Original Article The Effectiveness of Vitamin B12 for Relieving Pain in Aphthous Ulcers: A Randomized, Double-blind, Placebo-controlled Trial ---

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From the *Department of Nursing, Central Taiwan University of Science and Technology, Taichung, Taiwan; † Feng-Yuan Hospital Department of Health, Taichung, Taiwan. Address correspondence to Shu-Chin Chiu, RN, Feng-Yuan Hospital Department of Health, Taichung, Taiwan. E-mail: smileface0108@ gmail.com

Hsin-Li Liu, RN, MSN,* and Shu-Chin Chiu, RN†

ABSTRACT:

Aphthous ulcers, the most common oral mucosal lesions seen in primary care, occur in up to 2%-50% of the general population. Our objective was to confirm the analgesic benefit of treatment of mouth ulcers with vitamin B12 as adjunctive therapy. A randomized, doubleblind, placebo-controlled trial was performed with primary care patients. The intervention group received vitamin B12 ointment for 2 days. In total, 42 patients suffering from aphthous ulcers participated in the study: 22 were included in the intervention group and 20 in the control group. All parameters of aphthous ulcers of patients in the intervention group were recorded and compared with those in the control group. We assessed the patients’ pain levels before and after treatment using a visual analog scale. The statistical analyses were performed using a nonparametric Mann-Whitney test. Statistically significant differences in pain levels were found between the intervention group and the control group after 2 days of treatment (mean visual analog scale, 0.36 [95% CI, 0.01-0.71] vs. 1.80 [1.16-2.44]; p < .001). In conclusion, the results of this research study provide evidence that vitamin B12 is an effective analgesic treatment for aphthous ulcers. This study indicates that healthcare providers could use vitamin B12 as an adjunctive therapy for mouth ulcers, providing more effective pain management and improving the quality of life for patients with mouth ulcers. Ó 2015 by the American Society for Pain Management Nursing

Received April 18, 2014; Revised June 8, 2014; Accepted June 9, 2014. 1524-9042/$36.00 Ó 2015 by the American Society for Pain Management Nursing http://dx.doi.org/10.1016/ j.pmn.2014.06.008

BACKGROUND Aphthous stomatitis, also known as canker sores, is one of the most common oral mucosal inflammatory ulcerative diseases worldwide. The aphthous ulcer is characterized by localized, shallow, rounded, painful, small, clean borders; a Pain Management Nursing, Vol 16, No 3 (June), 2015: pp 182-187

B12 for Pain Control of Aphthous Ulcers

peripheral erythematous halo; and a yellow or grayish base. Aphthous ulcers usually occur in recurrent bouts at intervals of a few days to a few months (Porter et al. 2000; Porter et al. 1998; Ship et al. 2000) with three typical presentations: minor, major, or herpetiform ulcers. Minor aphthous ulcers are the most common form; these present as small (1 cm in diameter). Healing of this form of ulcer may take 20-30 days or longer than minor aphthous ulcers and often results in scarring (Scully & Porter, 2008). The third and least common recurrent aphthous ulcers are herpetiform ulcers, which present as multiple small and painful ulcers, together with clusters of pinpoint lesions, and often occur in multiples of 1-100, each 2-3 mm in diameter. The ulcers tend to fuse, producing large irregular ulcers (Porter et al., 1998; Scully 2006). Epidemiologic studies indicate that recurrent aphthous ulcers are prevalent worldwide and may affect 2%-50% of the general population, with most estimates being 5%-25% and with 3-month recurrence rates of up to 50% (Rees & Binnie, 1996; Scully & Porter, 2008). The cause of aphthous ulcers remains unknown; however, contributing factors include systemic diseases, nutritional deficiencies, food allergies, genetic predisposition, immune disorders, medications, human immunodeficiency virus infection, and the environment (Porter et al., 1998, 2000). Nutritional deficiencies or hematologic diseases have been documented in 20% of patients with recurrent aphthous ulcers (Nolan, McIntosh, Allam, & Lamey, 1991). Patients with recurrent aphthous ulcers who are treated by physicians for deficiencies in iron, folate, and vitamin B12 exhibit a 71% improvement in aphthous ulcers after replacement therapy (Olson, Feinberg, Silverman, Abrams, & Greenspan, 1982; Piskin, Sayan, Durukan, & Senol, 2002). Several vitamin B12 (cobalamin) treatments for recurrent aphthous ulcers aim to decrease the pain, healing time, and ulcer number and size and increase the frequency and duration of disease-free periods. Vitamin B12 may play an important role in the treatment of aphthous ulcers. The most common cause of vitamin B12 deficiency is food-cobalamin malabsorption resulting from gastric dysfunction (Dholakia et al., 2005). The prevalence of vitamin B12 deficiency increases with age and is highest among elderly individuals (>65 years old) (Dali-Youcef & Andres, 2009). Studies of the impact of age suggest a high prevalence of subnormal cobalamin concentrations (Dali-Youcef & Andres, 2009; Porter et al., 1998), and an inverse

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relationship between age and serum cobalamin concentration has been found in some reports (Allen, 2009). Burgan et al. investigated 143 patients experiencing recurrent aphthous stomatitis and found that 26.6% had a demonstrated B12 deficiency, in contrast to 12.6% of the control patients (Burgess & Haley, 2008). Piskin et al. (2002) reported that 35 patients with recurrent aphthous ulcers had vitamin B12 levels significantly lower than those of the 26 healthy control patients, whereas no significant differences were reported in the other hematologic factors measured. Volkov et al. (2009) used a randomized, double-blind, placebo-controlled trial to confirm the effectiveness of vitamin B12 in the treatment of recurrent aphthous ulcers. The study suggested that a 1000-mg daily dose of vitamin B12 dissolved under the tongue might prevent aphthous ulcers after 5-6 months of use. Such rapid relief has been termed the master key effect (Volkov, Press, & Rudoy, 2006). It is therefore suggested that high levels of vitamin B12 reduce the incidence of mouth ulcers (Volkov, Rudoy, Abu-Rabia, Masalha, & Masalha, 2005). Aphthous ulcers are sores that can occur anywhere inside the mouth, and this painful oral mucosal inflammatory ulcerative condition can often affect daily life activities such as eating, swallowing, and speaking (Tabolli et al., 2009). In the present study, we conducted a randomized, double-blind, placebocontrolled trial to determine the usefulness of vitamin B12 for relief of ulcer pain. Our objective was to confirm the analgesic benefit of the treatment of mouth ulcers with vitamin B12 as adjunctive therapy.

METHODS Eligibility Criteria Adult patients older than 18 years who had been suffering from aphthous ulcers and who were referred by physicians for inclusion in this study were evaluated. We excluded patients who had known systemic diseases concurrent with lesions in the mouth (Behc¸et’s disease, rheumatoid arthritis, lupus, and acquired immune deficiency syndrome), had received other concurrent treatment for aphthous ulcers, were pregnant or nursing, had Leber’s optic atrophy, suffered from psychosis, or had a known vitamin B12 deficiency. The intervention group received vitamin B12 ointment. Each oral ointment box contained 500 mg of vitamin B12, triamcinolone acetonide 0.1%, and natural cherry flavor; the weight of each box of ointment was 2 mg. The control group received placebo oral ointment (containing the same ingredients except for

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the vitamin B12). The two types of ointments and boxes were of identical shape, size, color, and flavor. The research was conducted between March 2012 and December 2013 in central Taiwan (the Taichung urban region) at a government hospitalsponsored dental clinic. At the baseline appointment, candidates received full written and verbal information about the study and possible side effects of treatment. The subjects completed the following steps: (a) Written, signed informed consent was obtained from each patient willing to participate in a protocol approved by the Research Review Board, Feng Yuan Hospital, Taichung, Taiwan. (b) Complete medical and dental histories were taken. (c) A routine clinical examination was performed, with special attention to the current ulcer. (d) An oral ointment was applied to the ulcer by the examiner and was explained to the patient by a dental physician. Procedures A research assistant in the clinical dental department recruited participants for 8 hours daily during the study period. Once consent had been obtained, baseline data and study measurements were recorded. Participants were randomly divided by computer-generated batch numbers into two groups: an intervention group and a control group. The physicians and the participants were blind to the group assignment until the end of the study. A detailed personal and ulcer assessment questionnaire was filled out by the dental physician; this included questions regarding the site of the ulcer, size of the ulcer, type of ulcer, ulcer history (number of ulcers experienced in the previous year), previous treatment, and medications received by a dental nurse. A package that contained one box of four doses per day was administered to each patient (qid) for 2 days. Subjects were asked to report whether the oral ointment reduced pain while in place. The research assistant was blind to the group assignments. The intervention group received treatment for 1 week. A visual analog scale (VAS) was used to evaluate pain. The VAS is an extensively used self-reporting device for pain measurement. The VAS in this study comprised a 10-cm horizontal line between poles connoting no pain (origin) to unbearable pain. Although the VAS adopted for this study was horizontal, some VAS scales are blank on one side and numerically labeled on the other side, with ‘‘no pain ¼ 0’’ on one end and ‘‘unbearable pain ¼ 10’’ on the other end. The VAS represents a continuum of pain intensity and is used to assess the level of pain at the time of reporting. The patient only sees the side with the single horizontal line with a no pain label at one end and an unbearable label at the other end. Subjects were told

to mark a vertical line at the point that best represented the present pain level of the ulcer. The research assistant recorded their baseline pain score using a VAS before patients were randomly assigned to the groups and after 2 days of treatment. Statistical Analysis Statistical analyses were performed using the SPSS version 18 statistical software package (SPSS, Inc., Chicago, IL, USA). Descriptive data were organized as medians or means with standard deviations for continuous variables and percentages for categorical data. The c2 test and Fisher’s exact test were used to compare categorical data. Continuous variables were expressed as means and standard deviation if normally distributed and compared by analysis of variance. The nonparametric Mann-Whitney test was used to compare the measurements of treatment effectiveness among the patients in the intervention and control groups, and their 95% confidence intervals (CI) were calculated for analysis. A p value of # .05 was considered to indicate statistical significance.

RESULTS Patient Recruitment and Baseline Characteristics Sixty-eight patients suffering from aphthous ulcers were referred by their physicians; 42 of these patients fulfilled the inclusion and exclusion criteria, agreed to participate, and were included in the study. The main reasons for patient unwillingness to participate were disagreeing with the possibility of being included in the control group and already undergoing aphthous ulcer treatment for 2 days. Twenty-two patients were randomly assigned to the intervention group and 20 to the control group. Table 1 shows the sociodemographic characteristics of the intervention and control groups. No statistically significant differences were found between the groups in terms of sex, age, marital status, education, cause of ulcer, ulcer size, number of ulcers in the past year, and type of ulcer. No abnormal laboratory values at study entry were found in either group. Comparison of Pain in the Treatment Groups Overall, patients experienced improvement in pain from baseline levels over the course of the study (Table 2). There was no significant difference in the change in pain score between the intervention and control groups before randomization (mean VAS, 5.73 [95% CI, 5.29-6.16] vs. 5.10 [4.20-6.00]; p ¼ .60). Statistically significant differences were found in pain levels between the intervention and control groups after 2

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B12 for Pain Control of Aphthous Ulcers

TABLE 1. Sociodemographic and Basic Clinical Characteristics of Population Intervention Group (n ¼ 22)

Control Group (n ¼ 20)

n (%)

n (%)

Gender Male 4 (18.2%) Female 18 (81.8%) Age (years) Mean (SD) 49.36 (16.03) Range 24  86 Marital status Single 1 (4.5%) Married 18 (81.8%) Widow 1 (4.5%) Education Primary school 2 (9.1%) High school 16 (72.8%) Academic 4 (18.2%) Cause of aphthous ulcer Unknown 12 (54.5%) Accident 10 (45.5%) Aphthous ulcer size (mm) Mean [95% CI] 6.95 [3.39-10.52] Number of aphthous ulcers in 1 year (frequency) Mean [95% CI] 1.82 [0.66-2.98] Type of aphthous ulcer Minor 16 (72.7%) Major 4 (18.2%) Minor clusters (herpetiform) 2 (9.1%)

8 (40.0%) 12 (60.0%) 56.30 (13.22) 39  81 3 (13.6%) 17 (77.3%) 2 (9.1%)

p .18* .14† .53‡

.25‡

2 (10.0%) 18 (90.0%) 0 (0%) .76* 12 (60.0%) 8 (40.0%) 5.50 [4.19-6.81] 2.43 [0.86-3.14]

.45† .42† .10‡

16 (80.0%) 0 (0%) 4 (20.0%)

CI ¼ confidence interval. *Fisher’s exact test. † Analysis of variance. ‡ 2 c test.

days of treatment (mean VAS, 0.36 [95% CI, 0.01-0.71] vs. 1.80 [1.16-2.44]; p < .001).

DISCUSSION Results of this double-blind, placebo-controlled study conducted with primary care patients indicate that vitamin B12 treatment as adjunctive care is associated

with a decreased level of pain caused by an aphthous ulcer and that vitamin B12 may significantly reduce the intensity of pain during healing. This outcome did not depend on initial blood vitamin B12 concentrations. Burgess and Haley (2008) conducted a trial in which patients were treated with 30 500-mg discs before sleep; these were exposed to saliva via adherent

TABLE 2. Pain Level before Randomization and after Treatment

Before level of pain Mean [95% CI] After level of pain Mean [95% CI] VAS ¼ visual analog scale. 95% CI: 95% confidence interval.

Intervention Group (n ¼ 22)

Control Group (n ¼ 20)

5.73 [5.29-6.16]

5.10 [4.20-6.00]

0.36 [0.01-0.71]

1.80 [1.16-2.44]

p .60

The Effectiveness of Vitamin B12 for Relieving Pain in Aphthous Ulcers: A Randomized, Double-blind, Placebo-controlled Trial.

Aphthous ulcers, the most common oral mucosal lesions seen in primary care, occur in up to ∼2%-50% of the general population. Our objective was to con...
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