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MuGard, an oral mucoadhesive hydrogel, reduces the signs and symptoms of oral mucositis in patients with lichen planus: a double-blind, randomized, placebo-controlled pilot study
Vol. 118 No. 6 December 2014
MuGard, an oral mucoadhesive hydrogel, reduces the signs and symptoms of oral mucositis in patients with lichen planus: a double-blind, randomized, placebo-controlled pilot study Inez Velez, DDS, MS,a Neil I. Spielholz, PT, PhD,b Michael A. Siegel, DDS, MS,c and Tulia Gonzalez, DDSd Nova Southeastern University, Fort Lauderdale, FL, USA
Objective. To determine if MuGard, a mouthwash shown to reduce the severity of oral mucositis when started before initiating antineoplastic therapy for head and neck cancers, is effective when painful, oral lesions are present in patients with biopsy-proven erosive oral lichen planus. Study Design. This was a double-blind, randomized, placebo-controlled pilot study at a college of dental medicine. Twenty patients with oral lichen planus were randomly assigned to receive either MuGard (n ¼ 10) or saline-bicarbonate control (n ¼ 10). One teaspoonful of the assigned mouthwash was swished for 1 minute, 5 times a day, for 14 days. Outcome measures (Oral Mucositis Assessment Scale scores and visual analog scale pain scores) were obtained before the start of treatment and repeated on days 2, 7, and 14. Results. Significant reductions in all outcome measures occurred in the MuGard-treated group. Number-needed-to-treat (NNT) to achieve a >50% reduction in averaged pain from baseline was 1.25, and to obtain complete relief, the NNT was 2.5. Conclusions. MuGard significantly reduces pain and ulceration associated with oral mucositis in patients with lichen planus. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:657-664)
Oral mucositis consists of inflammation and ulceration of the oral mucosa, associated with pain at rest, on swallowing, and on speaking. Pain can seriously affect a patient’s quality of life.1 Although the term oral mucositis is most commonly associated with antineoplastic therapy (both chemotherapy and radiotherapy), the term pertains to mucous membrane inflammation when used literally. Oral mucosal inflammation occurs in other conditions, such as lichen planus, systemic lupus erythematosus, pemphigus vulgaris, and Crohn disease.2 It is in this context that we use the term oral mucositis in this report. MuGard (Access Pharmaceuticals, Dallas, TX, USA) is a ready-to-use mucoadhesive, hydrogel oral rinse, with marketing allowance by the US Food and Drug A poster concerning this study was presented at the April 2014 meeting of the American Academy of Oral Medicine in Orlando, FL, USA. This study was funded by a President’s Faculty Research and Development Grant from Nova Southeastern University. Samples of MuGard and the saline-bicarbonate placebo were supplied by Access Pharmaceuticals. No author had a financial arrangement with Access Pharmaceuticals. a Professor and Director, Oral and Maxillofacial Pathology, Nova Southeastern University, College of Dental Medicine. b Professor, Oral Diagnostic Sciences, Nova Southeastern University, College of Dental Medicine. c Professor and Chair, Oral Medicine and Diagnostic Sciences, Nova Southeastern University, College of Dental Medicine. d Assistant Professor, Restorative Dentistry, Nova Southeastern University, College of Dental Medicine. Received for publication Apr 7, 2014; returned for revision Jul 1, 2014; accepted for publication Jul 13, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.07.007
Administration as a medical device. This designation is based on MuGard’s ability to form a thin adhesive coating on oral mucosal membranes, presumably protecting them from saliva and microorganisms. When started shortly before the institution of chemotherapy or radiotherapy for head and neck cancers (i.e., before the development of mucositis), MuGard lessened the severity of the developing mucositis and pain as compared to 2 published historical “controls,” (i.e., patients that did not receive MuGard treatment)3 and in a recent multicenter prospective randomized controlled trial (RCT).4 In the prospective multicenter study,4 the treated and placebo-treated patients started using MuGard immediately before antineoplastic therapy was initiated and then continued rinsing 4 times a day until they had received a cumulative radiation dose of 50 Gy to 72 Gy.4 Lichen planus is one of several autoimmune diseases that can be associated with oral mucosal inflammation, and when this occurs, it is termed erosive lichen planus.2 In light of the reported success of MuGard to slow the development and lessen the severity of the signs and symptoms of oral mucositis in patients receiving antineoplastic therapy,3,4 we instituted this small,
Statement of Clinical Relevance MuGard mouthwash safely and effectively reduces the signs and symptoms of oral mucositis in patients with oral lichen planus. However, studies are still needed to determine whether these benefits are lasting. 657
ORAL MEDICINE 658 Velez et al.
double-blind, randomized, placebo-controlled pilot study to determine if MuGard might help ameliorate the signs and symptoms of oral mucositis in patients with lichen planus who already had established lesions, as opposed to determining if it could lessen the development of oral mucositis, as in the antineoplastic studies.3,4 The use of MuGard was not intended as a curative therapeutic intervention; it was used only as a palliative treatment, hoping to relieve the discomfort. The Oral Mucositis Assessment Scale (OMAS) was used to score mucosal inflammation rather than to characterize the participant’s lichen planus. Other scoring instruments are available to assess lichen planus. However, to remain consistent with previous protocols using MuGard, the OMAS scoring was used in this study. Three research hypotheses were formulated and tested. These were that (1) daily use of MuGard will significantly reduce the objective signs of oral mucositis (ulceration and erythema) in patients with lichen planus compared to controls over a 14-day treatment period; (2) daily use of MuGard will significantly reduce the subjective pain associated with oral mucositis in patients with lichen planus compared to controls during this same period; and (3) the reduction in subjective pain will correlate with objective reduction in ulceration and erythema in the MuGard-treated participants.
METHODS This was a randomized, double-blind, placebocontrolled pilot study. Patients with documented erosive oral lichen planus, diagnosed clinically and histologically, were recruited from the dental clinics at Nova Southeastern University College of Dental Medicine. All the participants manifested at least the typical bilateral buccal mucosa lesions with erosions and striae. Lichenoid reactions were ruled out as much as possible by means of clinical presentation, hematoxylin-eosin histopathology, and immunofluorescence. The inflammatory infiltrate was evaluated to ensure that it was composed purely of lymphocytes and that no plasma cells or other cell types were present, as found in lichenoid drug reactions and other forms of oral lichenoid lesions. The project was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee. Written informed consent was obtained from all participants before they were enrolled. Patients were excluded if they were already using other oral rinses to coat the mucosa or were taking systemic steroids or other immune suppressors. Infants and pregnant women were also excluded, because there
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have been no reports establishing the safety of MuGard in these cohorts. Treatment consisted of a teaspoonful (5 mL) of MuGard or saline-bicarbonate control (both provided by the manufacturer). Patients were instructed to swish the liquid in the mouth for 1 minute, 5 times per day, for 14 days. Excess MuGard can be swallowed or expectorated, as no safety issues have been reported. Patients were instructed not to eat or drink for 1 hour after using their assigned rinse. Two primary outcome measures were employed. The first was the Oral Mucositis Assessment Scale (OMAS), introduced by Sonis et al. (1999)5 and validated as a reliable research instrument for evaluating oral mucous inflammation. In the original OMAS protocol, the clinician rates the extent of ulceration (0-3) and erythema (0-2) in 9 intraoral locations. For our study, we added a tenth, the gingiva (Supplemental Appendix A; available at www.oooojournal.net.). Since ulceration and erythema are rated separately, the worse-case scenario would be a total ulceration score of 30 and a total erythema score of 20, yielding a total mucositis score of 50. This is indicated by the formula Overall Mucositis Score ¼
N X i¼1
Ui þ
N X
Ri;
i ¼1
where Ui is each individual ulcerative measure (0-3) and Ri is each individual redness measure (0-2) (n ¼ 10 for all cases). While these summated mucositis scores can be compared over the 4 time intervals, Sonis et al.5 introduced another calculation which converted these summed scores into Mean Mucositis Scores (MMSs) by dividing each of the summations by the number of sites, namely 10 in our study. The effect of this division makes the maximum MMS ¼ 5. Reports by Sonis et al.5 and Baud et al.3 used this system. The second primary outcome measure was a visual analog scale (VAS) in which patients subjectively rated the pain they were experiencing. Since pain due to mucositis is experienced at rest as well as on speaking and swallowing, patients rated their pain separately for all 3 conditions (Supplemental Appendices B-D; available at www.oooojournal.net.). We then calculated an averaged pain score by dividing the total of the 3 conditions by 3. Each of these measures was obtained by an investigator (blinded to each patient’s treatment group) at initial intake and then repeated on days 2, 7, and 14 after the initiation of treatment. Since the purpose of this pilot study was to begin gathering data on the possible benefits of using MuGard to reduce the signs and symptoms of existing oral mucosal inflammation, we arbitrarily chose to enroll 20
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patients, 10 for each group. This figure was chosen for 2 reasons. First, repeated-measures (within-participants) design reduces the variance of estimates of treatment effects, thereby reducing the number of participants needed for statistical inferences.6 Second, the figure was based on the availability of patients to complete data collection within a 12-month period. Our plan was to then use the results to form the statistical basis for a larger prospective RCT. We also arbitrarily chose a 14day treatment time. Blinding After the initial evaluation, a research assistant randomly allocated to each participant a 14-day supply of identical-looking coded bottles which contained either MuGard (10) or the saline-bicarbonate control (10). This resulted in a 1:1 allocation ratio. The coded bottles were supplied by the manufacturer, who did not divulge the code until all data had been collected. Thus, neither the patient nor the investigator performing the subsequent evaluations was aware of the treatment the patient was receiving. Statistical analyses At the end of all data collection, each patient’s raw scores were compiled into a spreadsheet (baseline, 2 days, 7 days, and 14 days). However, before breaking the code, descriptive statistics were determined for all the combined (n ¼ 20) baseline data (Table I). Following this, the code was broken so that the participants could then be placed into their assigned treatment categories. Because of the relatively small sample size (n ¼ 10 in each group), the initial MMS and VAS scores of the 2 groups were compared using the nonparametric Mann-Whitney test to determine if the 2 groups were statistically similar before treatments began (Table II). Following this, the Friedman test, which is a nonparametric equivalent of the repeated-measures analysis of variance, was used to determine whether either group changed statistically (for better or for worse) compared to its own baseline values. The number-needed-to-treat (NNT) to achieve 2 different endpoints was also determined. One endpoint was a greater than 50% reduction in pain from baseline, and the second endpoint was to achieve complete relief of pain.
RESULTS Between September 2012 and September 2013, 20 patients, 14 women and 6 men, aged 61.5 14.0 years, were enrolled and studied. Table I shows the descriptive statistics of the primary outcome measures for the entire sample (n ¼ 20) before randomization into MuGard and placebo groups.
ORIGINAL ARTICLE Velez et al. 659
Table I. Descriptive statistics before randomization (n ¼ 20) Variable Ulceration Erythema Total of above Mean Mucositis Score Pain at rest Pain on swallowing Pain on speaking Averaged pain
Mean SD
Range
0-13 2-18 2-29 0.2-2.9 0-9 0-10 0-10 0.67-9.5
5.5 5.5 11.0 1.1 4.8 5.4 6.3 5.5
3.2 3.8 6.7 0.67 3.2 2.9 2.5 2.5
Although pain at rest, on swallowing, and on speaking ascend in that order, the Friedman test (a nonparametric equivalent of the repeatedmeasures analysis of variance) showed no statistically significant differences between these conditions. Similarly, the averaged pain scores were not significantly different from any of the 3 conditions. Therefore, we used the averaged pain scores as an appropriate surrogate for the 3 conditions.
Table II. Primary outcome measures comparing the MuGard-treated and placebo-treated participants following randomization but before starting treatment Variable
MuGard group
Placebo group
P
Gender F ¼ 6, M ¼ 4 F ¼ 8, M ¼ 2 distribution Age (y) 63.2 15.0 59.8 13.5 NS Ulceration 5.7 2.7 (3-11) 5.5 3.7 (0-13) 1.0 Erythema 5.2 4.7 (2-18) 5.8 2.9 (2-12) .69 Total of above 10.9 7.4 (5-29) 11.3 6.5 (2-25) .82 Mean Mucositis 1.09 0.74 (0.5-2.9) 1.13 0.65 (0.2-2.5) .82 Score Pain at rest 5.4 3.17 (2-9) 4.3 3.27 (0-9) .45 Pain on 6.3 2.58 (0-10) 4.5 3.10 (0-10) .18 swallowing Pain speaking 7.0 2.0 (0-10) 5.55 2.87 (2-9.5) .21 Averaged pain 6.2 2.2 (2-9) 4.8 2.6 (0.67-9.5) .20
Table II presents the primary outcome measures for the 2 groups following randomization but before the start of treatment. As seen, the Mann-Whitney test yielded probabilities of >.05 that the null hypothesis was true (i.e., that there were no significant differences between the groups at baseline for any of the primary outcome measures). However, power analyses of the data yielded values from 0.22 to 0.26 (not shown), raising the possibility of a type II error and that patients in the MuGard-treated group were actually slightly more involved at baseline for all outcome measures than the placebo-treated group. We revisit this point later. Table III presents the changes in the MMSs and averaged pain scores from baseline to 14 days for both groups. The Friedman test showed that the MuGardtreated group experienced significant reductions (P < .001) in both primary outcome measures over this time interval, while the placebo-treated group showed essentially no changes over the same 14-day interval.
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Table III. Changes in primary outcome measures during intervention period Group Mean Mucositis Scores MuGard Placebo Averaged pain scores MuGard Placebo
Baseline
2 Days
7 Days
14 Days
P
1.09 0.74 1.13 0.65
0.94 0.76 1.13 0.71
0.64 0.76 1.11 0.71
0.55 0.72 1.12 0.70
<.0001 NS
6.2 2.2 4.8 2.6
3.9 3.2 4.8 2.8
1.3 1.8 5.1 3.2
1.4 1.8 4.9 2.8
<.0001 NS
NS, not significant.
Fig. 1. MuGard-treated participants experienced an average decrease of 50% in their normalized (compared to baseline) Mean Mucositis Scores (OMAS)*. Conversely, participants in the placebo-treated group experienced essentially no change over the same period. Normalized values at different times are shown. Error bars ¼ SEM. (OMAS, Oral Mucositis Assessment Scale; SEM, standard error of the mean.) *Mean Mucositis Scores equals the sum of the ulceration sand erythema scores divided by 10 (the number of intraoral sites evaluated in the clinical examination).
The data in Table III are redisplayed in Figures 1 to 3 but shown as normalized to their baseline values. These figures show graphically the percent differences over time between the MuGard and placebo-treated groups for the primary outcome measures of MMSs (Figure 1), averaged pain scores (Figure 2), and the association between pain, ulceration, and erythema (Figure 3). As seen, MMSs, which are the summation of the ulceration and erythema scores divided by 10, are reduced to 50% of their baseline values in the MuGardtreated group but are essentially unchanged in the placebo-treated group. However, even more dramatic is the drop in averaged pain scores in the MuGard-treated participants. In this group, the mean averaged pain fell by approximately 80%, while in the placebo-treated group there was again essentially no change. Further evidence for the efficacy of MuGard to reduce pain in ulcerative lichen planus is the fact that 4 of the 10 participants (40%) in the MuGard-treated group reported no pain at the end of 14 days. Of the remaining 6 participants in this group, the smallest reduction in pain was 20% (1 participant); a second participant’s pain dropped by 38%; and the pain
Fig. 2. MuGard-treated participants experienced a decrease of normalized averaged pain of approximately 79% in the first 7 days, and this was maintained for the next 7 days. Placebotreated participants experienced essentially no changes from baseline over this same period. Normalized values at different times are shown. Error bars ¼ SEM. (SEM, standard error of the mean.)
of the other 4 fell by 71% to 80%. Conversely, in the placebo group, 8 participants (80%) reported no change in pain over the 14 days; another dropped by only 23%; and the greatest drop was by 44% (1 participant). Therefore, 80% of participants in the MuGard-treated group reported a >50% decrease in pain, whereas none in the placebo-treated group achieved this value. Using these percentages to dichotomize those who did or did not decrease their pain scores by >50% in each group, we obtain an NNT of 1.25. This means essentially that just 1 patient with ulcerative oral lichen planus has to be treated by MuGard compared with placebo to obtain a reduction in pain >50% compared to baseline over a 14-day period. Similarly, to achieve complete relief of pain, the NNT is 2.5. Figure 3 also shows that the decrease in pain in the MuGard-treated group is closely associated with the decrease in ulceration but less so with the decrease in erythema. Correlating normalized pain scores with normalized ulceration scores from baseline to 14 days in the MuGard-treated group yielded an r value of 0.98, a P value of .024, and an r2 value of 0.95. This means that 95% of the variation in the pain scores from baseline to 14 days is “accounted for” by the variation in the ulceration scores over the same period. Conversely, although correlating normalized pain with normalized erythema yielded an r value of 0.88, the
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Fig. 3. Showing that changes in pain are more closely associated with changes in ulceration than with changes in erythema. This suggests that MuGard affects ulceration more than it affects erythema.
Fig. 4. Normalized pain scores in the MuGard-treated group, showing that pain in all 3 conditions (rest, swallowing, and speaking) fell by similar amounts over the 14 days of treatment. This indicates that the drop in the averaged pain score was not due to one condition being more favorably affected than the others.
P value was .115, which is not significant. It is apparent, then, that MuGard treatment affects ulceration more than erythema, and it is the reduction in ulceration that is most closely correlated with the reduction in pain. Figure 4, which also shows normalized pain scores, shows that the drop in averaged pain experienced by the MuGard group was not due to a selective decrease in one or another of the 3 pain conditions (rest, swallowing, or speaking); rather, in essence, the pain experienced under all 3 conditions improved similarly. This finding further justifies using the averaged pain scores as a surrogate for the 3 separate scores. All participants who were entered into the study completed the study, and no adverse events were reported.
DISCUSSION MuGard has been shown to minimize (but not eliminate) the development of oral mucositis in patients undergoing chemotherapy, radiation therapy, or both during cancer therapy.3,4 In those studies, MuGard treatment was instituted prophylactically before the antineoplastic treatment began, and the investigators
ORIGINAL ARTICLE Velez et al. 661
then compared the development and severity of the signs and symptoms of oral mucositis. Our study differed not only with respect to the condition being treated (i.e., erosive oral lichen planus) but also because our patients presented with already-established signs and symptoms. Our goal was to determine if MuGard is effective in reducing signs and symptoms that were already present. Using the OMAS, a recognized research tool for oral mucosal inflammation associated with antineoplastic therapy,5 this pilot study produced encouraging results. They show that ulceration (as determined by an examiner) and pain (as experienced by the patient at rest, on swallowing, and on speaking) were reduced significantly over the 14 days of treatment. Pain was especially reduced and was highly correlated with the reduction in ulceration. Erythema was the least improved but was still less than at baseline. No statistically significant changes from baseline occurred in the placebo-treated group. A major limitation of our study, though, is the fact that unlike oral mucositis secondary to antineoplastic therapy, erosive oral lichen planus is an autoimmune disease, for which topical corticosteroids and calcineurin inhibitors are frequently used immunosuppressive therapeutic agents. While a head-to-head study comparing MuGard to these agents is in order, we endeavored in the meantime to get some idea of how our findings compare with those of studies that contributed to the use of these immunosuppressive agents. To do this, we identified studies since 1993 that used the 10-centimeter VAS (as we did) to record subjective levels of pain as a primary outcome measure.7 Our summary follows. We also point out that while these studies used the VAS, none mentioned whether the pain that the patients were asked to rate was their pain at rest, on swallowing, or on speaking. Apparently, patients were simply asked to “rate their pain” without any other directions (for contrast, see our Supplemental Appendices B-D; available at www.oooojournal.net.). Therefore, which pain these patients considered in their ratings is unknown. However, given that our study also showed that there was no statistically significant difference between pain ratings during the 3 conditions, we compare our averaged pain scores to those of these reports. Voute et al. (1993)8 compared fluocinonide 0.025% in an adhesive gel (n ¼ 20) to the placebo gel (n ¼ 20). After 9 weeks of treatment, 13 patients in the experimental group had complete remission of symptoms, and 6 in the placebo group also did. The authors did not present an NNT analysis, but with the information given, we calculate an NNT of 2.8 to obtain complete relief of pain compared to control. In our study, the NNT for complete relief was 2.5, but after just 2 weeks.
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Sardella et al. (1998)9 compared 5% mesalazine (n ¼ 11) to 0.05% clobetasol propionate (n ¼ 14). After 4 weeks, there was no statistically significant difference between the groups with respect to reports of complete relief, partial relief, or no relief (of pain/ discomfort). However, from a table of raw data given in the article, one can calculate that at baseline, the mean pain score for the entire group of 25 was 5.8 3.0 (similar to our entire group at baseline), which then dropped to 1.8 2.4, which is similar to the final averaged pain score in our MuGard group of 1.4 1.8 (which was achieved after just 2 weeks). Hegarty et al. (2002)10 compared fluticasone propionate spray to betamethasone sodium phosphate mouthrinse. From the little data given in Table II, we calculate that after 6 weeks the fluticasone group’s pain had dropped to 56% of baseline and that it had dropped to 70% of baseline for the betamethasone group. Both these final values are much poorer improvements than the drop to approximately 20% of baseline achieved by our MuGard-treated group after just 2 weeks. Campisi et al. (2004)11 compared 0.025% clobetasol delivered by a “new” delivery system (n ¼ 18) to the “conventional” formulation for delivering the drug (n ¼ 27). VAS scores were obtained at baseline, after 1 month, and after 2 months. Both groups were statistically similar at baseline, and pain in both groups decreased significantly. However, pain in the “new” formulation group decreased significantly more than in the conventional group. Although the article does not indicate how many (if any) patients obtained complete relief of pain, from the data given we see that pain in the “new” formulation group dropped to 16% of its baseline value, whereas in the conventional group it dropped to 48% of its baseline value. In our MuGard-treated patients, pain dropped to approximately 20% of the baseline value, which compares well with the drop to 16% of baseline experienced in the “new” formulation group in this study and is considerably better than the drop experienced by the “conventionally” treated group. Conrotto et al. (2006)12 compared 1.5% ciclosporin (n ¼ 20) to 0.025% clobetasol (n ¼ 19). Although VAS scores were obtained at baseline and then every 2 weeks during the 2 months of treatment, no VAS scores are given in the article. Instead, the authors categorize their findings as either “complete response,” “partial response,” or “no response.” The criteria used for determining “partial response” were not given. However, the authors concluded that there was no statistically significant difference between the groups with respect to the 3 categories after 2 months of treatments. From the data given in Table III, we
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see that 42% of patients in the clobetasol group achieved complete relief of pain, whereas 20% of patients in the ciclosporin groups attained this relief. In our study, 40% of MuGard-treated patients were pain-free after just 2 weeks. Choohakarn et al. (2008)13 compared aloe vera (n ¼ 27) to placebo gel (n ¼ 27). VAS scores were statistically similar at baseline. After 8 weeks of treatment, the authors categorized their findings as “complete response,” “good response,” poor response,” or “no response.” The authors clearly stated the VAS criteria used to form these categories. The aloe vera group did better than the placebo group. From the data given in Table III, we calculated an NNT of 3.4 to obtain complete relief compared with placebo after 8 weeks. In our study, we found an NNT of 2.5 after 2 weeks. Similarly, to achieve a >50% reduction in pain, the NNT for the aloe vera group is 1.2, which is the same as our 1.25, but again after just 2 weeks instead of 8. Swift et al. (2008)14 compared 1% pimecrolimus cream (n ¼ 10) to a placebo cream (n ¼ 10). After 4 weeks, the experimental group dropped from a baseline mean VAS score of 3.33 2.68 down to 2.08 2.29. The placebo group did not change. The authors state that this average value at the end of 4 weeks for the experimental group was significantly different from baseline, but the authors also report that at the end of 2 weeks, the average score was not significantly different from baseline. Therefore, our MuGard-treated participants achieved significantly lower pain scores at the end of just 2 weeks, compared to 1% pimecrolimus cream, which required 4 weeks. Radfar et al. (2008)15 compared 0.1% topical tacrolimus (n ¼ 15) with 0.05% clobetasol (n ¼ 15) for a total of 6 weeks (both groups also taking nystatin oral rinse). Although pain in both groups decreased significantly from baseline, there was no significant difference between the groups. Because of this nonsignificant difference between the groups either at baseline or during the study, the authors grouped the ‘before’ and ‘after’ findings together. From their Table III, we see that at the end of 2 weeks, there was no significant change from baseline, but at the end of 6 weeks, the decrease in mean pain was significant. However, from the data given, we also calculate that although the pain had dropped significantly, it was still 55% of its original value, compared to the drop of almost 80% in our MuGard-treated participants in just 2 weeks. Therefore, based on these findings, MuGard achieved more averaged pain relief than either tacrolimus or clobetasol.
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Carbone et al. (2009)16 compared 2 different concentrations of clobetasol, 0.025% (n ¼ 15) and 0.05% (n ¼ 15). The 2 groups had similar mean pain scores at the beginning, and both groups decreased significantly from baseline after 2 months. From the data given, we calculate that the 0.025% group dropped to 22% of its baseline pain score, while the 0.05% group dropped to 17% of its baseline value. These drops are similar to the drop for our MuGard-treated group, which dropped to approximately 20% of its baseline value, but again, this was achieved in just 2 weeks. Jajarm et al. (2011)17 compared low-intensity laser therapy (LILT) (n ¼ 11) to a group receiving a dexamethasone mouthrinse along with nystatin (n ¼ 13). The groups were statistically similar at baseline, and over 1 month both groups improved significantly from baseline, but not with respect to each other. From the data given in Table II, we calculated that pain scores in the LILT group decreased to 16% of baseline, and the dexamethasone group decreased to 17% of baseline. These values are similar to those of our MuGard-treated group, which decreased to almost 20% of baseline. In summary, although this indirect comparison between MuGard and topical immunosuppressant in reducing the pain experienced in erosive oral lichen planus does not substitute for a head-to-head RCT, it certainly indicates that such a comparative study, or a variant thereof, is warranted. It is important to bear in mind that no secondary therapeutic effect of MuGard has been studied or identified via our protocol. A second limitation of this study is its small sample sizes (10 in each group), but this was only a pilot study designed to form the basis for a larger RCT. And indeed, it could be argued that owing to this small sample size, the treatment group and placebo groups may not have been equivalent on their outcome measures at baseline (as we stated earlier). However, we point out that this possible nonequivalence at baseline (i.e., the MuGard group being perhaps more severely involved than the placebo group) makes the changes in the MuGard-treated group even more impressive, given that at the end of treatment, the MuGard-treated participants clearly had better results than those who received the placebo treatment. A third limitation of this study is the absence of a quality-of-life questionnaire. The latter would have given us some insight into the effect of the pain reductions on day-to-day living, which is clearly an important issue to patients.1 Furthermore, because of the short time span of this study (2 weeks of treatment), we do not know what the effect of continued treatment would have been, nor do we know if the benefits observed in the MuGard-treated group were long-lasting.
ORIGINAL ARTICLE Velez et al. 663
CONCLUSION Given the limitations discussed, our findings and the comparison to other immunosuppressive therapies justify future studies employing larger sample sizes, longer duration of treatment and follow-up, and head-to-head comparison with treatments that are currently in use. REFERENCES 1. Alvarado Y, Bellm LA, Giles FJ. Oral mucositis: time for more studies. Hematology. 2002;7:281-289. 2. Chi AC, Neville BW, Krayer JW, Gonsalvez WC. Oral manifestations of systemic disease. Am Fam Physician. 2010;82: 1381-1388. 3. Baud CM, Colon LE, Busse PM, Rana T, Talentowski D, Gerberich JL, Nowotnik DP, Howell SB. Protection from radiationinduced oral mucositis by MuGard oral rinse: a clinical study and in silico analysis. MASCC/ISOO International Symposium, Toronto, Canada, 2006. 4. Allison RR, Ambrad AA, Arshoun Y, et al. Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck. Cancer. 2014;120:Available at: http://onlinelibrary.wiley.com/doi/10.1002/cncr.28553/full: Accessed March 12, 2014. 5. Sonis ST, Ellers JP, Epstein JB, et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Cancer. 1999;85:2103-2113. 6. Howitt D, Cramer D. Introduction to Research Methods in Psychology. 3rd ed. Harlow, Essex, England: Pearson Education Limited; 2011:164, 170-181. 7. Cheng S, Kirtschig G, Cooper S, Thornhill M, Leonardi-Bee J, Murphy R. Interventions for erosive lichen planus affecting mucosal sites [review]. Cochrane Database Syst Rev. 2012;2: CD008092. 8. Voute ABE, Schulten E, Langendijk PNJ, Kostense PJ, van der Waal I. Fluocinonide in an adhesive paste for treatment of oral lichen planus: a double-blind, placebo-controlled clinical study. Oral Surg Oral Med Oral Pathol. 1993;75:181-185. 9. Sardella A, Demarosi F, Oltolina A, Rimondini L, Carrassi A. Efficacy of topical mesalazine compared with clobetasol propionate in the treatment of oral lichen planus. Oral Dis. 1998;4: 255-259. 10. Hegarty AM, Hodgson TA, Lewsey JD, Porter SR. Fluticasone propionate spray and betamethasone sodium phosphate mouthrinse: a randomized crossover study for the treatment of symptomatic oral lichen planus. J Am Acad Dermatol. 2002;47: 271-279. 11. Campisi G, Giandalia G, De Caro V, Di Liberto C, Arico P. A new delivery system of clobetasol-17-propionate (lipid-loaded microsphere 0.025%) compared with conventional formulation (lipophilic ointment in a hydrophilic phase 0.025%) in topical treatment of atrophic/erosive oral lichen planus: a phase IV, randomized, observer-blinded, parallel group clinical trial. Br J Dermatol. 2004;150:984-990. 12. Conrotto D, Carbone M, Carrozzo M, et al. Ciclosporin vs. clobetasol in the topical management of atrophic and erosive oral lichen planus: a double-blind, randomized controlled trial. Br J Dermatol. 2006;154:139-145. 13. Choonhakarn C, Busarcome P, Sripanidkulcha B, Sarakarn P. The efficacy of aloe vera gel in the treatment of oral lichen planus: a randomized controlled trial. Br J Dermatol. 2008;158:573-577.
ORAL MEDICINE 664 Velez et al. 14. Swift JC, Rees TD, Piemons JM, Hallmon WW, Wright JC. The effectiveness of 1% pimecrolimus cream in the treatment of oral erosive lichen planus. J Periodontol. 2005;76: 627-635. 15. Radfar l, Wild RC, Suresh L. A comparative treatment study of topical tacrolimus and clobetasol in oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105: 187-193. 16. Carbone M, Arduino PG, Carrozzo M, et al. Topical clobetasol in the treatment of atrophic-erosive oral lichen planus: a randomized controlled trial to compare two preparations with different concentrations. J Oral Pathol Med. 2009;38:227-233. 17. Jajarm HH, Falaki F, Mahdavi O. A comparative pilot study of low intensity laser versus topical corticosteroids in the treatment
OOOO December 2014 of erosive-atrophic oral lichen planus. Photo Med Laser Surg. 2011;29:421-425. Reprint requests: Neil I. Spielholz, PT, PhD Oral and Maxillofacial Pathology Nova Southeastern University College of Dental Medicine 3200 S University Dr Fort Lauderdale FL 33328 USA [email protected]
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ORIGINAL ARTICLE Velez et al. 664.e1
SUPPLEMENTAL APPENDIX A. ORAL MUCOSITIS ASSESSMENT SCALE (ADAPTED FROM SONIS ET AL., 1999) Patient ID: Date of evaluation: Location Upper lip Lower lip Right cheek Left cheek Right ventral & lateral tongue Left ventral & lateral tongue Floor of mouth Soft palate/fauces Hard palate Gingiva
Ulceration (circle) 0 0 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2
Erythema (circle) 3 3 3 3 3 3 3 3 3 3
0 0 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2
Grading key:
Ulceration
Erythema 0 ¼ none 1 ¼ not severe 2 ¼ severe
Presence of infection (circle): If yes, (circle):
0 ¼ no lesion 1 ¼ <1 cm2 2 ¼ 1 cm2 to 3 cm2 3 ¼ >3 cm2 Yes Local non-oral
No Systemic
SUPPLEMENTAL APPENDIX B. VISUAL ANALOG SCALE FOR PAIN AT REST Patient ID: Date: Instructions: You are being asked to rate the severity of the pain that you are experiencing now, while at rest. To help you do this, consider the horizontal line below. If the left-hand end is “No pain at all” (as indicated by the zero) and the right-hand end is “The worst pain I can imagine” (as indicated by the number 10), please place a vertical line on the horizontal line where you think your pain is located. j—————————————————————————————————————j 0 10 (No pain at all) (Worst pain I can imagine) SUPPLEMENTAL APPENDIX C. VISUAL ANALOG SCALE FOR PAIN ON SWALLOWING Patient ID: Date: Instructions: You are being asked to rate the severity of the pain that you have when swallowing. To help you do this, consider the horizontal line below. If the left-hand end is “No pain at all” (as indicated by the zero) and the righthand end is “The worst pain I can imagine” (as indicated by the number 10), please place a vertical line on the horizontal line where you think your pain is located when you swallow. You may swallow some saliva before making your mark. j————————————————————–————————————————j 0 10 (No pain at all) (Worst pain I can imagine)
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SUPPLEMENTAL APPENDIX D. VISUAL ANALOG SCALE FOR PAIN ON SPEAKING Patient ID: Date: Instructions: You are being asked to rate the severity of the pain that you have when speaking. To help you do this, consider the horizontal line below. If the left-hand end is “No pain at all” (as indicated by the zero) and the right-hand end is “The worst pain I can imagine” (as indicated by the number 10), please place a vertical line on the horizontal line where you think your pain is located when you speak. You may speak a few words before making your mark. j——————————————————————————————————————j 0 10 (No pain at all) (Worst pain I can imagine)
MuGard, an oral mucoadhesive hydrogel, reduces the signs and symptoms of oral mucositis in patients with lichen planus: a double-blind, randomized, placebo-controlled pilot study Inez Velez, DDS, MS,a Neil I. Spielholz, PT, PhD,b Michael A. Siegel, DDS, MS,c and Tulia Gonzalez, DDSd Nova Southeastern University, Fort Lauderdale, FL, USA
Objective. To determine if MuGard, a mouthwash shown to reduce the severity of oral mucositis when started before initiating antineoplastic therapy for head and neck cancers, is effective when painful, oral lesions are present in patients with biopsy-proven erosive oral lichen planus. Study Design. This was a double-blind, randomized, placebo-controlled pilot study at a college of dental medicine. Twenty patients with oral lichen planus were randomly assigned to receive either MuGard (n ¼ 10) or saline-bicarbonate control (n ¼ 10). One teaspoonful of the assigned mouthwash was swished for 1 minute, 5 times a day, for 14 days. Outcome measures (Oral Mucositis Assessment Scale scores and visual analog scale pain scores) were obtained before the start of treatment and repeated on days 2, 7, and 14. Results. Significant reductions in all outcome measures occurred in the MuGard-treated group. Number-needed-to-treat (NNT) to achieve a >50% reduction in averaged pain from baseline was 1.25, and to obtain complete relief, the NNT was 2.5. Conclusions. MuGard significantly reduces pain and ulceration associated with oral mucositis in patients with lichen planus. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;118:657-664)
Oral mucositis consists of inflammation and ulceration of the oral mucosa, associated with pain at rest, on swallowing, and on speaking. Pain can seriously affect a patient’s quality of life.1 Although the term oral mucositis is most commonly associated with antineoplastic therapy (both chemotherapy and radiotherapy), the term pertains to mucous membrane inflammation when used literally. Oral mucosal inflammation occurs in other conditions, such as lichen planus, systemic lupus erythematosus, pemphigus vulgaris, and Crohn disease.2 It is in this context that we use the term oral mucositis in this report. MuGard (Access Pharmaceuticals, Dallas, TX, USA) is a ready-to-use mucoadhesive, hydrogel oral rinse, with marketing allowance by the US Food and Drug A poster concerning this study was presented at the April 2014 meeting of the American Academy of Oral Medicine in Orlando, FL, USA. This study was funded by a President’s Faculty Research and Development Grant from Nova Southeastern University. Samples of MuGard and the saline-bicarbonate placebo were supplied by Access Pharmaceuticals. No author had a financial arrangement with Access Pharmaceuticals. a Professor and Director, Oral and Maxillofacial Pathology, Nova Southeastern University, College of Dental Medicine. b Professor, Oral Diagnostic Sciences, Nova Southeastern University, College of Dental Medicine. c Professor and Chair, Oral Medicine and Diagnostic Sciences, Nova Southeastern University, College of Dental Medicine. d Assistant Professor, Restorative Dentistry, Nova Southeastern University, College of Dental Medicine. Received for publication Apr 7, 2014; returned for revision Jul 1, 2014; accepted for publication Jul 13, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.07.007
Administration as a medical device. This designation is based on MuGard’s ability to form a thin adhesive coating on oral mucosal membranes, presumably protecting them from saliva and microorganisms. When started shortly before the institution of chemotherapy or radiotherapy for head and neck cancers (i.e., before the development of mucositis), MuGard lessened the severity of the developing mucositis and pain as compared to 2 published historical “controls,” (i.e., patients that did not receive MuGard treatment)3 and in a recent multicenter prospective randomized controlled trial (RCT).4 In the prospective multicenter study,4 the treated and placebo-treated patients started using MuGard immediately before antineoplastic therapy was initiated and then continued rinsing 4 times a day until they had received a cumulative radiation dose of 50 Gy to 72 Gy.4 Lichen planus is one of several autoimmune diseases that can be associated with oral mucosal inflammation, and when this occurs, it is termed erosive lichen planus.2 In light of the reported success of MuGard to slow the development and lessen the severity of the signs and symptoms of oral mucositis in patients receiving antineoplastic therapy,3,4 we instituted this small,
Statement of Clinical Relevance MuGard mouthwash safely and effectively reduces the signs and symptoms of oral mucositis in patients with oral lichen planus. However, studies are still needed to determine whether these benefits are lasting. 657
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double-blind, randomized, placebo-controlled pilot study to determine if MuGard might help ameliorate the signs and symptoms of oral mucositis in patients with lichen planus who already had established lesions, as opposed to determining if it could lessen the development of oral mucositis, as in the antineoplastic studies.3,4 The use of MuGard was not intended as a curative therapeutic intervention; it was used only as a palliative treatment, hoping to relieve the discomfort. The Oral Mucositis Assessment Scale (OMAS) was used to score mucosal inflammation rather than to characterize the participant’s lichen planus. Other scoring instruments are available to assess lichen planus. However, to remain consistent with previous protocols using MuGard, the OMAS scoring was used in this study. Three research hypotheses were formulated and tested. These were that (1) daily use of MuGard will significantly reduce the objective signs of oral mucositis (ulceration and erythema) in patients with lichen planus compared to controls over a 14-day treatment period; (2) daily use of MuGard will significantly reduce the subjective pain associated with oral mucositis in patients with lichen planus compared to controls during this same period; and (3) the reduction in subjective pain will correlate with objective reduction in ulceration and erythema in the MuGard-treated participants.
METHODS This was a randomized, double-blind, placebocontrolled pilot study. Patients with documented erosive oral lichen planus, diagnosed clinically and histologically, were recruited from the dental clinics at Nova Southeastern University College of Dental Medicine. All the participants manifested at least the typical bilateral buccal mucosa lesions with erosions and striae. Lichenoid reactions were ruled out as much as possible by means of clinical presentation, hematoxylin-eosin histopathology, and immunofluorescence. The inflammatory infiltrate was evaluated to ensure that it was composed purely of lymphocytes and that no plasma cells or other cell types were present, as found in lichenoid drug reactions and other forms of oral lichenoid lesions. The project was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee. Written informed consent was obtained from all participants before they were enrolled. Patients were excluded if they were already using other oral rinses to coat the mucosa or were taking systemic steroids or other immune suppressors. Infants and pregnant women were also excluded, because there
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have been no reports establishing the safety of MuGard in these cohorts. Treatment consisted of a teaspoonful (5 mL) of MuGard or saline-bicarbonate control (both provided by the manufacturer). Patients were instructed to swish the liquid in the mouth for 1 minute, 5 times per day, for 14 days. Excess MuGard can be swallowed or expectorated, as no safety issues have been reported. Patients were instructed not to eat or drink for 1 hour after using their assigned rinse. Two primary outcome measures were employed. The first was the Oral Mucositis Assessment Scale (OMAS), introduced by Sonis et al. (1999)5 and validated as a reliable research instrument for evaluating oral mucous inflammation. In the original OMAS protocol, the clinician rates the extent of ulceration (0-3) and erythema (0-2) in 9 intraoral locations. For our study, we added a tenth, the gingiva (Supplemental Appendix A; available at www.oooojournal.net.). Since ulceration and erythema are rated separately, the worse-case scenario would be a total ulceration score of 30 and a total erythema score of 20, yielding a total mucositis score of 50. This is indicated by the formula Overall Mucositis Score ¼
N X i¼1
Ui þ
N X
Ri;
i ¼1
where Ui is each individual ulcerative measure (0-3) and Ri is each individual redness measure (0-2) (n ¼ 10 for all cases). While these summated mucositis scores can be compared over the 4 time intervals, Sonis et al.5 introduced another calculation which converted these summed scores into Mean Mucositis Scores (MMSs) by dividing each of the summations by the number of sites, namely 10 in our study. The effect of this division makes the maximum MMS ¼ 5. Reports by Sonis et al.5 and Baud et al.3 used this system. The second primary outcome measure was a visual analog scale (VAS) in which patients subjectively rated the pain they were experiencing. Since pain due to mucositis is experienced at rest as well as on speaking and swallowing, patients rated their pain separately for all 3 conditions (Supplemental Appendices B-D; available at www.oooojournal.net.). We then calculated an averaged pain score by dividing the total of the 3 conditions by 3. Each of these measures was obtained by an investigator (blinded to each patient’s treatment group) at initial intake and then repeated on days 2, 7, and 14 after the initiation of treatment. Since the purpose of this pilot study was to begin gathering data on the possible benefits of using MuGard to reduce the signs and symptoms of existing oral mucosal inflammation, we arbitrarily chose to enroll 20
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patients, 10 for each group. This figure was chosen for 2 reasons. First, repeated-measures (within-participants) design reduces the variance of estimates of treatment effects, thereby reducing the number of participants needed for statistical inferences.6 Second, the figure was based on the availability of patients to complete data collection within a 12-month period. Our plan was to then use the results to form the statistical basis for a larger prospective RCT. We also arbitrarily chose a 14day treatment time. Blinding After the initial evaluation, a research assistant randomly allocated to each participant a 14-day supply of identical-looking coded bottles which contained either MuGard (10) or the saline-bicarbonate control (10). This resulted in a 1:1 allocation ratio. The coded bottles were supplied by the manufacturer, who did not divulge the code until all data had been collected. Thus, neither the patient nor the investigator performing the subsequent evaluations was aware of the treatment the patient was receiving. Statistical analyses At the end of all data collection, each patient’s raw scores were compiled into a spreadsheet (baseline, 2 days, 7 days, and 14 days). However, before breaking the code, descriptive statistics were determined for all the combined (n ¼ 20) baseline data (Table I). Following this, the code was broken so that the participants could then be placed into their assigned treatment categories. Because of the relatively small sample size (n ¼ 10 in each group), the initial MMS and VAS scores of the 2 groups were compared using the nonparametric Mann-Whitney test to determine if the 2 groups were statistically similar before treatments began (Table II). Following this, the Friedman test, which is a nonparametric equivalent of the repeated-measures analysis of variance, was used to determine whether either group changed statistically (for better or for worse) compared to its own baseline values. The number-needed-to-treat (NNT) to achieve 2 different endpoints was also determined. One endpoint was a greater than 50% reduction in pain from baseline, and the second endpoint was to achieve complete relief of pain.
RESULTS Between September 2012 and September 2013, 20 patients, 14 women and 6 men, aged 61.5 14.0 years, were enrolled and studied. Table I shows the descriptive statistics of the primary outcome measures for the entire sample (n ¼ 20) before randomization into MuGard and placebo groups.
ORIGINAL ARTICLE Velez et al. 659
Table I. Descriptive statistics before randomization (n ¼ 20) Variable Ulceration Erythema Total of above Mean Mucositis Score Pain at rest Pain on swallowing Pain on speaking Averaged pain
Mean SD
Range
0-13 2-18 2-29 0.2-2.9 0-9 0-10 0-10 0.67-9.5
5.5 5.5 11.0 1.1 4.8 5.4 6.3 5.5
3.2 3.8 6.7 0.67 3.2 2.9 2.5 2.5
Although pain at rest, on swallowing, and on speaking ascend in that order, the Friedman test (a nonparametric equivalent of the repeatedmeasures analysis of variance) showed no statistically significant differences between these conditions. Similarly, the averaged pain scores were not significantly different from any of the 3 conditions. Therefore, we used the averaged pain scores as an appropriate surrogate for the 3 conditions.
Table II. Primary outcome measures comparing the MuGard-treated and placebo-treated participants following randomization but before starting treatment Variable
MuGard group
Placebo group
P
Gender F ¼ 6, M ¼ 4 F ¼ 8, M ¼ 2 distribution Age (y) 63.2 15.0 59.8 13.5 NS Ulceration 5.7 2.7 (3-11) 5.5 3.7 (0-13) 1.0 Erythema 5.2 4.7 (2-18) 5.8 2.9 (2-12) .69 Total of above 10.9 7.4 (5-29) 11.3 6.5 (2-25) .82 Mean Mucositis 1.09 0.74 (0.5-2.9) 1.13 0.65 (0.2-2.5) .82 Score Pain at rest 5.4 3.17 (2-9) 4.3 3.27 (0-9) .45 Pain on 6.3 2.58 (0-10) 4.5 3.10 (0-10) .18 swallowing Pain speaking 7.0 2.0 (0-10) 5.55 2.87 (2-9.5) .21 Averaged pain 6.2 2.2 (2-9) 4.8 2.6 (0.67-9.5) .20
Table II presents the primary outcome measures for the 2 groups following randomization but before the start of treatment. As seen, the Mann-Whitney test yielded probabilities of >.05 that the null hypothesis was true (i.e., that there were no significant differences between the groups at baseline for any of the primary outcome measures). However, power analyses of the data yielded values from 0.22 to 0.26 (not shown), raising the possibility of a type II error and that patients in the MuGard-treated group were actually slightly more involved at baseline for all outcome measures than the placebo-treated group. We revisit this point later. Table III presents the changes in the MMSs and averaged pain scores from baseline to 14 days for both groups. The Friedman test showed that the MuGardtreated group experienced significant reductions (P < .001) in both primary outcome measures over this time interval, while the placebo-treated group showed essentially no changes over the same 14-day interval.
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Table III. Changes in primary outcome measures during intervention period Group Mean Mucositis Scores MuGard Placebo Averaged pain scores MuGard Placebo
Baseline
2 Days
7 Days
14 Days
P
1.09 0.74 1.13 0.65
0.94 0.76 1.13 0.71
0.64 0.76 1.11 0.71
0.55 0.72 1.12 0.70
<.0001 NS
6.2 2.2 4.8 2.6
3.9 3.2 4.8 2.8
1.3 1.8 5.1 3.2
1.4 1.8 4.9 2.8
<.0001 NS
NS, not significant.
Fig. 1. MuGard-treated participants experienced an average decrease of 50% in their normalized (compared to baseline) Mean Mucositis Scores (OMAS)*. Conversely, participants in the placebo-treated group experienced essentially no change over the same period. Normalized values at different times are shown. Error bars ¼ SEM. (OMAS, Oral Mucositis Assessment Scale; SEM, standard error of the mean.) *Mean Mucositis Scores equals the sum of the ulceration sand erythema scores divided by 10 (the number of intraoral sites evaluated in the clinical examination).
The data in Table III are redisplayed in Figures 1 to 3 but shown as normalized to their baseline values. These figures show graphically the percent differences over time between the MuGard and placebo-treated groups for the primary outcome measures of MMSs (Figure 1), averaged pain scores (Figure 2), and the association between pain, ulceration, and erythema (Figure 3). As seen, MMSs, which are the summation of the ulceration and erythema scores divided by 10, are reduced to 50% of their baseline values in the MuGardtreated group but are essentially unchanged in the placebo-treated group. However, even more dramatic is the drop in averaged pain scores in the MuGard-treated participants. In this group, the mean averaged pain fell by approximately 80%, while in the placebo-treated group there was again essentially no change. Further evidence for the efficacy of MuGard to reduce pain in ulcerative lichen planus is the fact that 4 of the 10 participants (40%) in the MuGard-treated group reported no pain at the end of 14 days. Of the remaining 6 participants in this group, the smallest reduction in pain was 20% (1 participant); a second participant’s pain dropped by 38%; and the pain
Fig. 2. MuGard-treated participants experienced a decrease of normalized averaged pain of approximately 79% in the first 7 days, and this was maintained for the next 7 days. Placebotreated participants experienced essentially no changes from baseline over this same period. Normalized values at different times are shown. Error bars ¼ SEM. (SEM, standard error of the mean.)
of the other 4 fell by 71% to 80%. Conversely, in the placebo group, 8 participants (80%) reported no change in pain over the 14 days; another dropped by only 23%; and the greatest drop was by 44% (1 participant). Therefore, 80% of participants in the MuGard-treated group reported a >50% decrease in pain, whereas none in the placebo-treated group achieved this value. Using these percentages to dichotomize those who did or did not decrease their pain scores by >50% in each group, we obtain an NNT of 1.25. This means essentially that just 1 patient with ulcerative oral lichen planus has to be treated by MuGard compared with placebo to obtain a reduction in pain >50% compared to baseline over a 14-day period. Similarly, to achieve complete relief of pain, the NNT is 2.5. Figure 3 also shows that the decrease in pain in the MuGard-treated group is closely associated with the decrease in ulceration but less so with the decrease in erythema. Correlating normalized pain scores with normalized ulceration scores from baseline to 14 days in the MuGard-treated group yielded an r value of 0.98, a P value of .024, and an r2 value of 0.95. This means that 95% of the variation in the pain scores from baseline to 14 days is “accounted for” by the variation in the ulceration scores over the same period. Conversely, although correlating normalized pain with normalized erythema yielded an r value of 0.88, the
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Fig. 3. Showing that changes in pain are more closely associated with changes in ulceration than with changes in erythema. This suggests that MuGard affects ulceration more than it affects erythema.
Fig. 4. Normalized pain scores in the MuGard-treated group, showing that pain in all 3 conditions (rest, swallowing, and speaking) fell by similar amounts over the 14 days of treatment. This indicates that the drop in the averaged pain score was not due to one condition being more favorably affected than the others.
P value was .115, which is not significant. It is apparent, then, that MuGard treatment affects ulceration more than erythema, and it is the reduction in ulceration that is most closely correlated with the reduction in pain. Figure 4, which also shows normalized pain scores, shows that the drop in averaged pain experienced by the MuGard group was not due to a selective decrease in one or another of the 3 pain conditions (rest, swallowing, or speaking); rather, in essence, the pain experienced under all 3 conditions improved similarly. This finding further justifies using the averaged pain scores as a surrogate for the 3 separate scores. All participants who were entered into the study completed the study, and no adverse events were reported.
DISCUSSION MuGard has been shown to minimize (but not eliminate) the development of oral mucositis in patients undergoing chemotherapy, radiation therapy, or both during cancer therapy.3,4 In those studies, MuGard treatment was instituted prophylactically before the antineoplastic treatment began, and the investigators
ORIGINAL ARTICLE Velez et al. 661
then compared the development and severity of the signs and symptoms of oral mucositis. Our study differed not only with respect to the condition being treated (i.e., erosive oral lichen planus) but also because our patients presented with already-established signs and symptoms. Our goal was to determine if MuGard is effective in reducing signs and symptoms that were already present. Using the OMAS, a recognized research tool for oral mucosal inflammation associated with antineoplastic therapy,5 this pilot study produced encouraging results. They show that ulceration (as determined by an examiner) and pain (as experienced by the patient at rest, on swallowing, and on speaking) were reduced significantly over the 14 days of treatment. Pain was especially reduced and was highly correlated with the reduction in ulceration. Erythema was the least improved but was still less than at baseline. No statistically significant changes from baseline occurred in the placebo-treated group. A major limitation of our study, though, is the fact that unlike oral mucositis secondary to antineoplastic therapy, erosive oral lichen planus is an autoimmune disease, for which topical corticosteroids and calcineurin inhibitors are frequently used immunosuppressive therapeutic agents. While a head-to-head study comparing MuGard to these agents is in order, we endeavored in the meantime to get some idea of how our findings compare with those of studies that contributed to the use of these immunosuppressive agents. To do this, we identified studies since 1993 that used the 10-centimeter VAS (as we did) to record subjective levels of pain as a primary outcome measure.7 Our summary follows. We also point out that while these studies used the VAS, none mentioned whether the pain that the patients were asked to rate was their pain at rest, on swallowing, or on speaking. Apparently, patients were simply asked to “rate their pain” without any other directions (for contrast, see our Supplemental Appendices B-D; available at www.oooojournal.net.). Therefore, which pain these patients considered in their ratings is unknown. However, given that our study also showed that there was no statistically significant difference between pain ratings during the 3 conditions, we compare our averaged pain scores to those of these reports. Voute et al. (1993)8 compared fluocinonide 0.025% in an adhesive gel (n ¼ 20) to the placebo gel (n ¼ 20). After 9 weeks of treatment, 13 patients in the experimental group had complete remission of symptoms, and 6 in the placebo group also did. The authors did not present an NNT analysis, but with the information given, we calculate an NNT of 2.8 to obtain complete relief of pain compared to control. In our study, the NNT for complete relief was 2.5, but after just 2 weeks.
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Sardella et al. (1998)9 compared 5% mesalazine (n ¼ 11) to 0.05% clobetasol propionate (n ¼ 14). After 4 weeks, there was no statistically significant difference between the groups with respect to reports of complete relief, partial relief, or no relief (of pain/ discomfort). However, from a table of raw data given in the article, one can calculate that at baseline, the mean pain score for the entire group of 25 was 5.8 3.0 (similar to our entire group at baseline), which then dropped to 1.8 2.4, which is similar to the final averaged pain score in our MuGard group of 1.4 1.8 (which was achieved after just 2 weeks). Hegarty et al. (2002)10 compared fluticasone propionate spray to betamethasone sodium phosphate mouthrinse. From the little data given in Table II, we calculate that after 6 weeks the fluticasone group’s pain had dropped to 56% of baseline and that it had dropped to 70% of baseline for the betamethasone group. Both these final values are much poorer improvements than the drop to approximately 20% of baseline achieved by our MuGard-treated group after just 2 weeks. Campisi et al. (2004)11 compared 0.025% clobetasol delivered by a “new” delivery system (n ¼ 18) to the “conventional” formulation for delivering the drug (n ¼ 27). VAS scores were obtained at baseline, after 1 month, and after 2 months. Both groups were statistically similar at baseline, and pain in both groups decreased significantly. However, pain in the “new” formulation group decreased significantly more than in the conventional group. Although the article does not indicate how many (if any) patients obtained complete relief of pain, from the data given we see that pain in the “new” formulation group dropped to 16% of its baseline value, whereas in the conventional group it dropped to 48% of its baseline value. In our MuGard-treated patients, pain dropped to approximately 20% of the baseline value, which compares well with the drop to 16% of baseline experienced in the “new” formulation group in this study and is considerably better than the drop experienced by the “conventionally” treated group. Conrotto et al. (2006)12 compared 1.5% ciclosporin (n ¼ 20) to 0.025% clobetasol (n ¼ 19). Although VAS scores were obtained at baseline and then every 2 weeks during the 2 months of treatment, no VAS scores are given in the article. Instead, the authors categorize their findings as either “complete response,” “partial response,” or “no response.” The criteria used for determining “partial response” were not given. However, the authors concluded that there was no statistically significant difference between the groups with respect to the 3 categories after 2 months of treatments. From the data given in Table III, we
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see that 42% of patients in the clobetasol group achieved complete relief of pain, whereas 20% of patients in the ciclosporin groups attained this relief. In our study, 40% of MuGard-treated patients were pain-free after just 2 weeks. Choohakarn et al. (2008)13 compared aloe vera (n ¼ 27) to placebo gel (n ¼ 27). VAS scores were statistically similar at baseline. After 8 weeks of treatment, the authors categorized their findings as “complete response,” “good response,” poor response,” or “no response.” The authors clearly stated the VAS criteria used to form these categories. The aloe vera group did better than the placebo group. From the data given in Table III, we calculated an NNT of 3.4 to obtain complete relief compared with placebo after 8 weeks. In our study, we found an NNT of 2.5 after 2 weeks. Similarly, to achieve a >50% reduction in pain, the NNT for the aloe vera group is 1.2, which is the same as our 1.25, but again after just 2 weeks instead of 8. Swift et al. (2008)14 compared 1% pimecrolimus cream (n ¼ 10) to a placebo cream (n ¼ 10). After 4 weeks, the experimental group dropped from a baseline mean VAS score of 3.33 2.68 down to 2.08 2.29. The placebo group did not change. The authors state that this average value at the end of 4 weeks for the experimental group was significantly different from baseline, but the authors also report that at the end of 2 weeks, the average score was not significantly different from baseline. Therefore, our MuGard-treated participants achieved significantly lower pain scores at the end of just 2 weeks, compared to 1% pimecrolimus cream, which required 4 weeks. Radfar et al. (2008)15 compared 0.1% topical tacrolimus (n ¼ 15) with 0.05% clobetasol (n ¼ 15) for a total of 6 weeks (both groups also taking nystatin oral rinse). Although pain in both groups decreased significantly from baseline, there was no significant difference between the groups. Because of this nonsignificant difference between the groups either at baseline or during the study, the authors grouped the ‘before’ and ‘after’ findings together. From their Table III, we see that at the end of 2 weeks, there was no significant change from baseline, but at the end of 6 weeks, the decrease in mean pain was significant. However, from the data given, we also calculate that although the pain had dropped significantly, it was still 55% of its original value, compared to the drop of almost 80% in our MuGard-treated participants in just 2 weeks. Therefore, based on these findings, MuGard achieved more averaged pain relief than either tacrolimus or clobetasol.
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Carbone et al. (2009)16 compared 2 different concentrations of clobetasol, 0.025% (n ¼ 15) and 0.05% (n ¼ 15). The 2 groups had similar mean pain scores at the beginning, and both groups decreased significantly from baseline after 2 months. From the data given, we calculate that the 0.025% group dropped to 22% of its baseline pain score, while the 0.05% group dropped to 17% of its baseline value. These drops are similar to the drop for our MuGard-treated group, which dropped to approximately 20% of its baseline value, but again, this was achieved in just 2 weeks. Jajarm et al. (2011)17 compared low-intensity laser therapy (LILT) (n ¼ 11) to a group receiving a dexamethasone mouthrinse along with nystatin (n ¼ 13). The groups were statistically similar at baseline, and over 1 month both groups improved significantly from baseline, but not with respect to each other. From the data given in Table II, we calculated that pain scores in the LILT group decreased to 16% of baseline, and the dexamethasone group decreased to 17% of baseline. These values are similar to those of our MuGard-treated group, which decreased to almost 20% of baseline. In summary, although this indirect comparison between MuGard and topical immunosuppressant in reducing the pain experienced in erosive oral lichen planus does not substitute for a head-to-head RCT, it certainly indicates that such a comparative study, or a variant thereof, is warranted. It is important to bear in mind that no secondary therapeutic effect of MuGard has been studied or identified via our protocol. A second limitation of this study is its small sample sizes (10 in each group), but this was only a pilot study designed to form the basis for a larger RCT. And indeed, it could be argued that owing to this small sample size, the treatment group and placebo groups may not have been equivalent on their outcome measures at baseline (as we stated earlier). However, we point out that this possible nonequivalence at baseline (i.e., the MuGard group being perhaps more severely involved than the placebo group) makes the changes in the MuGard-treated group even more impressive, given that at the end of treatment, the MuGard-treated participants clearly had better results than those who received the placebo treatment. A third limitation of this study is the absence of a quality-of-life questionnaire. The latter would have given us some insight into the effect of the pain reductions on day-to-day living, which is clearly an important issue to patients.1 Furthermore, because of the short time span of this study (2 weeks of treatment), we do not know what the effect of continued treatment would have been, nor do we know if the benefits observed in the MuGard-treated group were long-lasting.
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CONCLUSION Given the limitations discussed, our findings and the comparison to other immunosuppressive therapies justify future studies employing larger sample sizes, longer duration of treatment and follow-up, and head-to-head comparison with treatments that are currently in use. REFERENCES 1. Alvarado Y, Bellm LA, Giles FJ. Oral mucositis: time for more studies. Hematology. 2002;7:281-289. 2. Chi AC, Neville BW, Krayer JW, Gonsalvez WC. Oral manifestations of systemic disease. Am Fam Physician. 2010;82: 1381-1388. 3. Baud CM, Colon LE, Busse PM, Rana T, Talentowski D, Gerberich JL, Nowotnik DP, Howell SB. Protection from radiationinduced oral mucositis by MuGard oral rinse: a clinical study and in silico analysis. MASCC/ISOO International Symposium, Toronto, Canada, 2006. 4. Allison RR, Ambrad AA, Arshoun Y, et al. Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck. Cancer. 2014;120:Available at: http://onlinelibrary.wiley.com/doi/10.1002/cncr.28553/full: Accessed March 12, 2014. 5. Sonis ST, Ellers JP, Epstein JB, et al. Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Cancer. 1999;85:2103-2113. 6. Howitt D, Cramer D. Introduction to Research Methods in Psychology. 3rd ed. Harlow, Essex, England: Pearson Education Limited; 2011:164, 170-181. 7. Cheng S, Kirtschig G, Cooper S, Thornhill M, Leonardi-Bee J, Murphy R. Interventions for erosive lichen planus affecting mucosal sites [review]. Cochrane Database Syst Rev. 2012;2: CD008092. 8. Voute ABE, Schulten E, Langendijk PNJ, Kostense PJ, van der Waal I. Fluocinonide in an adhesive paste for treatment of oral lichen planus: a double-blind, placebo-controlled clinical study. Oral Surg Oral Med Oral Pathol. 1993;75:181-185. 9. Sardella A, Demarosi F, Oltolina A, Rimondini L, Carrassi A. Efficacy of topical mesalazine compared with clobetasol propionate in the treatment of oral lichen planus. Oral Dis. 1998;4: 255-259. 10. Hegarty AM, Hodgson TA, Lewsey JD, Porter SR. Fluticasone propionate spray and betamethasone sodium phosphate mouthrinse: a randomized crossover study for the treatment of symptomatic oral lichen planus. J Am Acad Dermatol. 2002;47: 271-279. 11. Campisi G, Giandalia G, De Caro V, Di Liberto C, Arico P. A new delivery system of clobetasol-17-propionate (lipid-loaded microsphere 0.025%) compared with conventional formulation (lipophilic ointment in a hydrophilic phase 0.025%) in topical treatment of atrophic/erosive oral lichen planus: a phase IV, randomized, observer-blinded, parallel group clinical trial. Br J Dermatol. 2004;150:984-990. 12. Conrotto D, Carbone M, Carrozzo M, et al. Ciclosporin vs. clobetasol in the topical management of atrophic and erosive oral lichen planus: a double-blind, randomized controlled trial. Br J Dermatol. 2006;154:139-145. 13. Choonhakarn C, Busarcome P, Sripanidkulcha B, Sarakarn P. The efficacy of aloe vera gel in the treatment of oral lichen planus: a randomized controlled trial. Br J Dermatol. 2008;158:573-577.
ORAL MEDICINE 664 Velez et al. 14. Swift JC, Rees TD, Piemons JM, Hallmon WW, Wright JC. The effectiveness of 1% pimecrolimus cream in the treatment of oral erosive lichen planus. J Periodontol. 2005;76: 627-635. 15. Radfar l, Wild RC, Suresh L. A comparative treatment study of topical tacrolimus and clobetasol in oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008;105: 187-193. 16. Carbone M, Arduino PG, Carrozzo M, et al. Topical clobetasol in the treatment of atrophic-erosive oral lichen planus: a randomized controlled trial to compare two preparations with different concentrations. J Oral Pathol Med. 2009;38:227-233. 17. Jajarm HH, Falaki F, Mahdavi O. A comparative pilot study of low intensity laser versus topical corticosteroids in the treatment
OOOO December 2014 of erosive-atrophic oral lichen planus. Photo Med Laser Surg. 2011;29:421-425. Reprint requests: Neil I. Spielholz, PT, PhD Oral and Maxillofacial Pathology Nova Southeastern University College of Dental Medicine 3200 S University Dr Fort Lauderdale FL 33328 USA [email protected]
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SUPPLEMENTAL APPENDIX A. ORAL MUCOSITIS ASSESSMENT SCALE (ADAPTED FROM SONIS ET AL., 1999) Patient ID: Date of evaluation: Location Upper lip Lower lip Right cheek Left cheek Right ventral & lateral tongue Left ventral & lateral tongue Floor of mouth Soft palate/fauces Hard palate Gingiva
Ulceration (circle) 0 0 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2
Erythema (circle) 3 3 3 3 3 3 3 3 3 3
0 0 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2
Grading key:
Ulceration
Erythema 0 ¼ none 1 ¼ not severe 2 ¼ severe
Presence of infection (circle): If yes, (circle):
0 ¼ no lesion 1 ¼ <1 cm2 2 ¼ 1 cm2 to 3 cm2 3 ¼ >3 cm2 Yes Local non-oral
No Systemic
SUPPLEMENTAL APPENDIX B. VISUAL ANALOG SCALE FOR PAIN AT REST Patient ID: Date: Instructions: You are being asked to rate the severity of the pain that you are experiencing now, while at rest. To help you do this, consider the horizontal line below. If the left-hand end is “No pain at all” (as indicated by the zero) and the right-hand end is “The worst pain I can imagine” (as indicated by the number 10), please place a vertical line on the horizontal line where you think your pain is located. j—————————————————————————————————————j 0 10 (No pain at all) (Worst pain I can imagine) SUPPLEMENTAL APPENDIX C. VISUAL ANALOG SCALE FOR PAIN ON SWALLOWING Patient ID: Date: Instructions: You are being asked to rate the severity of the pain that you have when swallowing. To help you do this, consider the horizontal line below. If the left-hand end is “No pain at all” (as indicated by the zero) and the righthand end is “The worst pain I can imagine” (as indicated by the number 10), please place a vertical line on the horizontal line where you think your pain is located when you swallow. You may swallow some saliva before making your mark. j————————————————————–————————————————j 0 10 (No pain at all) (Worst pain I can imagine)
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SUPPLEMENTAL APPENDIX D. VISUAL ANALOG SCALE FOR PAIN ON SPEAKING Patient ID: Date: Instructions: You are being asked to rate the severity of the pain that you have when speaking. To help you do this, consider the horizontal line below. If the left-hand end is “No pain at all” (as indicated by the zero) and the right-hand end is “The worst pain I can imagine” (as indicated by the number 10), please place a vertical line on the horizontal line where you think your pain is located when you speak. You may speak a few words before making your mark. j——————————————————————————————————————j 0 10 (No pain at all) (Worst pain I can imagine)