⁰ For effective treatment of CD, at least 10,000 mouse units of Myobloc™ are needed to produce the same effect as 200 mouse units of BOTOX® (see Table 1). This means a tenfold increase in the amount of neurotoxin protein delivered, although Myobloc™ has less inactive neurotoxin protein than BOTOX®.³ Myobloc does not appear to be accompanied by a similar development of clinical resistance to the affect of BTX-B.¹¹ According to information provided by the US FDA, there may be a reduction of treatment benefits with succeeding treatment sessions and/or a lessening of benefit with the uppermost level of dosing examined. Although no definite conclusions may be drawn, data provided by the US FDA suggests that resistance may be possible.¹²

Side effects of Myobloc™ seem to be similar to those of the other BTXs with the exception of dry mouth. Although mild, this occurs in up to 34% of CD patients treated with an effective dose of 10,000 units.¹¹ This is a systemic effect of the neurotoxin and is indicative of a difference between BTX-A and BTX-B. It may be possible to exploit this and other differences and find indications for which Myobloc™ is superior to BOTOX® and vice versa.

Table 1: A review of BTX forms currently available.

Indications

Cosmetic¹³

The principal area for cosmetic use of BTX is in the upper face. Glabellar frown lines, horizontal forehead lines and lateral orbital lines (crows feet) are commonly treated and respond well. More recently, the ability of BTX to produce a modest brow lift, to correct eyebrow asymmetry, to open the eyes, to soften perioral wrinkles, to lift the corners of the mouth, and to improve neck lines have excited interest in the mid and lower face.

Hyperhidrosis

BTX has been used successfully to treat hyperhidrosis affecting a number of areas. It was initially used in Frey’s syndrome, which led to treatment of the palms and axillae. The face and feet are also treated. More recently, the use of BTX to reduce sweating was shown to be effective in improving benign familial pemphigus.¹⁴ This may lead to the use of BTX for other intertriginous dermatoses where sweating is thought to play a role.

Headache and Migraine¹⁵

Early in the cosmetic use of BTX, alleviation of tension headaches was reported, and migraine headaches were also reported to have improved. Subsequent studies have provided conflicting results. Unquestionably, some patients have fewer and less severe migraines after BTX injection, but it has been difficult to establish a scientific basis for this in placebo-controlled, double blind studies. Further work in this important area will establish the indications, effective injection techniques, and possibly further define the pathogenesis of migraine, which should not respond to BTX injections according to current theories.

Conclusion

The clinical indications of the botulinum neurotoxins continue to expand dramatically. At the same time, our background knowledge is also expanding and a form of the B serotype is now commercially available. Differences have been established between BTX-A and BTX-B including different sites of action, different dosages and different side-effect profiles.¹⁶ Clinical experience with BTX-B is currently so limited that conclusions about these differences are premature.

References

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5. Borodic G. Myasthenic crisis after botulinum toxin. Lancet 352(9143):1832 (1998 Dec).
6. Polo JM, Martin J, Berciano J. Botulism and pregnancy. Lancet 348(9021):195 (1996 Jul).
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10. Brashear A, Lew MF, Dykstra DD et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A responsive cervical dystonia. Neurology 53(7), 1439-46 (1999 Oct).
11. Myobloc™ package insert. Elan Pharmaceuticals, Dublin, Ireland.
12. US FDA. BLA 99-1396. Response Submission to Complete Review Letter. Elan Pharmaceuticals. Botulinum Toxin Type B for Treatment of Cervical Dystonia: Supplemental Clinical Review. (2000 Dec).
13. Carruthers A, Carruthers J. Botulinum Toxin Type A: History and Current Cosmetic Use in the Upper Face. Sem Cutan Med Surg 20(2):71-84 (2001 Jun).
14. Glogau RG. Treatment of Palmar Hyperhidrosis with Botulinum Toxin. Sem Cutan Med Surg 20(2):101-8 (2001 Jun).
15. Carruthers A, Langtry JA, Carruthers J, Robinson G. Improvement of Tension- Type Headache When Treating Wrinkles with Botulinum Toxin A Injections. Headache 39(9):662-5 (1999 Nov/Dec).
16. Carruthers A, Carruthers,J. Toxins 99, new information about the botulinum neurotoxins. Dermatol Surg 26:174-6 (2000 Mar).