This study suggests that patient-applied 2-octyl cyanoacrylate bioadhesive is an effective new treatment modality for pain relief of aphthous ulcers.

RAU major is manifested by patients displaying one or more ulcers similar in appearance to RAU minor, but these major ulcers typically are larger than 1 cm in diameter, last from several weeks to months and tend to heal with scarring. Approximately 10 percent of aphthous ulcer sufferers will get this form. The least common form of RAU is given the name "herpetiform." Less than 10 percent of aphthous ulcers are of this type, and the real prevalence is probably lower owing to its similarity in appearance to intraoral herpes simplex lesions and the misdiagnosis of the two conditions. Herpetiform ulcers appear as numerous (10–50 or more) small (1- to 3-mm) ulcerations—miniature clinical examples of RAU minor—which appear in clusters, most frequently in the posterior areas of the oral cavity.

All three forms of RAUs occur only on mucosal tissues not bound to bone. To state it differently, aphthous ulcers are confined to the nonkeratinized mucosa of the mouth—specifically, the labial and buccal mucosa, which are the areas most frequently involved; the maxillary and mandibular vestibules; the floor of the mouth; the ventral surface of the tongue; the soft palate; the pharyngeal mucosa; and the nonattached gingival tissues. Aphthous ulcers are not found on the hard palate, the dorsum of the tongue or attached gingiva.

Besides the pain and discomfort experienced when the ulcers are present, few other signs and symptoms accompany these lesions. Occasionally, a patient may have sub-mandibular lymphadenopathy with soreness on node palpation, but temperature elevation and other constitutional signs and symptoms usually are lacking. Pain is noted to increase with consumption of spicy, hot foods and acidic liquids, as well as from irritation caused by rough foods or oral muscular movements.

Although topically applied anesthetics do reduce or eliminate the discomfort of recurrent aphthous ulcers, the relief tends to be of short duration.

The ulcers of RAU minor typically last from seven to 10 days from time of first observance to complete healing, though the range can extend from three to 14 days. Frequency of recurrence varies among patients, some experiencing only one or two episodes a year and others experiencing RAUs every few weeks to months.^1,2,4–6

The etiology of aphthous ulcers appears to be multifactorial, with numerous causal and precipitating events. Chief among them are genetic predisposition; allergic factors, including those associated with medications; stress, anxiety and hormonal factors; trauma; and, certainly, an immunological element. Clinicians should make every effort to identify either local or systemic etiologies so as to decrease the frequency, severity and duration of the aphthous ulcer episodes. Unfortunately, the majority of patients, even after extensive investigations, will show no signs or symptoms of systemic or underlying associated disease.^7–13

If identification and management of potential local or systemic etiologies, or both, do not provide relief from RAUs, treatment is directed primarily at pain reduction and decreasing the duration of the ulcers. Management is currently by prescription or over-the-counter, or OTC, palliative medications in ointment or rinse formulations or in the form of topical barrier devices. Although topically applied anesthetics do reduce or eliminate discomfort, the relief tends to be of short duration; furthermore, some of the formulations are distasteful to patients. Barrier devices, ointments and self-applied liquids, which form a protective coating, also have had some success in alleviating the discomfort of ulcers. Their shortcomings are the length of time the barrier stays in place or provides relief, the ability to apply the barrier to ulcerations in certain areas of the mouth and the sensation of discomfort on application of the barrier.

The immunoactive agents, specifically the corticosteroids, remain the principal modality in treatment of RAUs. Topical steroids in liquid or ointment form are used most frequently, while systemic or injectable formulations are retained for the major form of the disease. Most steroids will provide short-term pain relief, and some have been shown to reduce healing time, but all have the problem of being prescription medications, being costly and having the potential for significant side effects and systemic implications. Also used in the management of aphthous ulcers are medications that inhibit components of the inflammatory reaction and others that act as chemical cauteries.^6,14–20 However, the anti-inflammatory products typically do not provide immediate pain relief, and the cauteries are difficult to safely apply.

In this article, we report on evaluations of a novel tissue bioadhesive in the management of aphthous ulcers. We examine the protocols and results of an initial clinical trial and a subsequent definitive clinical study with this barrier device, and our discussion will center around its possible use as an OTC product for consumer use.

Several cyanoacrylate products have been developed for medical use as biocompatible tissue adhesives for wound closure, but in dentistry, investigational use of cyanoacrylates has been limited.

	MATERIALS

TOP ABSTRACT MATERIALS METHODS ANALYSES RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The bioadhesives evaluated were formulations of 2-octyl cyanoacrylate, or 2-OCA. The cyanoacrylates are a group of compounds that polymerize in an exothermic reaction on contact with a fluid or with basic substances to form strong bonds. Several cyanoacrylate products have been developed for medical use as biocompatible tissue adhesives for wound closure, including formulations of butyl cyanoacrylate and 2-OCA derivatives.^21,22

In a recent clinical study of 130 patients, Quinn and colleagues²³ reported that 2-OCA tissue adhesive effectively closed lacerations while reducing procedure time and discomfort as compared with closure using conventional monofilament suture. In dentistry, investigational use of cyanoacrylates has been limited.^24,25 Jasmin and colleagues²⁶ published anecdotal observations that cyanoacrylate tissue adhesive may reduce pain and healing time in pediatric patients with RAUs. Hassan and colleagues²⁷ studied 40 subjects who each had two simultaneous RAU lesions. For each subject, isobutyl cyanoacrylate was applied to one lesion and petroleum jelly was applied to the other. In addition to pain reduction, a majority of lesions treated with cyanoacrylate were healed at the fifth day of the trial, while healing of the majority of petroleum jelly–treated lesions was not seen until the seventh day of the study.

	METHODS

TOP ABSTRACT MATERIALS METHODS ANALYSES RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
We conducted the study in two phases. The objectives of the clinical trial (Phase 1) were to assess the overall safety of an investigator-applied barrier and evaluate its efficacy in reducing pain, as well as look at its effects on ulcer healing time. When we analyzed the results of this trial, we decided to proceed with a definitive study (Phase 2) in which we would evaluate the equivalency of a patient-applied adhesive to a predicate device approved by the U.S. Food and Drug Administration. The bioadhesives are considered a device because they achieve their intended purpose through mechanical action, as opposed to a drug, which achieves its purpose through metabolism and chemical action. A manufacturer wishing to introduce a new medical device for sale in the United States is required by federal law to show that the device is equivalent to a "predicate" device—one already approved by the FDA and marketed for the same intended use.

For the studies described here, the investigators at the sites mentioned performed all examinations, imaging, bioadhesive applications, and medical and dental interviews. The study coordinators were responsible for overseeing all other aspects of patient visits, including clinical records and patient diaries.

Phase 1. Phase 1 involved application of the bioadhesive by the investigators. This study, conducted at the University of North Carolina Hospitals and approved by the hospitals’ institutional review board, or IRB, used a single-blinded, randomized, sham-controlled design with three parallel arms:

– Arm A—topical application of 2-OCA tissue adhesive Formulation 1 (Closure Medical Corp.) at baseline (day one) and on days two, three and four;

– Arm B—topical application of 2-OCA tissue adhesive Formulation 2 (Closure Medical Corp.) at baseline (day one) and days two, three and four (Formulation 2 contained the same components as Formulation 1, but also contained a color additive [D&C violet no. 2] to aid in visualization of the adhesive during application and a plasticizing agent to enhance flexibility of the polymerized film; this adhesive had a slightly longer polymerization, or setting, time);

– Arm C—simulated device, or sham, application using sterile saline at baseline (day one) and days two, three and four.

After a telephone screening, investigators invited potential subjects to visit the study site for formal entry into the study. When subjects provided informed consent to participate, investigators reviewed them against inclusionary and exclusionary criteria. Inclusion criteria required that subjects be 18 years of age or older; have a single, painful ulcer less than 48 hours old, located on unkeratinized oral mucosa; and have a history of at least two self-reported episodes of RAUs during the previous year. During their study participation, subjects were required to abstain from the use of topical or systemic formulations of anti-inflammatory medications, steroids, analgesics, mouthwashes containing alcohol or tooth-bleaching agents. Exclusion criteria included a history of major apthae, Behçet’s syndrome, immune dysfunction, active infectious disease or unstable organic disease. Additional exclusions included any history of drug or alcohol abuse, a history of tobacco use within six months of baseline, chronic use of anti-inflammatory drugs within one month of baseline, antibiotic use within 15 days of baseline, and analgesic use within the 24 hours of baseline. Subjects with conditions that might preclude accurate RAU pain assessments (such as migraine headaches or orthodontic braces) also were excluded.

After confirming each subject’s eligibility, investigators obtained a baseline ulcer image, and the subject recorded an unchallenged pain score. The ulcer then was challenged with a 5-second timed oral rinse of 20 milliliters of room-temperature orange juice. Fresh cans of the same brand of orange juice were used throughout the study. The investigator applied one of the two device formulations or sham to the ulcer (the technique for this is described in the next paragraph) and challenged the ulcer again with orange juice, then documented a postapplication, postchallenge pain score (using a verbal pain scale that is described below). At the conclusion of this session, subjects received instructions on when and how to record self-assessments of pain in their diaries and were told to report the following day and every day until healing for examination, imaging, reapplication of device and pain assessments.

The technique for applying the device was as follows. The investigator removed excess saliva from the ulcer area with dry 2 x 2-in. sterile gauze and applied the bioadhesive or sham by wiping an applicator tip slightly moistened with the device over the ulcer area gently and quickly in one motion. The liquid bioadhesive sets into a film within a few seconds.

Subjects used the following verbal rating scale, or VRS, to assess their own pain: 0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain, 4 = very severe pain. Investigators made no attempt to standardize the VRS scale between subjects; however, it was assumed that pain scales remained constant within subjects during the relatively brief period of the study. Pain assessments were recorded in a patient diary at baseline (before treatment) and four times daily until the time of complete ulcer healing. Each subject recorded challenged pain assessments (orange juice challenge) under the supervision of a clinical examiner until the time of ulcer healing. An investigator also documented ulcer healing and ulcer size daily; the ulcers were photographed with an intraoral video camera that incorporated an image standardization device and were saved using a computer software program (Figure 2). Discussion and results of the imaging portion of this study are published elsewhere.²⁸ The investigator also performed safety assessments and intraoral examinations daily.

View larger version (99K): [in this window] [in a new window]   Figure 2. The intraoral camera with attached image standardization device. The computer screen shows a subject’s ulcer with calibration tip.

– Arm A—Formulation 1 (formulated 2-OCA adhesive) (Closure Medical Corp.), 1.5 mL packaged in a prefilled bottle and supplied with single-use applicator swabs, applied by the study subject four times a day until resolution of ulcer pain;

– Arm B—control device (sham), 1.5 mL of sterile water packaged in a prefilled bottle and supplied with single-use applicator swabs, applied by the study subject four times a day until resolution of ulcer pain;

– Arm C—Carrington Patch, a freeze-dried hydrogel with aloe vera extract, 12 patches per box, applied by the study subject four times a day until resolution of ulcer pain.

Subjects were seen every day and images of their ulcers, as well as pain assessments, were recorded.

The study protocol for this Phase 2 study of self-applied device was essentially the same as that in Phase 1, with the main difference being that the subjects were given one of the three devices and specific instructions on how and when to apply it to their ulcers themselves.

Clinical evaluators at the three centers were calibrated in the study protocol by a study monitor. With the exception of the clinical coordinators, all evaluators were dentists. Subjects were seen every day and images of their ulcers as well as pain assessments, were recorded. Subjects did self-assessments of pain and recorded them in a study diary beginning at baseline (before initial device application) and then according to a schedule of four daily assessments until ulcer healing occurred. Subjects recorded two challenged pain assessments on day one, one before and one immediately after device application. The challenge stimulus consisted of 20 mL of orange juice held in the ulcer area for five seconds before being swallowed. A clinical evaluator performed safety assessments and intraoral examinations daily. The evaluator also asked each patient if he or she felt discomfort resulting from the application of the device. As in Phase 1 of the study, the investigator documented ulcer healing daily with computer imaging of the ulcer by means of an intra-oral video camera that featured an image standardization device.

	ANALYSES

TOP ABSTRACT MATERIALS METHODS ANALYSES RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Phase 1: investigator-applied treatments. "Time to no pain" was defined as the time at which patients recorded a VRS score of zero followed by two consecutive scores of zero (no pain) in their diaries. Healing was defined as reepithelialization of the lesion. Under this definition, tissue erythema may or may not have resolved. A biostatistician conducted pairwise comparisons (device application vs. simulated application with saline) at the = .05 level. Intergroup differences in mean VRS scores (challenged and unchallenged) were evaluated using Wilcoxon signed rank tests. Intergroup differences in the time to complete ulcer healing and resolution of pain were evaluated using Cochran-Mantel-Haenszel, or CMH, testing. Our findings relating to device discomfort and safety are noted narratively.

Phase 2: subject-applied treatments. Definitions for time to no pain and lesion healing were the same as those we used in Phase 1. Intergroup differences in the reduction of VRS pain from preapplication challenge to postapplication challenge were evaluated using CMH testing. The bio-statistician analyzed unchallenged VRS for time to total pain relief by CMH and a log-rank test, using a Cox proportional hazards regression model, stratified by clinical site. Likewise, time to ulcer healing was analyzed using a stratified survival regression. The level for statistical significance was established a priori at = .05.

	RESULTS

TOP ABSTRACT MATERIALS METHODS ANALYSES RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Phase 1: investigator-applied treatments. A total of 42 adult patients, 18 years of age or older, of both sexes were enrolled in this phase of the study. These subjects all reported a history of RAUs and reported to the clinic with at least one minor aphthous ulceration less than 48 hours old. We dismissed two subjects from participation during the conduct of the study; therefore, we included these subjects only in the pain reduction analysis.

Short-term pain reduction. We assessed short-term pain reduction by comparing VRS pain scores after an orange juice challenge and after application of the randomized arm device with VRS pain scores reported by subjects at baseline. The CMH test for this comparison, using data stratified by baseline pain score, revealed significant pain reduction for Formulation l (P = .024) and Formulation 2 (P = .009) compared with sham applications. Short-term pain reduction, as measured by average change in VRS scores, was –1.15 (standard deviation, or SD, ± 0.55) for Formulation 1, –1.31 (SD ± 1.03) for Formulation 2 and –0.50 (SD ± 0.60) for the sham control. Median reduction in VRS scores was –1 for formulations 1 and 2 and 0 for the sham control.

Long-term pain reduction. Long-term pain reduction for the ulcer episode is demonstrated by the statistical significance of an analysis of the VRS scores when subjected to a "survival analysis" of the elapsed time to total pain relief (defined as time at which patients recorded a VRS score of zero followed by two consecutive scores of zero, meaning no pain, in their diaries). When we controlled for baseline pain, we found this analysis to indicate that patients treated with Formulation 1 reported total pain relief significantly earlier than did sham-treated patients (P = .036). The time to total pain relief for patients using Formulation 2 when compared with that of the sham-treated patients was not significantly different (P = .880). Long-term pain reduction, as measured by average mean number of days to complete cessation of pain was 4.69 (SD ± 1.70) for Formulation 1, 4.85 (SD ± 2.23) for Formulation 2, and 5.64 (SD ± 2.71) for the sham control. The median number of days to pain cessation was 4.0 for formulations 1 and 2 and 5.5 for the sham control.

Time to healing. A comparison of the elapsed time between subjects’ enrollment and healing of their lesions as recorded by the clinical investigators was documented by morphometric analysis of the stored image sequence of each lesion.²⁸ The time to complete ulcer healing was significantly reduced for patients treated with Formulation 1 over that experienced by those who received sham treatment (P = .021). While mean time to healing was 1.3 days less for Formulation 2–treated lesions than for sham-treated lesions, this failed to achieve statistical significance (P = .117). Mean time to healing was 6.9 days (SD ± 2.2) for Formulation 1, 7.5 days (SD ± 3.9) for Formulation 2, and 8.8 days (SD ± 2.0) for the sham control.

Adverse effects and device safety. Of the 28 subjects who received one of the 2-OCA formulations, none showed evidence of abnormal or delayed healing. There was no instance of increased inflammation or secondary infection. Three subjects reported minor discomfort or pain associated with application of the device. One subject described this as a "burning at the ulcer site" when the device was applied. Two subjects described this as "stinging" at the time of application.

Phase 2: Subject-applied treatments. A total of 155 subjects were enrolled at the three clinical study sites in Phase 2. A number of subjects were excluded from analyses, except for the intent-to-treat analysis, owing to their failure to meet specific inclusion and/or exclusion criteria (a failure discovered subsequent to enrollment in the study).

Short-term pain reduction. Immediate pain reduction can be demonstrated by comparing the pain response to an orange juice challenge without the device in place and the same challenge administered with the device in place. The results seen in Table 1 indicate that subjects in both the Carrington Patch and Formulation 1 treatment arms showed significant pain reduction compared with subjects in the sham treatment group (P < .05). Pain reduction was not significantly different between the active devices.

Minor difficulties and discomforts also were reported by subjects in the Carrington Patch arm of the study. Several subjects reported difficulty in targeting the gelatin disk to the ulcer site. Other subjects reported the device’s "sliding off" and "not staying applied well." Reports of irritation or discomfort during device application were similar to those seen with the 2-OCA device (Formulation 1) and were of minor severity and short-lived. Unintended "sticking" of the patch to a tooth and a sensation of the "cheek and gum being glued together" were reported. These events were considered minor. One subject reported a "nauseating taste" associated with the patch. Because the hydrogel material is considered tasteless, the subject may have been describing the sensation of the material as it hydrates on the oral mucosa.

	DISCUSSION

TOP ABSTRACT MATERIALS METHODS ANALYSES RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The limited adverse effects from the 2-OCA applications used in this study are not surprising. The cyanoacrylate material polymerizes almost immediately into an inert film through an exothermic reaction. The small volumes of material ( 3 milligrams) that are dispensed by the sponge applicators that were used in this study typically are insufficient to generate a sensation of warmth. Such a small amount also is insufficient to effectively bond tissues of the mouth together. Discomfort from the application of Formulation 1 and the patch was reported infrequently and was similar to reports of discomfort from sham device application. All adverse effects related to device applications were of minor severity and short duration.

A consistent finding in both phases of this study is immediate pain relief, defined as a reduction in pain scores from an orange juice challenge, seen with the application of Formulation 1 to aphthous ulcer lesions. A significantly shorter period to complete resolution of pain was seen with the investigator-applied Formulation 1; however, this was not the case with subjects’ applications of the product. Significantly reduced time to healing also was seen with professional applications, but not with subject applications, of Formulation 1. There are a number of possible explanations for the disparity in these results. It is possible that the investigators, using direct visualization of the ulcer area rather than a mirror, did a better job of placing the cyanoacrylate material on the ulcer than did the subjects. Complete coverage may be important to acceleration of healing and reductions in time to complete pain relief. In a report on the imaging and measurements of lesion size from Phase 1 of this study, time to lesion healing was correlated with maximum ulcer size.²⁸ Larger lesions take longer to heal. The bioadhesive may inhibit the maximum size of lesions by functioning as an efficient barrier if it completely covers the lesion. However, it is possible that the lesion size in the Formulation 1 group was limited by some factor other than the efficacy of the device. A greater proportion of initially small lesions may have been allocated to the Formulation 1 group. Although this explanation is possible, the random assignment of subjects in the study design suggests that the chance of this occurring simply as a result of sampling is less than 5 percent. OTC and prescription medications and devices are available for the management of aphthous ulcers. They range from plain "coatings" to cauteries to anti-inflammatories, but none appears to be completely effective. Bioadhesives represent safe, easy-to-use, inexpensive nonprescription therapies and therefore may become a valuable addition to ulcer management.

	CONCLUSIONS

TOP ABSTRACT MATERIALS METHODS ANALYSES RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Formulation 1 demonstrated equivalent pain relieving characteristics to the predicate Carrington Patch in the subject-applied phase of this study. The bioadhesive may have an advantage in terms of patient acceptance, in that the device is applied as a very thin layer while the patch has an easily discerned thickness when first applied. This study suggests that patient-applied 2-OCA bioadhesive is an effective new treatment modality for pain relief of aphthous ulcers. Further, professional applications of this product also may expedite ulcer healing and reduce time to complete pain cessation.