DOJ

Contents
Volume 15 Number 4
April 2009

What stands in the way of treating palmar hyperhidrosis as effectively as axillary hyperhidrosis with Botulinum Toxin Type A
Antranik Benohanian MD
Dermatology Online Journal 15 (4): 12

Montreal University Hospital Center, Hôpital Saint-Luc, Montreal, Quebec, Canada. info@benohanian.com




Abstract

Botulinum Toxin type A (BTX-A) has revolutionized the treatment of focal hyperhidrosis (HH) in recent years and has dramatically reduced the invasive surgical techniques that have been performed in the past to control severe focal HH unresponsive to topical therapies. Whereas BTX-A injections are easily performed to control axillary HH with little or no analgesia, pain management is a must during the injection of palmar and plantar HH with BTX-A because of the intense pain generated with the 30 to 40 needle punctures needed on each hand or foot through the densely innervated skin present in those areas. For that reason, many physicians who contentedly treat axillary HH with BTX-A injections, refuse to do so for palmar and plantar HH. Although pain is the major stumbling block deterring patients and physicians from choosing this treatment option, it is not the only one. Many other factors may play a role in deciding whether or not to treat palmar and plantar HH with BTX-A injections. This article reviews these factors and presents some personal data from patients who have already been treated with BTX-A injections on the palms and soles and who came back once or more for repeat treatments when the effect of BTX-A started to fade away. "Jet Anesthesia" was the pain management method used in this group.

Focal hyperhidrosis (HH) is a disease that affects 2.8 percent of the population [1]. The hands and feet are affected in about 60 percent of patients [2] alone or in combination with other sites. The highest prevalence ever reported for palmar HH was 4.36 percent among the Chinese adolescents [3]. Depending on its severity, palmar HH may become a socially embarrassing condition for the patient with serious social and occupational impairment [4, 5, 6].

Botulinum neurotoxin serotype A (BTX-A) has revolutionized the treatment of focal hyperhidrosis [7]. However, in the region of the palms and soles, the intense pain associated with the injection of BTX-A into this densely innervated skin [8] is a major concern to patients and healthcare professionals alike. Although clinicians contentedly treat axillary HH with BTX-A injections, many of them are reluctant to treat palmar and plantar HH. The ability to inject BTX-A on the palms and soles without causing pain to the patient is an important feature in the treatment of palmoplantar HH. According to Kranz et al. local pain associated with needle injection consists of three major components: 1) the needle prick itself, 2) the injected volume suppressing the local tissue and 3) the injected substance interacting with the tissue [9].

When treating axillary HH with BTX-A, Vadoud-Seyedi et al. [10] found that reconstitution of BTX-A in saline or lidocaine proved to be equally effective for short- and long-term results. Because injections of BTX-A reconstituted in lidocaine were associated with significantly reduced pain, they concluded that lidocaine-reconstituted BTX-A may be preferable for treating axillary HH. They also proposed that this procedure should be evaluated for palmar and plantar HH. Skin thickness in humans varies between body regions, races, and gender, but of all the skin covering the body none is tougher or thicker than that covering the palms and soles. It is a well-known fact that a needle prick on the palm generates much more pain than a needle prick under the arms where anesthesia is not a must before BTX-A injections. Therefore, the results obtained during the treatment of the axillae with BTX-A injections [10] could not be extrapolated to areas with a thicker epidermis such as the hands and feet. Furthermore, whereas needle delivery of lidocaine acts reasonably well against the second and third components of pain associated with injection (see above, [9]), it is totally useless during the insertion of the needle itself. Finally, though the mixing of lidocaine with BTX-A seems appealing, it is worth mentioning that manufacturers recommend the use of saline as a diluent [11].

One valid option would be the use of needle free anesthesia, through a pressurized device, which causes considerably less pain [12] or even eliminate it altogether without the need for any sedation. When the trigger of the pressurized needle free injector device is activated, it releases the spring propelling the lidocaine, through a small orifice about four times smaller than a 30 Gauge needle at a very high speed. As most of the pain occurs during the prick itself, the advantage of a small orifice coupled with a high-speed penetration of the anesthetic through the pressurized device, result in a significant reduction of the amount of pain during the injection [13]. The anesthetic disperses subepidermally where most sensory nerve endings lie.


Anasthesia for BTX-A

The current methods to counter the pain induced by BTX-A injection into the palms and soles with a needle are either inadequate or too invasive. They consist of:

  • Topical anesthetics such as EMLA which has been used with poor response on the palms and soles [14, 15] probably due to the presence of a thick horny layer that prevents its penetration. It is also time consuming as about 30 to 45 minutes are needed to get some effect on normal skin other than the palms and soles.

  • Vibration anesthesia has been reported with inconsistent results [16, 17].

  • Cryoanalgesia from iced water was found to be more effective than either ethyl chloride spray or ice packs [18]. Mild tingling sensation is felt lasting for few minutes after the injections. However, cryoanalgesia can freeze up the needle, slowing down the diffusion of the injectate [19].

  • Pressurized, needle-free "jet" injector devices such as Dermojet® have been used safely to inject BTX-A itself, directly into the dermis in plantar HH without prior anesthesia [20]. Pain of injection was rated as acceptable in all patients treated with the Dermojet® [15], nevertheless, the authors do not recommend its use on palmar skin because of possible injury to the superficial palmar nerves or vessels. Naumann et al. compared BTX-A injection with Dermojet® versus needle injection and concluded that both techniques led to a significant reduction in hyperhidrosis, however, the needle injection was much more effective in controlling excessive sweating than the Dermojet® technique [15].

  • Nerve Blocks have been considered as the gold standard of anesthesia for palmar and plantar HH [21]. However, many physicians cannot or will not perform reliable nerve blocks, and many patients will not accept a nerve block (or will not return for another treatment if a nerve block must be repeated) [22]. Nerve blocks have the following potential drawbacks: neural injury, vascular puncture, impaired hand dexterity for hours or days after the anesthesia, reactive hyperemia that increases the tendency to bleed from the injection sites, and nerve scarring from potential repeated injury with the needle [23].

  • Bier's Block, in experienced hands, is considered as an excellent way to provide anesthesia but systemic effects could result from the sudden release of anesthetic into systemic circulation. Also, finding a vein for catheter placement could occasionally be difficult [24, 25].

  • General anesthesia or intravenous sedation anesthesia is more invasive and time consuming then other previously enumerated methods.


    Unwanted side effects of BTX-A

    Although pain is the main factor deterring many patients and physicians from using BTX-A in treating palmar and plantar HH, it is not the only one. Other factors that may play a role include:

  • Muscle weakness: has been reported to occur, especially on the hands. Prevalence and importance of hand or finger weakness vary according to doses of BTX-A injected and to how weakness is defined and measured (EMG, functional grip and strength tests or patient subjective evaluation) [26-31]. Weakness was reported to occur in 5 to 77 percent of patients; it was self-limited and reversible, lasting between 10 and 42 days [27, 28, 29, 30, 31]. Subepidermal injection of BTX-A is preferred to the subcutaneous injection in order to avoid functional reduction of manual dexterity [32]. Pain is due to the presence of a rich network of nerve endings at the subepidermal dermis. Subcutaneous injections, although less painful than subepidermal injections [33], could induce more weakness due to diffusion of the toxin to the underlying muscles. Despite careful technique and small doses of BTX-A injected subepidermally, the toxin may still diffuse to underlying muscles, potentially causing some weakness.

  • Bleeding during the procedure: reactive hyperemia occurs mostly with the use of a nerve block or a Bier's block and it increases the tendency to bleed from the injection sites thus washing away part of the injected toxin.

  • Off-label indication: Although other formulations of botulinum toxins exist worldwide, BOTOX® is currently the only BTX-A formulation commercially available in North America. It is important to emphasize that Regulatory Agencies worldwide recognize that each formulation is unique and that Units of biological activity of one formulation cannot be compared to nor converted into Units of any other botulinum toxin. BOTOX® was approved for severe axillary HH by the FDA in 2004 and by Health Canada in 2001, but at the moment is not indicated for the treatment of palmar and plantar HH.

  • Antibody formation: Because the effects of BTX-A are transient and reversible, repeated injections are necessary to maintain control of the hyperhidrosis. Since BTX-A is a protein of bacterial origin, concerns about the formation of neutralizing antibodies to BTX-A with repeated treatment have been raised. Factors that predispose patients to the development of these antibodies are not completely understood, but experience has shown that risk increases with higher mean dose per treatment session, higher total cumulative dose, shorter interinjection intervals and protein load of the formulation [34, 35]. In 1997, a new formulation of BTX-A (BOTOX®) with a reduced protein load was introduced; this formulation was shown to be less immunogenic than the original formulation [35]. Latest data derived from neurological applications (adult spasticity and cervical dystonia) indicate that antibody formation rate remains low, occurring in approximately 1 percent of patients receiving repeat injections with this most recent formulation [36, 37].

  • BTX-A toxicity. Based on studies done on primates, the lethal dose of BTX-A, (BOTOX®) is estimated at 40 U/kg [38, 39].

  • Lidocaine neurotoxicity [40].

  • Needle phobia, vasovagal shocks are other concerns that a physician may face occasionally.

  • Cost could be an issue in some patients although most insurance companies and some government health plans cover this procedure.

  • Poor or abbreviated response. BTX-A (BOTOX®) is most effective on the axillae where its average duration of efficacy is about 7 months [41]. Hands and feet are much more difficult to treat and the duration of action is more variable especially on the feet where a higher dose of BTX-A and an adjunct topical formulation is often required for patients declaring partial or no response. Higher doses provide better results but may also increase the risk of developing BTX-A neutralizing antibodies as mentioned above. Therefore, whenever possible, a combination treatment with topical formulation is favored over injection of increasingly higher doses [42].


    Novel approach to anesthesia

    A novel approach to treat palmar and plantar HH is the delivery of tiny amounts of anesthetics (0.02 to 0.04 cc per spurt) through a needleless injector prior to BTX-A injections with needles. The device must have an adjustable volume ranging from 0.02 to 0.1 cc at least and an adjustable pressure (0 - 350 psi) that allows gradual increase of the pressure until a visible subepidermal wheal is obtained. This is an important safety issue because by increasing the pressure gradually, we avoid any injury to the superficial vessels and nerves lying under the skin of the palm, particularly. The use of a small volume, e.g. 0.03 cc, will also contribute to the safety issue because there is a decrease of penetration depth with decreasing injection volume [43]. The small volume of the injected anesthetic 0.03 cc minimizes the interstitial pressure and causes much less pain than the standard 0.1 cc fixed volume found on the standard needle free injectors such as the Dermojet®. On a visual analog scale (VAS), the pain is felt more on the fingers (VAS 2/10) than on the palm of the hand (VAS 0.5/10). The sound of the device is sometimes more disturbing to the patient than the pain itself.

    A device such as the Med-Jet MBX II (MIT Canada) fulfills all the needed requirements to safely perform the needle free anesthesia. The device system consists of a CO2 powered variable dose injector (0.02 to 0.3 cc) to which a 12 cc disposable syringe is attached containing the anesthetic (2% lidocaine with or without epinephrine). When the trigger is pulled, the injected material reaches the targeted depth in the skin. The starting pressure is usually around 130 psi (range 0 to 350 psi) depending on the epidermal thickness. This device has been approved by Health Canada and the European Union. FDA approval is pending.

  • The potential for blood to splash back into the injector led to concerns in 1980 over contamination between patients. The metal component of the Med-Jet MBX II can be detached and autoclaved at 134ºC for 30 minutes between each patient. Dimache et al. reported that jet injectors can be safely used in the medical practice if they are protected by the sterile anticontaminant disposable device [44, 45]. The Med Jet MBX II is now equipped with a sterile disposable anticontaminant nozzle, easily replaced within a few seconds. Tests are underway to prove that changing this disposable anticontaminant nozzle between patients will be safe enough to treat more than one patient in a same setting. Until then, we recommend the use of a sterile device for each patient.

  • The injection technique for the hands and feet has already been reported [46, 47, 48]. To treat the hands, the patient is installed in supine position. The device is prepared by adjusting the volume per spurt to 0.02-0.03 cc. The pressure system is set to 130 psi (part per square inch) and a first injection is launched at the centre of the palm. Usually an anesthetic wheal is formed instantly. If the wheal fails to appear, pressure is raised by increments of 10 psi, until a lidocaine wheal is formed. Once the wheal is visible, injections are continued evenly at 1.5 to 2 cm intervals over the whole palmar surface including the fingers. Although BTX-A injection with a needle could be done after each single wheal formation, it is usually performed after the induction of 3 to 8 wheals as desired, (in order to decrease the time spent manipulating the device unnecessarily). More details about the apparatus and the injection techniques for the hands and feet can be found in previous reports [46, 47, 48].

    Jet anesthesia prior to BTX-A injection with needle offers the following advantages:

  • Anesthesia is instantaneous at the intended site of BTX-A injection with a needle.

  • The technique is rapid and non-invasive. A video showing the entire procedure can be downloaded here. The whole procedure may take less than 10 min. per palm while anesthesia with a nerve block may take a much longer time, up to 90 minutes per palm [26].

  • The volume injected per spurt is 0.03 cc of 2 percent lidocaine without epinephrine targeted to the superficial dermis where most of nerve endings lie. The total amount of the anesthetic used for both hands hardly exceeds 2 cc thus neurotoxicity from lidocaine becomes less of a concern.

  • The bleeding is minimal compared to the other methods. This could be explained by the augmented local hydrostatic pressure that compresses blood vessels at the injection site similar to tumescent anesthesia but on a smaller scale. Further bleeding could be avoided by using lidocaine with epinephrine without the fear of affecting BTX-A potency [10, 49, 50].

  • The technique has the advantage of concomitantly mapping out the intended sites for BTX-A injection.

  • At our clinic, vasovagal shock reflexes occurred less frequently with jet anesthesia than with the nerve block (personal observations).

  • On VAS the score of pain is on average 0.5 to 1 on the palms and up to 2 at the tip of the fingers. None of the 150 patients treated in our clinic experienced a pain more intense than 2 on VAS.

    Some critics have justifiably argued that the safety and the duration of efficacy with the jet anesthesia technique prior to injection of BTX-A with needle have not been clinically studied [24, 51].

    Regarding the safety issue, the critics are right for pointing out the fact that if the device is not used in the proper way, nerve or vessel damage, particularly on the palms of the hands, may result from deeper penetration of the injectate. This could happen when a spring loaded injector, like Dermojet®, which has a fixed pressure (above 300 psi) and a fixed volume (0.1 cc) is used on the hands. However, this disadvantage does not apply to plantar nerves and vessels due to their deeper location [20]. Jet anesthesia replaced the nerve block technique at our clinic prior to the injection of BTX-A with needle for palmar and plantar HH since August 2004. The technique has been performed over 150 times in patients suffering from palmar and plantar HH. Because of the off-label nature of the treatment, all patients have to sign a written consent prior to treatment in order to provide them with adequate information on benefits and risks associated with the procedure.

    To evaluate more objectively the value of this procedure in the context of BTX-A injection for palmar and plantar HH, we conducted telephone and e-mail surveys to evaluate the duration of efficacy of BTX-A (BOTOX®) with jet anesthesia. Data were collected from 35 patients with palmar HH and 13 for plantar HH who were treated more then once with BTX-A between August 2004 and September 2008 (Table 1). The doses received per treatment varied between 100 to 200 U (BOTOX®)/ hand or foot according to the size of the area injected and failure to respond to lower doses.

    The longest remissions observed were of 24 months in 2 patients treated for palmar HH and of 11 months in 1 patient for plantar HH (Table 2). On average, the remission was of approximately 7 months for palmar HH and 4 months for plantar HH (Table 2). Even though the sample of patients is fairly small, these results seem nevertheless to be consistent with the duration of the effect obtained after treatment of palmoplantar HH with BTX-A with the traditional methods of anesthesia or analgesia [7, 28, 29, 52, 53]. Furthermore, we noticed that patients tended to ask more frequently for repeat injections after using needle free anesthesia than when we were using the nerve block method. Further studies are needed to corroborate these observations.

    The results from the treatment of plantar HH with BTX-A, were less convincing; only 7 patients out of 13 had a reasonable remission of at least 4 months. Treatment of plantar HH remains a therapeutic challenge irrespective of the anesthesia methods used. For that reason we warn our patients that the chances of success with BTX-A, even at doses reaching 200 U (BOTOX®) per foot, are not as high as on the hands but adjunct treatments with topical formulations or iontophoresis or both often help to provide better results [42]. For a few of our patients, treatment for palmar HH resulted in a better control of axillary or plantar HH as well.


    Conclusion

    Although BTX-A injections have revolutionized the treatment of axillary HH, palmar HH has always remained a therapeutic challenge. Sweaty hands, apart from their psychological, social, and occupational impact, may also interfere with the fingerprint authentication process. In an era in which more and more companies rely on fingerprints to verify employee identity instead of badges or passwords that can be lost, forgotten, or shared, it becomes of utmost importance to treat palmar HH more effectively.

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