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DRJ Dent Res J Dental Research Journal Dental Research Journal 1735-3327 2008-0255 Medknow Publications Pvt Ltd India DRJ-12-197 Letter to Editor Use of pure nicotine for the treatment of aphthous ulcers Kalantar Motamedi Mahmood R Golestannejad Zahra Dental Students Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Torabinejad Dental Research Center and Department of Oral Medicine, School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran Address for correspondence:Mahmood Kalantar Motamedi, Dental Students Research Center, Hezar-Jarib Ave., School of Dentistry, Isfahan University of Medical Sciences, Isfahan, Iran kalantardnt@hotmail.com Mar–Apr 2015 12 2 197 198 Copyright: © Dental Research Journal 2015

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 <p>Editor,</p> <p>We aimed to evaluate the therapeutic effect of pure nicotine on recurrent aphthous ulcers (RAUs). These lesions are characterized by the formation of painful oral ulcers that are usually isolated, but may also be found in clusters. Cigarette smoking has been reported to be protective against RAUs. <sup> <xref ref-type="bibr" rid="ref1">1</xref> </sup>These ulcers are less common among users of smokeless tobacco than non-users, <sup> <xref ref-type="bibr" rid="ref2">2</xref> </sup>and among smokers than non-smokers. <sup> <xref ref-type="bibr" rid="ref3">3</xref> </sup></p> <p>There are two probable theories regarding the preventive effect of smoking on RAUs:</p> <p> <list list-type="order"> <list-item> <p>Cigarette smoking prevents aphthous ulcers by causing an increase in localized keratinization of the oral mucosa; alternatively,</p> </list-item> <list-item> <p>Nicotine via several possible mechanisms could modulate local immune responses, as it has been shown to induce T-cells anergy <sup> <xref ref-type="bibr" rid="ref4">4</xref> </sup>and inhibits the production of pro-inflammatory cytokines, such as interleukin (IL)-2, IL-6, IL-8, IL-10 and tumor necrosis factor α. <sup> <xref ref-type="bibr" rid="ref5">5</xref> </sup>, <sup> <xref ref-type="bibr" rid="ref6">6</xref> </sup>, <sup> <xref ref-type="bibr" rid="ref7">7</xref> </sup>It can also activate the release of adrenocorticotrophic hormone and cortisol, <sup> <xref ref-type="bibr" rid="ref8">8</xref> </sup>leading to further suppression of inflammatory pathways.</p> </list-item> </list>The second mechanism is more acceptable as Bazrafshani et al. linked the minor aphthous ulcers to pro-inflammatory cytokines, including IL-1B and IL-6. <sup> <xref ref-type="bibr" rid="ref9">9</xref> </sup>In addition, as shown in an animal study, the therapeutic role of pure nicotine can be related to the promotion of angiogenesis and wound healing via the activation of nicotinic acetylcholine receptors. <sup> <xref ref-type="bibr" rid="ref10">10</xref> </sup>The theory that nicotine is known as the protective factor is also supported by three case reports, in which aphthous ulcers were prevented or healed while the patients used nicotine replacement materials. <sup> <xref ref-type="bibr" rid="ref11">11</xref> </sup>, <sup> <xref ref-type="bibr" rid="ref12">12</xref> </sup>, <sup> <xref ref-type="bibr" rid="ref13">13</xref> </sup></p> <p>Nicotine replacement materials are available in various types, such as chewing gums, transdermal patches, tablets, and lozenges. It is worth mentioning that a number of studies have reported that pure nicotine (not the other components of tobacco) is a safe component, although it depends on the dose. Transdermal nicotine did not cause a significant increase in cardiovascular events in high-risk outpatients with cardiac disease. <sup> <xref ref-type="bibr" rid="ref14">14</xref> </sup>, <sup> <xref ref-type="bibr" rid="ref15">15</xref> </sup>A review of adverse effects did not find evidence of excess adverse cardiovascular events related to nicotine patches. <sup> <xref ref-type="bibr" rid="ref16">16</xref> </sup>Nicotine gum used in another study, <sup> <xref ref-type="bibr" rid="ref17">17</xref> </sup>appeared to be safe and unrelated to any cardiovascular illness or other serious side effects; however, about 25% of nicotine gum users reported at least one adverse effect, while most were very minor and transient. The considerable side effects mostly reported with nicotine gum, including hiccoughs, gastrointestinal disturbances, jaw pain, and oral problems (e.g., mouth or throat irritation, and excessive salivation), are not seen with transdermal patch. <sup> <xref ref-type="bibr" rid="ref18">18</xref> </sup>The only side effect which appears with the use of the nicotine patch is skin sensitivity and irritation. This might affect up to 54% of patch users, but it is usually mild. <sup> <xref ref-type="bibr" rid="ref18">18</xref> </sup></p> <p>Until date, tobacco has had only a prophylactic role against aphthous ulcers, therefore the role of submerged nicotine in tobacco, as a therapeutic factor should be taken into account. We tried to conduct a review about the role of pure nicotine for preventing aphthous ulcers, yet there were only three available case reports considering this issue. Initially during 1991, as part of a case report, three non-smoking patients with RAUs were prescribed to use nicotine tablets. In each case the ulcers healed and new ulcers did not appear during the nicotine therapy. <sup> <xref ref-type="bibr" rid="ref11">11</xref> </sup>Afterwards, another interesting report suggested that using nicotine replacement patches may regress aphthous ulcers. This study was based on a woman suffering from Behcet′s syndrome, who was a former smoker and after cessation, nicotine replacement patches were prescribed to treat her ulcers. This led to regression of all her ulcers. <sup> <xref ref-type="bibr" rid="ref13">13</xref> </sup>Later, another study reported a case of complex aphthosis where the patient began to have aphthous ulcers, once she had quit smoking. This patient was treated by the use of nicotine lozenges as well. <sup> <xref ref-type="bibr" rid="ref12">12</xref> </sup>The dosing was different in these reports. Bittoun prescribed up to 8 mg nicotine/day, <sup> <xref ref-type="bibr" rid="ref11">11</xref> </sup>while Scheid et al. suggested 14 mg/day, <sup> <xref ref-type="bibr" rid="ref13">13</xref> </sup>and in the study of Hill et al. the initial dose was 15 mg of nicotine/day, and after withdrawal of the replacement therapy, intake of only a lozenge containing 5 mg nicotine resolved the recurrent ulcers within the first 24 h. <sup> <xref ref-type="bibr" rid="ref12">12</xref> </sup>Obviously, there is no consensus on the effective dose of nicotine replacement materials to prevent or cure the RAUs. It should be noticed that the dosing for aphthous treatment is lower than that used for smoking cessation; hence, the side effects could be lower, as in the study of Hill et al. <sup> <xref ref-type="bibr" rid="ref12">12</xref> </sup>no side effects were noted when using nicotine lozenges.</p> <p>To summarize, the use of pure nicotine in therapeutic forms, seems to be a proper alternative to treat aphthous ulcers; however, there has not been any evidence-based case-control study to prove such claim.</p> <p>Considering all the above-mentioned points, we have two suggestions for future research:</p> <p> <list list-type="order"> <list-item> <p>Case-control studies should be performed, investigating whether the use of a nicotine replacement material upon occurrence of aphthous ulcer primary symptoms (in the first 24-48 h, inspired from Hill et al.′s study <sup> <xref ref-type="bibr" rid="ref12">12</xref> </sup>) is efficient or not. Nicotine might be useful even after the ulcers have occurred to regress and heal the ulcers.</p> </list-item> <list-item> <p>Case-control studies should be performed, determining the influence of nicotine replacement material intake for longer periods by smoking or non-smoking individuals (inspired from the latter of the three above-mentioned case reports). This long-term protocol might be useful for patients suffering from consecutive RAUs by preventing ulcer recurrence.</p> </list-item> </list>Conveying such studies might be helpful to reach a clinical method to cure painful aphthous ulcers using pure nicotine rather than corticosteroids, which have several side effects. 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