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Botulinum toxin for hyperhidrosis

 

Clinical bottom line

On the basis of limited information from four randomised studies, botulinum toxin appears to be effective for hyperhidrosis


Several strains of botulinum toxin exist, the most commonly used in medicine are botulinum toxin A and B. Botulinum toxin A is commercially manufactured as Botox and Dysport. These are different agents, with one mouse unit of botox being approximately equivalent to three mouse units of dysport. The toxin is licensed as a treatment for a number of indications, mainly dystonias and spasm, but is also commonly used for cosmetic reasons to reduce the effects of ageing. When injected into muscle the toxin blocks the release of acetylcholine at the neuromuscular junction. This reduces muscle tone, which alleviates symptoms. It has been assumed that botulinum toxin will also inhibit other cholinergic mechanisms, such as sweat production.

Hyperhidrosis is a rare condition in which large quantities of water and electrolytes are exuded from the body. In severe cases, hands and feet may drip with secretions. The condition has a considerable emotional and social burden. When other treatments have failed, surgical intervention is possible but the risk of compensatory sweating in other areas exists. Another possibility is to use botulinum toxin.

Search

PubMed was searched for randomised, double blind, controlled trials of botulinum toxin for the treatment of hyperhidrosis. Free text terms included 'botulinum toxin', 'botox', 'dysport' and 'hyperhidrosis'.

Results

Several studies were identified of which four [1-4] were randomised and double blind and details of these are shown in Table 1 (bottom of page). Three of the four trials scored highly with a commonly used 5-point quality scoring system [Jadad et al, 1996], though they differed in the type of botulinum toxin A, dose, number of injections, duration of observations, and choice of outcome.

Two trials [Naumann et al, 2001; Schnider et al, 1999] were conducted in patients with axillary hyperhidrosis over 13 and 16 weeks, and two studies conducted over four and 13 weeks were in patients with palmer hyperhidrosis.

Outcome data were presented in slightly difference ways in the trials, but all showed greater improvement (reduction in sweating) with botulinum toxin A than with placebo. The largest study [Naumann et al, 2001] reported greater than 50% reduction in axillary sweating from baseline in 198/242 (82%) patients given botulinum toxin and 16/78 (21%) given placebo at 16 weeks. The additional benefit achieved with toxin over that achieved with placebo was 61%, suggesting an NNT of less than 2. Patient global ratings in this study were equivalent to moderate improvement. If information for vaguely similar outcomes is pulled together across other trials an improvement of roughly 30% is shown with botulinum toxin over that occurring with placebo. This could also be regarded as moderate improvement.

Adverse events were relatively uncommon. To note though is that two patients with severe and socially limiting axillary hyperhidrosis experienced increased palmer sweating after treatment with botulinum toxin. Since the toxin decreases muscle tone it is possible that grip strength could be reduced in patients with palmer hyperhidrosis, but there was no evidence of this in the trial by Lowe and colleagues.

Comment

The results are interesting but should be interpreted with caution. The main caveat is that there are limited data at present. With one exception, the studies were small and used within patient comparisons. That doses and outcomes differed also muddies the waters, and it is difficult to say whether the effects of the toxin are greater with increased dose. It does appear, though, that botulinum toxin reduces symptoms in this rare condition. The report of increased palmer sweating in patients with axillary hyperhidrosis should be noted, and it was not reported in the trial whether this subsided as the effects of treatment wore off.

There will be issues of patient selection, since the site and number of injections required will impact on the feasibility and acceptability of treatment. At present this is an off-license indication for botulinum toxin. It does not provide a cure, and repeated injections would be required to limit symptoms in the long-term. In patients with palmer hyperhidrosis, another consideration might be the long-term effects on muscle tone.

References

  1. Lowe NJ et al. Efficacy and safety of botulinum toxin type A in the treatment of palmer hyperhidrosis: a double-blind, randomised, placebo-controlled study. Dermatologic Surgery 2002;28:822-27.
  2. Neumann N et al. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel groups, double blind, placebo controlled trial. BMJ 2001; 325:1-4
  3. Schnider P et al. A randomised, double-blind, placebo-controlled trial of botulinum toxin for severe axillary hyperhidrosis. British Journal of Dermatology 1999;140:677-680.
  4. Schnider P et al. Double-blind trial of botulinum A toxin for the treatment of focal hyperhidrosis of the palms. British Journal of Dermatology 1997; 136: 548-552.
  5. Jadad A et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials. 1996; 17:1-12.

Table 1: Randomised, double blind trials of botulinum toxin for hyperhidrosis

Reference

Condition, drug & dose

Design

Patient characteristics

Results

Adverse effects

Quality score

Naumann et al 2001 Axillary hyperhidrosis

Botulinum toxin type A (Botox)

50 U per axilla or placebo (10-15 intradermal injections distributed within the hyperhidrotic area as defined by Minor's iodine starch test)

Reconstituted with 4 ml of 0.9% sterile saline
R, DB, placebo controlled multicentre parallel group study, 16 wks

Botulinum toxin
n= 242
Placebo
n= 78
> 50 mg sweat per axilla over five minutes while at rest at room temperature (gravimetric test)

Severity sufficient to interfere with daily living
Patients with >50% reduction from baseline axillary sweating at 4 and 16 weeks (measured gravimetrically)
4 weeks
botulinum toxin 227 patients
placebo 28 patients
16 weeks
botulinum toxin 198 patients
placebo 16 patients

Mean patient global (SD) at 16 weeks (-4, very substantial worsening to +4, complete abolition of signs and symptoms)
botulinum toxin 2.6 (1.6)
placebo 0.3 (1.2)
One patient withdrew due to an adverse effect unrelated to trial treatment R= 2
DB= 2
WD= 1
QS= 5
Schnider et al 1999 Axillary hyperhidrosis

Botulinum toxin type A (Dysport)

200 mU or placebo (6 intracutaneous injections into each axilla)

Reconstituted with 0.6 ml of 0.9% sterile saline
R, DB, placebo controlled within patient study, 13 wks

n= 13
Patients with severe axillary hyperhidrosis resistant to conventional treatment and socially handicapped by the condition Mean difference (95% CI) at 3, 8 and 13 weeks between the botulinum-treated axilla and the placebo-treated axilla (measured by digital image analysis of ninhydrin sheets (Moberg 1959).
3 weeks
-34.5% (-49.7 to -19.5%)
8 weeks
-36.9 (-50.7 to -23.1%)
13 weeks
-28.4% (-38.9 to -18%)

Patient global rating of improvement (worse to marked improvement) with toxin compared with placebo
3 weeks
marked improvement: 10
moderate improvement: 2
mild improvement 1
8 and 13 weeks
marked improvement: 10
moderate improvement: 3
Two patients reported pruritis at the toxin-treated axilla and at both axilla respectively, lasting for 1 week. Two patients reported mild constipation and increased palmar sweating R= 2
DB= 2
WD= 1
QS = 5
Lowe et al 2002 Palmar hyperhidrosis for >6 mths

Botulinum toxin type A (preparation not specified)

100 U or placebo (15 intradermal injections into the palm &amo; finger tips). One palm injected with active, the other with placebo.

Reconstituted with 1.5 ml of 0.9% sterile saline
R, DB. Placebo controlled within patient study, 4 wks

n= 19
At least 40 mg/min sweat production (gravimetric assessment) and unsatisfactory response to previous treatment Mean sweat production at baseline approx 300mg/ 5 min (measured gravimetrically). At 7 and 28 days was reduced
7 days
botulinum toxin 155 mg/ 5 min
placebo 275 mg/ 5 min
28 days
botulinum toxin 100 mg/5 min
placebo 210 mg/ 5 min

Patient assessment of severity of hyperhidrosis (baseline 8.5) at 7 and 28 days (10 cm VAS)
7 days
botulinum toxin 6
placebo 7.5
28 days
botulinum toxin 4
placebo 7

No significant difference in grip strength was seen between palms
One patient reported tingling and numbness in hand (active treatment), on patient with weakness in one hand (placebo), one patient with pain in both hands and one patient with osteoarthritis (judged to unrelated to study drug). R= 2
DB= 2
WD= 1
QS= 5
Schnider et al 1997 Palmar hyperhidrosis

Botulinum toxin type A (Dysport 120 mU)

120 mU or placebo (subcutaneous injections at six sites into palm). One palm injected with active, the other with placebo.

Reconstituted with 0.5 ml of 0.9% sterile saline
R, DB, placebo controlled, within patient study, 13 wks

n= 11
Palmar hyperhidrosis resistant to conventional treatments. Socially handicapped by condition

Baseline values not provided
Mean sweat production after 13 wks:
Dysport 31%(95% CI 20-42%) reduction
Placebo about 1.2%

Pain at injection site - 3 pts
Transient muscle weakness at injection site lasting 2-5 wks - 3 pts
R=1
DB=1
W=0
QS=2