Treatment Strategies for Recurrent Oral Aphthous Ulcers

Disclosures

Am J Health Syst Pharm. 2001;58(1) 

In This Article

Treatment Selection

Before initiating medications for RAU, clinicians should determine whether well-recognized causes are contributing to the disease. Screening tests for allergies and nutritional deficiencies should be performed, and the roles of stress and trauma should be assessed. Skin-patch tests for allergies to food additives, flavoring agents, and essential oils may be helpful. A gluten-free diet has shown success in reducing RAU episodes, both in the presence and in the absence of celiac disease.[5] Hematologic testing should be considered in patients with a history of RAU exceeding six months, since patients with nutritional deficiencies respond well to replacement therapy. Stress may play a significant role in the development and recurrence of aphthous ulcers; relaxation and imagery training has produced significant reductions in ulcer frequency.[1]

An undefinable disease cause and unpredictable disease course in most patients make patient education about the goals of therapy essential. The primary goals are to control the local pain, reduce the duration of the ulcers, and restore normal oral function. Secondary goals are to decrease the frequency and severity of recurrences and ultimately to keep the patient in remission.

The American Academy of Oral Medicine (AAOM) has recommended topical treatments for oral conditions.[4] Topical medications include anesthetics, antihistamines, antimicrobials, and anti-inflammatory agents. However, evidence of successful use of these agents for aphthous ulcers is primarily anecdotal. Of the medications listed by AAOM, only corticosteroids have been studied in well-designed clinical trials in patients with RAU.

Topical agents address the primary goals of RAU therapy, including reduction in ulcer pain and duration, while decreases in ulcer frequency and prolongation of remission remain elusive. In limited trials, tetracycline mouth rinse, betamethasone gel, beclomethasone spray, and amlexanox significantly reduced ulcer duration and pain. In contrast, chlorhexidine mouthwash had no significant effect on ulcer pain or duration in most studies.

Tetracycline mouthwash had no adverse effects when its use was limited to five days; however, extended use may predispose patients to oral fungal infections. After two weeks of therapy, chlorhexidine mouthwash caused brown staining of teeth and oral mucosa. This adverse effect may be especially problematic in RAU patients who repeatedly use the mouth-wash for symptomatic relief.

The impact of topical betamethasone and beclomethasone on the hypothalamic- pituitary-adrenal (HPA) axis was not assessed during any of the trials. Fluocinonide gel applied to the oral mucosa in patients with erosive lichen planus had no effect on serum or urine cortisol levels over a three-week period. However, cases of HPA axis suppression have resulted from unregulated use of long-acting, highly potent topical corticosteroids.[47,48] Therefore, extended use of these products in patients with RAU requires monitoring for HPA axis suppression.

Amlexanox produced significantly higher rates of complete ulcer healing and complete resolution of pain than placebo vehicle. The ability of amlexanox to reduce ulcer frequency was not examined because the studies lasted only 4-10 days. However, in view of its antiallergic, anti-inflammatory mechanism of action, amlexanox would not be expected to affect ulcer frequency or keep patients in remission. Amlexanox is among the least expensive of the topical medications for RAU (Table 3).

Oral corticosteroids are indicated only in severe cases of major RAU,[1,14] after an inadequate response to topical corticosteroid therapy,[14] or in the presence of nonoral (i.e., esophageal and colonic) aphthae, as seen in Behçet's syndrome. Oral corticosteroid use for aphthous ulcers has not been studied in controlled clinical trials; instead, information comes from case reports.[1,14] Recommendations include giving oral prednisone 40-60 mg/day for four to seven days 14 and then tapering the dosage over two weeks.[1] Adverse reactions to systemic corticosteroid therapy in patients with HIV include cushingoid facies, thrush, reactivation of herpes simplex virus, and accelerated progression of Kaposi's sarcoma.[14] Such adverse events place oral corticosteroids among the last treatment options for RAU in HIV-seropositive patients.

Levamisole reduced the frequency and duration of aphthae in five of seven studies when administered either at the first sign of ulceration or routinely for several days every one to two weeks. Subjective improvement was found in six of the studies. However, the reductions in pain often did not parallel the reductions in frequency and duration. Most of the trials neglected to exclude concurrent medications used in managing aphthae, which may have contributed to the disparity between subjective and objective findings. Levamisole yielded remissions lasting at least six months in many patients who had complete healing of ulcers. The major adverse effects associated with levamisole were taste disturbances and nausea, although only one patient withdrew as a result of either event. Overall, levamisole was well tolerated, though plagued with a peculiar dosage schedule.

Thalidomide has pronounced efficacy in healing oral aphthae. In two trials involving difficult cases, thalidomide completely healed 48-55% of patients, compared with 7-9% of patients receiving placebo.[42] However, the effect of thalidomide was temporary, with most patients having recurrent ulcers an average of 20 days after stopping therapy. Thalidomide also significantly increased subjective improvement. Adverse effects were frequent during thalidomide therapy. Headaches, somnolence, and constipation all occurred in greater than 10% of patients, while peripheral neuropathy occurred in up to 6%.

Neuropathy associated with thalidomide is manifested by painful paresthesia of the hands and feet, often accompanied by sensory loss in the lower limbs.[43,50] Irreversible neuropathy may result if treatment is continued too long or signs of motor dysfunction develop.[42] Neuropathy limits long-term use of thalidomide. Most reported cases occurred at dosages of 100-300 mg/day given for more than six months.[42,50] In the trials reviewed, 10 of 169 patients given thalidomide (versus 5 of 127 placebo recipients) developed evidence of peripheral neuropathy within 35 days of therapy at dosages of 100 or 300 mg/ day. In one uncontrolled study, thalidomide 50 mg three times a week for 17 months was effective and did not produce evidence of polyneuropathy in 43 patients with Behçet's syndrome.[51] Further studies of low-dose thalidomide are needed to establish the minimal effective dosage.

Therapy with thalidomide requires teaching patients to identify the early signs of neuropathy and to understand the risk of teratogenicity. Prickling, tingling, numbness, or pain in the extremities suggests the need for an examination by a physician. Patients should be evaluated at baseline and monthly for the first three months, after which examinations for manifestations of neuropathy should continue periodically.[52] Sensory nerve action potential amplitude (SNAP) testing should be performed at baseline and every six months.[52] A SNAP test result more than 40% lower than the baseline result is predictive of neuropathy and requires drug discontinuation. All patients, pharmacists, and physicians must participate in the System for Thalidomide Education and Prescribing Safety (STEPS) program (1- 888-4-CELGEN). Patients must meet eligibility criteria to receive the drug. Informed consent must be obtained to ensure education about contraceptive measures for men and women, the frequency of pregnancy testing, and the symptoms and evaluation of peripheral neuropathy. Pharmacist registration in the STEPS program ensures that prescriptions are filled only after physician registration in the program is verified and a signed informed-consent document is collected and filed with the initial prescription.

On the basis of efficacy, cost, and safety, topical medications remain the treatment of first choice for patients with RAU (Figure 1). Amlexanox is the most extensively studied and most cost-effective of the topical agents. Levamisole can significantly reduce ulcer duration, frequency, and pain in patients with minor RAU and may prove to be the safest and most effective systemic agent for maintaining remission in these patients. Thalidomide has shown the largest margin of efficacy in patients with severe RAU. However, long-term administration is required to maintain remission. Extended treatment has resulted in peripheral neuropathy, a potentially irreversible condition. In addition, headache and somnolence may reduce patient compliance with thalidomide therapy. Significant costs, frequent adverse effects, and extensive exclusion criteria limit thalidomide use to patients with severe RAU as an alternative to systemic cortico-steroids.

. Treatment algorithm for recurrent aphthous ulcers (RAU). Chlorhexidine and levamisole were not effective in all clinical trials.

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