AGD - Academy of General Dentistry

Recurrent aphthous ulcers (RAU) are a common and painful condition. This article describes a randomized, double-blind clinical trial of an over-the-counter medicated intraoral adhesive patch for treatment of RAU. Subjects were randomly assigned to either an active drug (patch with extract of glycyrrhiza root) or placebo patch treatment group (both n = 23) at onset of a lesion. Lesion size and pain report (unstimulated and stimulated) were assessed at intervals. A no-treatment group (n = 23) also was recruited and assessed similarly. By the eighth day, the ulcer size for the active treatment group was significantly lower (p < 0.05), while the lesions in the no-treatment group increased 13% from baseline. By the fourth day, the active treatment group reported significantly less pre-stimulus pain (p < 0.01); at this point, 81% of this group reported no pre-stimulus pain, compared with 63% of the placebo patch group and 40% of the no-treatment group.

Received: March 21, 2007

Recurrent aphthous ulcers (RAU) (commonly referred to as canker sores) are a common condition in which recurrent episodes of one or more shallow ulcers of various sizes and shapes appear on the oral mucosa at intervals ranging from a few days to a few months.

Typical appearances of RAU include minor, major, and herpetiform (not to be confused with herpetic lesions).^1,2 Minor RAU is the most common manifestation, appearing as painful, clearly defined ulcers with shallow necrotic centers that may be covered by a grey or yellow pseudomembrane. The margins are slightly raised and there usually is an erythematous halo.³ Minor aphthous ulcers are less than 10 mm in diameter and typically heal within 10–14 days.⁴ There are no significant complications from unhealed aphthous ulcers, although the acute mouth pain can interfere with patients’ quality of life and affect their ability to eat, drink, or speak. RAU affects approximately 20% of the

U.S.

adult population.⁵

The onset of RAU typically occurs in childhood, with a reported point prevalence of 1.6% among children in the U.S. between the ages of 2 and 17.⁶ In a 2004 study, Rivera-Hidalgo et al examined 17,235 adults age 17 and older and reported that adults younger than 40 had nearly twice the prevalence of RAU (22.54%) compared to those older than 40 (13.42%).⁷

The etiology of RAU has not been established definitively but the cause of the condition is likely multifactorial. Family history and twin studies have suggested a genetic predisposition.8,9 When both parents have a history of aphthous ulcers, the likelihood of offspring developing aphthous ulcers can be as high as 90%.^10,11

There is evidence that aphthous lesions initiated by trauma may result from an abnormal oral mucosal cytokine cascade that leads to an enhanced cell-mediated immune response.¹² While local trauma and stress are the most frequent precipitating factors, RAU also has been associated with diet and food allergy, hormonal changes, the use of certain medications, and microbiological factors.^13-15

Topical treatment is predicated by excluding a number of more serious systemic diseases and immune disorders that can cause aphthous-like oral ulceration, including HIV infection, Behcet’s disease, lupus, pharyngitis, adenitis (FAPA) syndrome, cyclic neutropenia, hematinic deficiencies, and gastrointestinal diseases (Crohn’s disease).^4,16

The most common treatments for uncomplicated RAU are topical and involve antimicrobial mouthwashes, local anesthetics, or local anesthetics combined with a film-forming gel covering. These treatments have not been shown to alter the recurrence or remission rates of aphthous lesions.^2,4,17 When palliative topical treatments are ineffective, systemic steroids, thalidomide, colchicine, dapsone, and pentoxifylline can be prescribed; however, while these medications often are effective at reducing lesion duration, side effects and toxicity can be problematic, contraindicating them for primary intervention of uncomplicated lesions.¹⁸ Laser ablation can provide short-term symptomatic relief and may be useful for cases of severe ulceration resulting from systemic disease; however, this option offers limited practical benefit.¹⁹

Of the topical interventions, the ones most commonly available over the counter utilize one of four mechanisms: mouthrinses with oxygenating agents; applying a non-water-soluble anesthetic (such as benzocaine via paste, liquid, or gel) to the lesion; placing a film-forming gel made with a polymerizing material (such as cyanoacrylate or cellulose) that has been suspended in an evaporating solvent to prevent irritants such as acids and salts from contacting the lesion; or a combination of the non-water soluble anesthetic and the film-forming gel.^20-22

Das et al proposed a new treatment approach for topical management of RAU that utilized elements of licorice root (glycyrrhiza).²³ Licorice root was used as a prescribed treatment for gastric ulcers until the 1970s. A 1989 study investigated licorice root in the treatment of aphthous ulcers and reported that partially deglycyrrhizinated licorice (DGL) was effective when patients gargled a strong warm-water solution of DGL four times daily.²³ Unfortunately, licorice root used in this manner is unfeasible due to its unpalatable strong taste. However, the taste is mild and palatable when used in small amounts and coupled with a self-adhering, time-release, dissolving oral patch. A patch of this nature could be an effective intervention for treatment of RAU; however, no studies have assessed this approach to topical therapy.

This article sought to determine whether a dissolving oral patch made with hydrophilic food gums for adhesion and structure and with glycyrrhiza complex herbal extract (Cankermelts, Orahealth, Bellevue, WA; 877.672.6541) would shorten healing time and reduce lesion size and pain when placed in topical contact with an RAU lesion. The patch was compared with both a placebo patch treatment group and with a no-treatment control group who had similar examination protocols but agreed to leave their canker sores untreated.

All subject selection, recruitment, and experimental procedures were approved by the University of Washington Institutional Review Board. Subjects were recruited through advertisements and flyers within the University of Washington community and by public service announcements. To be included, subjects had to be 18 years old and have self-reported RAU. Individuals were excluded if they reported current use of tobacco products, anti-inflammatory drugs, antibiotics, and/or medication for canker sores; reported a previous diagnosis of Bechet’s syndrome, Sjogren’s syndrome, immune disorder (for example, lupus), or infectious disease (for example, HIV or herpes); were currently undergoing chemotherapy or radiation therapy; or were pregnant or planning to become pregnant within the next three months.

Subjects were instructed to contact the Research Study Coordinator at the first signs of an aphthous ulcer, at which point they were scheduled immediately for a screening session. At the screening session, written informed consent was obtained and subjects completed a demographic questionnaire and a questionnaire developed for this study describing the characteristics of the RAU (for example, onset, duration, frequency, and precipitating factors). Subjects with an ulcer less than 36 hours old were examined by a dentist board-certified in oral medicine. The specialist confirmed the diagnosis of one or more RAU and assessed the patient for other mucosal diseases that might exclude the patient from participation. The diagnosis of RAU was satisfied by history and lesion appearance (for example, classic appearance of shallow, round-to-oval ulceration with characteristic halo).

Subjects satisfying the inclusion criteria were assigned at random to either a licorice patch treatment group (with water extract of glycyrrhiza root; n = 23) or an active placebo group, which received a patch with powdered star anise fruit (which tastes like licorice) at a level chosen to produce an equivalent flavor (n = 23). The placebo patch was designated as an “active” placebo since star anise has been shown to have a very mild antibiotic effect, which may have affected the course of the RAU lesions in some way. Subsequently, a no-treatment control group (n = 23) was recruited and included for assessment following the same pattern as the other two groups, utilizing the same examination sequencing but with an additional follow-up session scheduled at ten days.

After the initial examination on the first day, subjects were evaluated on days three, four, and eight; in addition, the no-treatment group was evaluated on the tenth day. Subjects in both treatment groups were instructed to use the patches for 16 hours per day (but not while sleeping) and to keep usage logs. They were instructed to cease using the patches at least 30 minutes before arriving at the clinic for each follow-up visit to avoid measuring immediate or short-term pain reduction caused by the patch.

At each examination, a registered dental hygienist photographed the RAU with a digital camera. A periodontal probe with millimeter markings (PCPUNC156) was held close to the photographed ulcer to calibrate measurements and determine the dimensions of the ulcer. A colored print of the image was used for subsequent analysis of size. Lesion dimensions were determined by a single board-certified oral medicine specialist who was blinded to the subject’s status. The white ulcerous region of the lesion was outlined using a 0.5 mm medium lead pencil. The long axis of an ellipse across the ulcer was designated as the major axis length, while the minor axis was designated as the widest spot of the lesion perpendicular to the major axis. The length of each axis was measured on the photograph with a digital caliper and the length was corrected (to the nearest 0.5 mm) against the image of the periodontal probe.

Each subject was asked to rate baseline pain on an anchored ordinal scale of 0–10, with 0 indicating no pain and 10 indicating the worst possible pain. This rating was taken with no stimulation and again after the ulcer was swabbed with a saturated solution of sodium chloride and distilled water (intended to simulate stimulation caused by foods).

Statistical analyses were performed using SPSS for PC. ANOVA tests were used to compare all three groups and t-tests were used for pairwise comparisons between groups.

There were no significant differences between groups regarding gender or age. Initially, the ulcer size was somewhat larger among those selected at random for the licorice patch treatment group (Chart 1) than for those in either the active placebo or the no-treatment groups. At the fourth visit (day eight), the ulcer size of the licorice patch treatment group was significantly lower; by contrast, lesions in the no-treatment group had increased in size from baseline by 13%. The licorice patch treatment group experienced an average reduction in ulcer size of 90% by the fourth visit. The active placebo group experienced an average size reduction of 68.5%.

Pre-stimulus pain levels at baseline were higher for the licorice patch treatment group than for either of the other two groups (Chart 2). By the third visit (that is, the third day of treatment and the fourth day of the study), the licorice patch treatment group subjects reported significantly less pre-stimulus pain than subjects in the other groups. By the fourth visit (day eight), pain levels in the licorice patch treatment group continued to remain lower than those reported by the active placebo and no-treatment groups but the difference was not significant.

Post-stimulus pain likewise was significantly lower among the licorice patch treatment subjects by the third visit (three days of treatment; day four of the study) (Chart 3). By the fourth visit (day eight), subjects using the licorice patch reported lower pain levels than the active placebo and no-treatment subjects but again, the difference was not significant. At the fourth visit, the difference in post-stimulus pain between licorice and no-treatment groups reached near-significance (p = 0.06). After three days of treatment, 81% of the licorice patch treatment group reported no pre-stimulus pain, compared to 63% of the placebo patch group and 40% of the no-treatment subjects.

For both the placebo and licorice patch groups, there was no significant difference in terms of the time between the patient’s discovery of the new ulcer and the initiation of treatment (22.3 hours for the placebo group compared with 18.3 hours for the licorice patch treatment group). Usage logs for the first three days showed that mean usage of the licorice patch was not significantly different (8.6 hours per day) than mean usage of the placebo patch (7.9 hours per day).

From Charts 1–3, it is apparent that most of the significance found between groups involved the no-treatment and the licorice patch groups, with the placebo patch group results showing some effect (although less) compared to the licorice patch group. There are several possible explanations for these findings.

One potentially confounding factor that was not anticipated during development of the study was the possible effect of adding Chinese star anise (Illicium verum Hook) to the placebo patch for the purpose of producing an equivalent (licorice) taste as a means of ”blinding” both the recipient and the hygienist to the fact that the patient was in a control group. It is possible that the inclusion of anise produced (or at least contributed to) a therapeutic effect of the placebo patch. Chinese star anise has been used in traditional medicine to treat infant colic and has demonstrated potential antibiotic properties.^24,25 As a result, the placebo group should be characterized as an active (rather than an inert) placebo control group.

The patch vehicle itself may lead to improvement in terms of the pain and size of lesions.²⁶ It is possible that the patch protected the lesion from additional mechanical or chemical (for example, food acids) trauma; the patch also may have reduced the possibility of superinfection.

This study shows that both the size and pain of lesions from uncomplicated (minor) aphthous ulceration can be reduced significantly by using an adhesive patch impregnated with glycyrrhiza (licorice) root extract. The adhesive patch containing licorice root extract reduced the size of the aph-thous ulcers significantly after seven days of treatment, compared to the placebo and no-treatment groups. This period represents a significant reduction in healing time, assuming that a component of healing may be equated with visual resolution of the ulcer. The placebo patch appeared to have a benefit in reducing ulcer size compared to no treatment but not as significantly as the patch with the glycyrrhiza extract.

In addition to speeding healing of the ulcers, the adhesive patch containing glycyrrhiza extract helped to reduce both pre- and post-stimulus pain after three days of treatment, compared to the active placebo and the no-treatment conditions. This represents a significant reduction in healing time, assuming that a component of healing is equated with a reduction of pain perception. By the fourth visit (the eighth day of the study), the active treatment group still reported less pre-and post-stimulus pain than the other groups, although the differences were not significant. This difference may be due to the relatively small size of the experimental groups and a basement effect in pain levels.

Genotoxic studies indicate that glycyrrhiza is neither mutagenic nor teratogenic.²⁷ No adverse or side effects were reported by subjects in this short-term study and none would be expected given the time-limited approach for treating aphthous lesions and the low dose of medication incorporated into the patch itself (less than 0.015–0.229 mg/kg of body weight per day). This point is of special significance, considering that most prescribed therapeutic approaches for the treatment of aphthous ulceration involve a number of pharmaceuticals with well-known potential for adverse side effects (for example, antimicrobial compounds, colchicine, dapsone, thalidomide, and immunosuppresants).

The results of this study indicate that using an adhesive patch containing intraoral glycyrrhiza root extract for treatment of RAU offers significant benefits both in terms of reduction of pain and in visual resolution of the ulcers.

This study was supported by NIH/NIDCR Grant R41-DE015740-01 and the Orahealth Corp.

Dr. Martin is an associate professor of Oral Medicine, University of Washington in Seattle, where Dr. Sherman is a clinical assistant professor, Departments of Oral Medicine and Physical Medicine and Rehabilitation. Dr. Burgess is currently in private practice and acts as a science consultant for Orahealth Corporation in Bellevue, WA. Dr. van der Ven is an affiliate instructor, Department of Oral Medicine, University of Washington and in private practice in Federal Way, WA.

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