A preliminary study of a new painless and effective botulinum toxin
A jet nebulizer delivery for treatment of primary hyperhidrosis
Background: Hyperhidrosis is a chronic disease characterized by increased sweat production. Local injections of botulinum toxin A (BTX-A) have been extensively used for treatment of primary hyperhidrosis. The current treatment for this condition involves several intradermal injections, resulting in poor patient compliance due to injection-related pain. Therefore, new protocols, including an improved anesthetic regimen, are required.
Aim: We designed the present study to determine whether JetPeel™-3 could be used to deliver lidocaine prior to the standard BTX-A multiple injections or deliver lidocaine together with BTX-A in order to determine the protocol giving better results in terms of pain, sweating, and patient satisfaction in subjects affected by primary axillary, palmar, or plantar hyperhidrosis.
Materials and methods: Twenty patients with a visual analog scale (VAS) sweating ≥ 8 cm were randomized to receive lidocaine sprayed with JetPeel™-3 followed by multiple injections of BTX-A or lidocaine and BTX-A sprayed together with JetPeel™-3. Efficacy of treatment was measured by VAS for pain and sweating at 3-month follow-up. Patient satisfaction was assessed using a 5-point scale.
Results: Both BTX-A delivery modalities significantly reduced visual analog scale sweating, if compared with baseline (all P<0.001). Delivery of lidocaine and BTX-A by JetPeel™-3 significantly reduced VAS pain and sweating, if compared with lidocaine delivered by JetPeel™-3 followed by BTX-A multiple injections (all P<0.001). Patient satisfaction with the procedure was higher in the group receiving lidocaine and BTX-A treatment by JetPeel™-3, if compared with JetPeel™-3 used only for lidocaine delivery plus BTX-A multiple injections (P<0.001). No side effects were observed.
Conclusion: JetPeel™-3 can be used safely to treat palmar, plantar, and axillary hyperhidrosis, significantly reducing pain and sweating and improving patient satisfaction, if compared with standard therapy. The protocol based on JetPeel™-3 also requires a reduced quantity of BTX-A, if compared with standard therapy.
Keywords: hyperhidrosis, JetPeel™-3, botulinum toxin A, anesthesia, pain, sweating
Hyperhidrosis is an eccrine sweat gland disorder resulting in an increase in sweating which goes beyond what is physiologically appropriate for temperature regulation, and can affect hands, palms, feet soles, axillae, face, and head. Primary hyperhidrosis is generally idiopathic and may be exacerbated under conditions of stress. It equally affects men and women (∼3% of the population) and its burden is mainly due to the significant social stigma and reduced quality of life.
Management of hyperhidrosis
The management of hyperhidrosis includes the use of topical antiperspirants such as aluminum chloride or tannic acids, oral anticholinergic medications such as glycopyrrolate and propantheline or iontophoresis.6 Local injections of botulinum toxin A (BTX-A) are effective in treating primary hyperhidrosis, because BTX-A blocks the release of acetylcholine from the presynaptic nerve terminal with a temporary and reversible local chemodenervation. However, as a great number of painful intradermal injections are required, many patients complain of pain during injections, causing poor compliance in the regular re-injection follow-up. Unfortunately, commonly used pain relief methods such as topical anesthesia, cooling of the skin and use of needles of reduced size have proven unsuccessful, requiring the design of new protocols.
A previous study in our laboratories showed that JetPeel™-3 (TavTech Ltd., Yehud, Israel) can be used successfully to deliver lidocaine with an anesthetic power superior to topical anesthetic cream in the aesthetic medicine setting. In the present study, we tested the hypothesis that JetPeel™-3 can be used to deliver lidocaine prior to standard BTX-A multiple injections or to deliver lidocaine plus BTX-A, in order to determine the protocol giving better results in terms of pain, sweating, and patient satisfaction.
Materials and methods
This study was performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board at the Poliambulatorio del Secondo Parere (Modena, Italy), where the study was performed.
Twenty patients, 13 women and 7 men, aged 39±2.63 years (mean ± standard error of the mean), were enrolled in this study. All patients signed the informed consent. Only patients affected by primary axillary, palmar, or plantar hyperhidrosis with a visual analog scale (VAS) sweating ≥ 8 cm. Exclusion criteria were neuromuscular disease, concomitant drug treatment interfering with neuroglandular transmission, infections, dermatitis or other skin diseases, allergy or sensitivity to the study medication, previous treatment with BTX-A in the 12 months preceding the study, pregnancy and breastfeeding.
JetPeel™-3 is a medical device that can be used for dermoabrasion, dark spot removal, fine wrinkle smoothing, skin cleansing, squeezing of enlarged pores, dermoepidermal hydration and oxygenation, improvement in microcirculation rheology, dermal lymph drainage and transdermal drug delivery. Moreover, it can be used to achieve effective skin disinfection and/or surface sterilization and induce local anesthesia, avoiding the use of needles.21 A mixture of saline and oxygen is forced into a channel, which accelerates the droplets (200 m/sec) outside through a specific nozzle, delivering a powerful jet of microdroplets containing water, drug, air and oxygen (diameter 5–200 μm) onto the skin surface.
Patients were randomized to receive a single session of 1) lidocaine 2% (Astra Formedic, Milan, Italy; 5 mL) delivered by JetPeel™-3 and subsequent multiple BTX-A (100 U/vial; Bocouture®, Merz Aesthetics, Frankfurt am Main, Germany; BTX-A was reconstituted in 5 mL of saline solution) injections in the area affected by hyperhidrosis (group A [n=10]) or 2) lidocaine 2% (5 mL) and BTX-A injections (50 U/vial diluted into 5 mL of lidocaine for each palm, axilla, or foot) administered together with JetPeel™-3 (Figure 1) over the area affected by hyperhidrosis (group B [n=10]). In patients affected by axillary hyperhidrosis, the area was shaved 2 days before the procedure. Patients were instructed not to use antiperspirants or deodorants for at least 24 hours prior to treatment. Patient follow-up was performed at 3 months.
Measurement of pain, sweating, and patient satisfaction
Pain was rated using a visual analog scale (VAS) (0= minimum pain; 10= maximum pain). The patients were asked to quantify the intensity of sweating on a VAS (0= minimum sweating; 10= maximum sweating) before and after treatment. Patients’ satisfaction with the procedure was rated on a 5-point scale (1= none; 2= poor; 3= moderate; 4= good; 5= very good).
Data were analyzed using GraphPad Prism 6 software (GraphPad Software, Inc., La Jolla, CA, USA). Data were checked for normality using the D’Agostino and Pearson normality test. A two-sample unpaired Student’s t-test was applied to analyze differences in VAS pain and patient satisfaction between the two treatment groups. Differences in VAS sweating between the two drug delivery modalities were analyzed using two-way analysis of variance followed by Sidak’s multiple comparisons test.
Patients from group A had axillary hyperhidrosis (n=3), plantar hyperhidrosis (n=3) or palmar hyperhidrosis (n=4). Patients belonging to group B had axillary hyperhidrosis (n=2), plantar hyperhidrosis (n=4), or palmar hyperhidrosis (n=4). Both BTX-A delivery modalities significantly reduced VAS sweating, if compared with baseline (all P<0.001). VAS sweating decreased from a baseline value of 8.7±0.3 cm to 4±0.2 cm in the group receiving lidocaine by JetPeel™-3 and multiple BTX-A injections. VAS sweating decreased from a baseline value of 8.9±0.2 cm to 2.2±0.3 cm in the group receiving lidocaine and BTX-A by JetPeel™-3. Delivery of lidocaine and BTX-A by JetPeel™-3 significantly reduced VAS pain and sweating, if compared with lidocaine delivered by JetPeel™-3 followed by BTX-A multiple injections (all P<0.001; Figure 2A and B). Patient satisfaction with the procedure was higher in the group receiving lidocaine and BTX-A treatment by JetPeel™-3, if compared with JetPeel™-3 used only for lidocaine delivery plus BTX-A multiple injections (P<0.001; Figure 2C). Cold-related pain was observed during axillary treatment in a patient after BTX-A injections. However, the patient completed the procedure successfully and the pain resolved within 20 minutes. No side effects were observed.
Hyperhidrosis is overproduction of sweat by the exocrine sweat glands and is characterized by enormous psychosocial stress. We found that delivering BTX-A and lidocaine together with JetPeel™-3 resulted in a significant reduction in VAS pain and sweating at 3-month follow-up, if compared with lidocaine delivered by JetPeel™-3 and BTX-A multiple injections into the dermis. The greater benefit was observed when delivering the anesthetic together with BTX-A using JetPeel™-3, delivering a reduced quantity of BTX-A, further supporting the use of the jet nebulizer drug delivery versus standard injections. This evidence suggests a more direct penetration of the drug when using JetPeel™-3. Many studies have investigated the persistence of BTX-A injection for treatment of hyperhidrosis. For example, Naver et al reported a median duration of 10 months after injecting a mean dose of 60 mU BTX-A in 55 patients affected by axillary hyperhidrosis and a dose of 170 mU in 94 patients affected by palmar hyperhidrosis. Furthermore, Schnider et al14 injected 200 U of BTX-A in 13 subjects affected by axillary hyperhidrosis and found that the difference in VAS between the BTX-A-treated and placebo-treated axillae was −56.5% after 3 weeks, −67.4% after 8 weeks, and −62.5% after 13 weeks. In a further study, an injection of 100 U of BTX-A per palm in 36 patients affected by palmar and plantar hyperhidrosis resulted in a significant improvement at 6-month follow-up. In a further clinical study, Xeomin® (Merz Pharmaceuticals, Frankfurt, Germany), a type of BTX-A, was injected into patients affected by axillary hyperhidrosis, while patients affected by palmar hyperhidrosis, were injected with Xeomin® and Neurobloc® (Eisai Europe Ltd, Hatfield, UK), a type of BTX-B. At the 3-week follow-up, all patients, treated for axillary and palmar hyperhidrosis, reported a significant improvement in dermatology Life Quality Index (DLQI) score. Andrade et al found two efficient non-invasive methods, iontophoresis and phonophoresis, to administer BTX-A in patients with bilateral primary palmar hyperhidrosis. BTX-A efficacy lasted over 16 weeks after the end of treatment. In our previous study, JetPeel™-3 was used to successfully deliver carbocaine, resulting in significantly increased anesthesia in patients undergoing hyaluronic acid-based facial rejuvenation procedures, if compared with topical anesthetic cream.
The present study shows that JetPeel™-3 can be efficiently and safely used to treat palmar, plantar and axillary hyperhidrosis, delivering both anesthetic and BTX-A at the same time. Our protocol results in a significant reduction in pain and sweating and an increase in patient satisfaction, if compared with standard therapy, also requiring a reduced quantity of BTX-A used. A limitation of our study is the small number of patients involved in our preliminary investigation.
The authors contributed equally to this work. The authors hereby certify that all work contained in this article is original. The authors claim full responsibility for the content of the article. Written informed consent was obtained from the patients for publication of the data included in this manuscript.
The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.