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Cryosurgical Treatment of Warts: Dimethyl Ether and Propane Versus Liquid Nitrogen -- Case Report and Review of the Literature

October 2011 | Volume 10 | Issue 10 | Original Article | 1174 | Copyright © October 2011


effective alternatives to in-office cryotherapy. One manufacturer went so far as to say their product is “the most successful method of wart removal used by physicians.” We describe the case of a 25-year-old male with persistent post-inflammatory hyperpigmentation secondary to self-administered treatment with an OTC wart removal product containing DMEP.

Case

A 25-year-old male presents with a brown-grey macule following treatment with an OTC wart-freezing product. The patient sought treatment from his primary care physician four years earlier when he presented with a viral wart, and his physician recommended an OTC wart freezing product containing dimethyl ether and propane. The patient described the formation of a hemorrhagic blister and scab. When the scab fell off two to three weeks later, the wart remained. Treatment was repeated. Again a hemorrhagic blister formed over the frozen area, concealing a smaller wart which had not been eradicated. This time, however, a permanent brown-grey discoloration remained.

CONCLUSION

In a 1996 study, Caballero et al. demonstrated equal efficacy with physician-administered DMEP and liquid nitrogen cryotherapy in the treatment of verruca vulgaris. The authors concluded that no clinically relevant differences in efficacy, safety, and tolerability exist between the two agents.5 Subsequent to these findings, DMEP-containing cryotherapy devices have become commonplace in the primary care setting. Manufacturers of OTC wart-freezing products have used this data to propel their products to the reach of the consumer. However, a careful evaluation of the study design brings the validity of the aforementioned conclusions into question.
Subjects were randomized to receive cryotherapy with either liquid nitrogen or DMEP. Following treatment, patients were assessed at one-week and again at a 15-day end-of-trial appointment to determine efficacy. In selecting an end date that precludes the detection of disease recurrence, the study fails to provide an accurate measure of the efficacy of cryotherapy with DMEP. Furthermore, as evidenced by the presented case, tissue exposed to cryotherapy may form a hemorrhagic blister and eschar which may conceal underlying residual disease well beyond the 15-day end-of-trial appointment.
In a similar study, Erkens et al. extended the end-of-trial appointment date to 2.5 months. At 2.5 months, 58% (25/43) of patients treated with liquid nitrogen were cured versus 28% (14/50) of those patients treated with DMEP (P=0.01).6 Thus, with adequate follow up, liquid nitrogen appears to demonstrate therapeutic superiority; however, additional studies are needed to validate these findings.
Prior to this report, Burkhart et al. conducted an in vitro study comparing OTC wart-freezing products to in-office cryotherapy with liquid nitrogen. The tip of a thermometer was placed in direct contact with both liquid nitrogen and DMEP expelled from OTC wart-freezing products. Liquid nitrogen produced a recorded temperature of -100°C, the instrument's lower limit of detection, in less than 15 seconds. Despite manufacturer claims that the DMEP mixture freezes warts at a temperature of -57°C, the lowest temperature recorded when the thermometer was placed in direct contact with the coolant was -20°C at 45 seconds. Interestingly, when the device was used as per the package insert and the thermometer was placed in direct contact with the device's foam applicator tip, the lowest temperature recorded was -9°C.7 This study illustrates that cryotherapy with DMEP, if used as per package insert, is unlikely to produce tissue temperatures cold enough to generate intracellular ice crystal formation or ischemic necrosis, phenomena that are seen at temperatures less than -40°C and -15°C, respectively. This study also illustrates that liquid nitrogen produces a more rapid rate of tissue cooling, associated with a higher degree of cellular necrosis. Collectively, these findings cast doubt on manufacturers' claims that these OTC products reproduce in-office cryotherapy with liquid nitrogen.
It is also important to note that in previous studies, cryotherapy with DMEP was administered by trained health care professionals using a patented applicator device.5 Conversely, OTC wart-freezing products are typically administered by untrained individuals, using a different applicator system. On this basis, conclusions made regarding the safety and efficacy of in-office DMEP cryotherapy may not be applicable to similar OTC products. Despite having been on the market for several years, published data attesting to the efficacy of OTC wart-freezing therapies containing DMEP appears to be nonexistent.
Nevertheless, OTC wart-freezing products are marketed to the general public as a safe treatment modality for adults and children at least four years of age. One manufacturer even makes it known that both dimethyl ether and propane are commonly used in hairspray products. Such statements are misleading and dangerous, as they suggest that these entities are completely benign. Two case series describing significant cold thermal burns resulting from use of these products suggest otherwise.8,9 Furthermore, it is clear from the presented case that permanent post-inflammatory hyperpigmentation is another potential adverse effect.
Post-inflammatory hyperpigmentation can be seen in the setting of epidermal inflammation, where melanocytes are stimulated to increase the production of melanin. Disruption of the melanocytes in the stratum basalis may result in pigment incontinence as melanin becomes trapped by macrophages in the dermis. As evidenced by the presented case, the resulting dermal melanosis is often permanent. It is important to point out that melanocytes are much more delicate cells that keratinocytes. Thus, while OTC wart-freezing therapies may not achieve temperatures ad-