Botulinum toxin type A by iontophoresis for primary palmar hyperhidrosis

Abstract

To the Editor: Botulinum toxin type A (BTX-A) is known to inhibit acetylcholine release in eccrine sweat glands, and is an effective therapy for primary palmar hyperhidrosis (PPH). Intradermal palmar injections are painful, however, and require regional anesthesia. We show here, in a small, double-blind, randomized, placebo-controlled study, that BTX-A can be delivered painlessly and effectively to the palms through iontophoresis. This should be regarded as a pilot study. PPH is one of the most debilitating types of hyperhidrosis.1Baumgartner F. Toh Y. Severe hyperhidrosis: clinical features and current thoracoscopic surgical management.Ann Thorac Surg. 2003; 76: 1878-1883Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar Most conventional treatments, which include tap water or glycopyrrolate iontophoresis, systemic anticholinergics, and selective endoscopic sympathectomy, are of limited effectiveness or may be associated with major side effects. BTX-A injections, the latest addition to the arsenal of treatments, are effective but are limited by the need for regional anesthetic. This small, double-blind, randomized, placebo-controlled study shows that BTX-A can be delivered painlessly to the palms by iontophoresis. We recruited 8 patients with PPH (6 females, 2 males; age range, 21-35 years; mean ± SD, 29 ± 6 years) into our trial. They were refractory to conventional therapy and adversely affected both socially and professionally by their condition. BTX-A (Allergan Ltd; High Wycombe, Bucks, UK; 100 mouse units [MU] per vial) was reconstituted in 2.7 ml of preservative-free saline, and the same amount of saline acted as placebo. The hand to be treated with BTX-A was randomly selected and the other hand acted as placebo-treated control. Neither patient nor assessor (K.S.) was aware of which hand was treated with BTX-A or placebo, and all data remained computer-coded until the completion of data analysis. Results are given as mean ± SEM. The paired Student t test was used for continuous variables, and statistical significance was regarded as P < .05. All analyses were performed using GraphPad Prism (v 3.02; GraphPad Software Inc, San Diego, Calif). We used the Phoresor II PM700 (Iomed Inc, Salt Lake City, Utah), which has a circular drug-delivery reservoir (Moor Instruments Ltd, Devon, UK) covering 0.64 cm2, acting as the drug-delivery cathode. Nine sites on each hand were treated with a maximum of 2.5 mA, or else with the highest comfortable current, with the total dosage extending to 15.0 mA per minute at each site. Palmar sweating was assessed by gravimetry and by Minor's starch iodine test at baseline and at 14 days posttreatment.2Lowe N. Yamauchi P. Lask G. Patnaik R. Iver S. Efficacy and safety of botulinum toxin type A in the treatment of palmar hyperhidrosis: a double-blind, randomized, placebo-controlled study.Dermatol Surg. 2002; 28: 822-827Crossref PubMed Scopus (133) Google Scholar Patients were also asked to quantify the effect of treatment at baseline and 14 days posttreatment using a 100-point visual analogue scale.3Simonetta M. Cauhepe C. Magues J. Senard J. A double-blind, randomized, comparative study of Dysport vs. Botox in primary palmar hyperhidrosis.Br J Dermatol. 2003; 149: 1041-1045Crossref PubMed Scopus (95) Google Scholar On follow-up, the assessor and patient were both blinded to the response given at baseline. All 8 patients completed the study. At baseline the difference in mean sweat production between the treated hands (215 ± 40 mg/5 min) and control hands (166 ± 34 mg/5 min) was not statistically significant. Palmar sweating in the BTX-A–iontophorezed hands was significantly reduced at 14 days posttreatment (215 ± 113 to 119 ± 34 mg/5 min; P < .05). Sweating in the saline-iontophorezed control hand showed an increase at 14 days following treatment (166 ± 34 to 249 ± 66 mg/5 min), although that change was not statistically significant (Fig 1). With data normalized for inter-day variability using the saline-treated control hand, sweat rate decreased significantly in the BTX-A–treated hand, from 215 ± 40 to 71 ± 23 mg/5 minutes (P < .01). This correlates to a mean improvement of 66%. The fold-change (1 = no change) in the saline-treated control hand and BTX-A–treated hand was 1.94 ± 0.42 and 0.34 ± 0.07, respectively. The difference was statistically significant (P < .01). The changes in sweating as assessed by Minor's starch-iodine test, though patchy and difficult to quantify accurately, largely paralleled the gravimetric results. Relative anhidrosis took a roughly circular shape in some patients' palms, with a radius measuring between 0.3 cm and 1.5 cm (Fig 2). Patients' subjective reporting, not statistically significant between the hands at baseline, showed no significant change in the untreated hands from baseline to 14 days posttreatment (65 ± 8 to 55 ± 19). The BTX-A–treated hand, however, showed a significant improvement (68 ± 5 to 45 ± 9; P < .01), corresponding to a 34% improvement from baseline. No side effects were reported. It is intuitively reasonable that iontophoresis should be of use in delivering BTX-A. It might drive compounds into the skin by ion-electric field interaction, by increasing skin permeability, or by increasing bulk flow.4Pikal M. The role of electroosmotic flow in transdermal iontophoresis.Adv Drug Deliv Rev. 2001; 46: 281-305Crossref PubMed Scopus (222) Google Scholar Its mechanism is not yet fully understood, but iontophoresis can deliver small molecules like lidocaine into the skin reliably.5Zempsky W. Parkinson T. Lidocaine iontophoresis for topical anesthesia before dermatologic procedures in children: a randomized controlled trial.Pediatr Dermatol. 2003; 20: 364-368Crossref PubMed Scopus (25) Google Scholar In vitro studies suggest that larger molecules and polypeptides like calcitonin and insulin can also be delivered transdermally.6Prausnitz M. Mitragotri S. Langer R. Current status and future potential of transdermal drug delivery.Nat Rev Drug Dis. 2004; 3: 115-124Crossref PubMed Scopus (1041) Google Scholar Iontophoresis is reported to transport compounds through the skin by increased current-induced water/solvent flux and increased pore size,7Manabe E. Numajiri S. Sugibayashi K. Morimoto Y. Analysis of skin permeation-enhancing mechanism of iontophoresis using hydrodynamic pore theory.J Control Release. 2000; 66: 149-158Crossref PubMed Scopus (26) Google Scholar and eccrine glands should be accessible through the ducts, so even BTX-A, which is quite large (900 kDa),8Chen F. Kuziemko G.M. Stevens R.C. Biophysical characterization of the stability of the 150-kilodalton botulinum toxin, the nontoxic component, and the 900-kilodalton botulinum toxin complex species.Infect Immun. 1998; 66: 2420-2425PubMed Google Scholar should penetrate the skin. For these reasons we undertook a preliminary study before this one, which suggested that BTX-A iontophoresis reduces palmar sweating by up to 81%, and that this effect lasts some 3 months.9Kavanagh G. Shams K. Case report: BOTOX iontophoresis.Br J Dermatol. 2004; 151: 1093-1095Crossref PubMed Scopus (53) Google Scholar Our gravimetric results correlate well with the findings of previous studies of intradermal BTX-A injections in the treatment of PPH. Using the same amount of BTX-A, these studies show a gravimetric improvement in sweat rate of between 57% and 71%.3Simonetta M. Cauhepe C. Magues J. Senard J. A double-blind, randomized, comparative study of Dysport vs. Botox in primary palmar hyperhidrosis.Br J Dermatol. 2003; 149: 1041-1045Crossref PubMed Scopus (95) Google Scholar, 10Schnider P. Moraru E. Kittler H. Binder M. Kranz G. Voller B. Treatment of focal hyperhidrosis with botulinum toxin type A: long-term follow-up in 61 patients.Br J Dermatol. 2001; 145: 289-293Crossref PubMed Scopus (80) Google Scholar Our iontophoresis of BTX-A yields a similar result, at least in the short term. Interestingly, our starch-iodine results suggest that the relatively anhidrotic areas surrounding the treatment sites were typically larger than the 0.64 cm2 covered by our drug-delivery electrode. Our mean reduction of sweating was also larger than would be anticipated from the total treated area. This would be in keeping with a diffusion area of 1 cm, as reported after the intramuscular injection of BTX-A.11Coleman M.K. Botulinum toxin in facial rejuvenation. Mosby, London2004Google Scholar Sweating actually increased slightly in the control palms, perhaps by a compensatory mechanism which is also observed in a small proportion of patients treated with BTX-A for hyperhidrosis.