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Recurrent aphthous stomatitis (RAS) is a common disorder of the oral mucosa that affects about 25% of the population.1-3 The disease is characterized by recurring painful ulcers of the mouth that are round or ovoid and have an inflammatory halo (Figure 1 and Figure 2). The ulcers commonly first appear in childhood. They usually have a familial history and tend to abate around the third decade.1,2
A diagnosis of RAS should be reserved for recurrent ulcers confined to the oral mucosa, and not associated with systemic diseases such as Behcet’s syndrome, inflammatory bowel disease, gluten sensitivity, human immunodeficiency virus (HIV), pemphigus, and pemphigoid.3 This ailment affects the nonkeratinized mucosa such as the floor of the mouth, buccal and labial mucosa, and the ventral surface of the tongue.
RAS has been has been further classified according to size of the lesions and the tendency for scarring. The lesions are designated: major aphthae, minor aphthae, and herpetiform ulcers.4 Cross-sectional studies suggest that women are affected more than men. It is more common in whites, nonsmokers, people younger than 40 years, and people of high socioeconomic status.5,6
Although the etiology of RAS has not been established, various factors have been suggested. These include a possible immunologic relationship involving a cross reactivity with Staphylococcus sanguis; deficiencies of iron, vitamin B1, vitamin B2, and vitamin B6; and sensitivity and allergy to foods and other substances.7,8 The pathogenesis is primarily a cell-mediated immune response involving tumor necrosis factor alpha (TNFα), interferon gamma, mononuclear lymphocytes, neutrophils, T cells, intinterleukin-2 (IL-2), interleukin-10 (IL-10), and natural killer cells activated by IL-2.9,10
Role of the Sympathetic Nervous System
It is hypothesized that one of the main functions of the sympathetic nervous system is to diminish cellular permeability. Thus, sympathetic nervous system hypofunction may lead to absorption of chemicals and toxins, such as bacteria and viruses, into tissues that were supposed to be impervious, leading to inflammation and other related adverse consequences.11 Genetic predisposition to increased cellular permeability or acquired trauma is theorized to be a factor as to why various tissues or organs are involved, but this is not necessarily the same in all women with the sympathetic neural hyperalgesia edema syndrome.11
Catecholamines are the most common neurotransmitter in the sympathetic nervous system, and they increase intracellular cyclic adenosine monophosphate, which, in turn, inhibits certain pro-inflammatory cytokines.12-14 Therefore, stimulation of the sympathetic nervous system may negate their pro-inflammatory effects.12
Treatment of patients suffering sympathetic hypofunction with sympathomimetic amines, eg, dextroamphetamine sulfate, may restore nervous system function to normal and may reverse the various symptoms resulting from diminished sympathetic nervous system activity.11 It has been hypothesized that dextroamphetamine sulfate may work by stimulating the sympathetic nerve fiber to release more dopamine, which, in turn, leads to diminished cellular permeability.11,15
A 22-year-old woman sought help from a medical and reproductive practice to diagnose the cause of and ameliorate her vasomotor symptoms (especially hot flashes whenever eating), severe fatigue, weight gain of unknown etiology, chronic mouth ulcers, insomnia, and dyspnea on exertion. The mouth ulcers started at age 3 and would present for about 20 days per month. She had never had a period of long remission in 15.5 years. A febrile illness would intensify them in number and severity and could cause them to be present all month.
Hypothyroidism was excluded as a cause of heat intolerance and fatigue through demonstration of normal thyroid function tests with her sera-free thyroxin of 1.00 ng/dL (nl 0.9 to 1.7), serum triiodothyronine of 153 ng/dL (nl 80 to 195), and thyroid stimulation hormone level of 1.19 mcU/nl (nl 0.3 to 4.00). A rare pheochromocytoma was excluded by demonstrating normal 24-hour urine for total metanephrines (247 ug/24 hr [nl <900]) along with normal normetanephrines at 193 ug/24 hr (nl <600), and normal dopamine at 27 ug/24 hr (nl <500).
Her menstrual cycles occurred every 22 to 25 days, though her serum follicle-stimulating hormone was not increased to explain her vasomotor symptoms. Interestingly, it was actually low at 0.3 mIU/mL; luteinizing hormone was also low at <0.1 IU/L, and serum estradiol was low at <10 pg>
Her complete blood count and complete metabolic profile were normal, and thus she did not have anemia, chronic liver or kidney disease, or a calcium disorder to explain the fatigue. After excluding known physical causes of heat intolerance and chronic fatigue syndrome, the patient was advised of previous successful amelioration of heat intolerance by treatment with the sympathomimetic amine dextroamphetamine sulfate in both women with normal estrogenic levels and those with estrogen deficiencies.16,17 The same drug was also very effective in treating chronic fatigue syndrome.18,19
Following treatment with 15-mg amphetamine salts extended-release capsules, whose main ingredient is dextroamphetamine sulfate, she showed a marked decrease in the frequency of the aphthous ulcers and significant improvement in her heat intolerance and fatigue. Since the dosage was increased to 20 mg, she has not had any heat intolerance, chronic fatigue, or aphthous ulcers in more than 2 years. The 65-inch-tall patient started treatment weighing 145 pounds. Her weight decreased by 13 pounds and has been maintained at about 132 pounds during the time of treatment.
Based on the very positive response of his sister, the younger brother of the patient in Case 1 sought medical help at the age of 17. His main complaint was severe hot flashes during which he frequently would need to excuse himself from class at school and go to the bathroom to quickly remove his clothes. He also stated that he had RAS since childhood, but his description seemed consistent with the typical normal recurrence rate. Also, the severity of RAS was not nearly as great as his sister’s condition.
His evaluation to diagnose a thyroid disorder or pheochromocytoma as the etiologic factor was similar to his sister’s. These entities were also excluded.
The amphetamine salts as extended-release capsules were similarly prescribed, and his heat intolerance immediately dissipated. He had no aphthous ulcers while on amphetamine salts. v would have been expected during the few months he had taken the medication. However, he had an unusual idiosyncratic reaction in that he developed joint pain.
He stopped the amphetamine salts and his joint pain went away, but his vasomotor instability immediately returned. Interestingly, so did his aphthous ulcers. He was switched to pure dextroamphetamine sulfate extended-release capsules, and his vasomotor symptoms stopped. This drug, however, did not produce joint pain. He has not had any aphthous ulcers since he started taking the medication (1.5 years).
Ship20 has described etiologic factors associated with RAS, which include localized issues such as trauma, smoking, and dysregulated saliva composition. Systemic factors include Behcet’s disease, mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome, Crohn’s disease, ulcerative colitis, HIV, Marshall syndrome, and cystic neutropenia.20
Emotional factors have been implicated, including stress and psychological balance.20 Some women seem to get these mouth ulcers related to their menstrual cycle, especially premenstrually.20
Genetics may also play a role. Susceptibility to RAS is significantly increased by its presence in one or both parents, and especially in identical twins.21 In fact, RAS tends to develop at an early age, particularly if both parents have a positive history of RAS.22 In the two cases presented neither parent had a history of RAS. However, the fact that both siblings developed RAS at an early age strongly suggests genetic factors.
Certain genes, specifically human leukocyte antigens (HLAs), have been identified in patients with RAS. These include HLA-A2, HLA-B5, HLA-B12, HLA-B44, HLA-B52, HLA-DR2, HLA-DR7, and the HLA-DQ series.23
Microbial etiologies have been proposed, but to date there have not been any solid associations.24 Allergic and immunologic etiologic factors along with certain side effects to medication have also been considered.24-26
The possibility exists that successful treatment of RAS with dextroamphetamine sulfate may be restricted to just a minority of cases that have a hereditary component, as in the two cases reported. However, it is possible that the large variety of etiologic factors have one common pathway, and that the majority of cases of RAS will respond to sympathomimetic amines.
Convincing case reports and published series (though no randomized controlled studies) have shown a rapid, effective amelioration of a wide variety of chronic disorders following treatment with dextroamphetamine sulfate that were refractory to standard therapy.11,15 These disorders include, but are not limited to, those listed in Table 1.
The hypothesized mechanism is that these disorders, which, similar to RAS, could have genetic predisposition, immune issues, trauma, infection, etc., are commonly united in that a particular tissue (and sometimes multiple tissues and organs) has increased permeability or a decreased local immune defense that allows harmful chemicals and/or other toxic factors, eg, microbes, to permeate the tissue. This leads to inflammation followed by pain. There is evidence that possibly through the stimulation of the release of dopamine by the sympathetic nerve fibers that innervate the tissue, cellular permeability is decreased, thus impeding the absorption of these toxic factors.11-13,15
Thus, many of these disorders have been treated with glucocorticoids and biological agents that suppress immune factors (eg, TNFα inhibitors), but with only fair success. However, these therapies can cause considerable risk of infection, or even cancer, not to mention many immediate side effects. In contrast, dextroamphetamine sulfate is generally well tolerated and causes no known long-term risks. It theoretically inhibits the offending agent from causing inflammation rather than treating the inflammation once it occurs.
Behcet’s disease is characterized by recurring oral and genital ulcers and eye lesions. It is a multisystem disorder resulting from vasculitis of small and medium vessels and inflammation of epithelium.27 Though it usually affects adults, several cases have been reported in children.27-29 Though Behcet’s disease was entertained by the various pediatricians who evaluated Case 1, the patient had no vaginal or ocular lesions.
On the other hand, in a case involving a young child with severe vulvovaginitis, various pediatricians evaluated the patient as having a possible variant of Behcet’s disease even though she did not have RAS or ocular ulcers. The patient also suffered from chronic fatigue syndrome similar to the patient in Case 1. She showed dramatic improvement following treatment with dextroamphetamine sulfate in her vulvovaginitis (completely eradicated it), and the treatment markedly helped her chronic fatigue syndrome (similar to Case 1).30 Interestingly, the patient’s mother did not have RAS or vulvovaginitis but did have severe pelvic pain, which was also helped immensely by dextroamphetamine sulfate.
As mentioned, aphthous stomatitis has been associated with Crohn’s disease and ulcerative colitis. Both of these disorders have been shown to improve with sympathomimetic amine therapy despite previous failure with mesalamine, immunosuppressive therapy, and even surgery.31,32
Akintoye and Greenberg2 discussed in detail the management of RAS. Obviously, if local topical agents, or correction of vitamin or mineral deficiency by, for example, zinc therapy, improve the aphthous stomatitis, these relatively innocuous treatments would seem a better choice than sympathomimetic amines.2-4 However, before corticosteroid and immunosuppressive agents are employed, sympathomimetic amine therapy should be considered.27,33-35
It is the authors’ hope that this case report will encourage others to try this therapy and report their results, whether positive or negative, in an effort to determine which types of RAS respond best to it and to determine whether this therapy works only in a minority of RAS cases or in a majority of them. Ideally, if there is enough interest, a multicenter randomized controlled study may be initiated.
It should be noted that amphetamines have potential abuse, especially for high-school and college students who use them to focus better on their studies and to improve memory. The dosages used to accomplish better focus are similar to dosages used for treating RAS. In extremely high dosages a state of euphoria could be achieved, though this would probably require an entire month’s prescription. In the dosages used for RAS the drug can be stopped abruptly without weaning, with no or very little withdrawal effects and no drug dependence. The most common side effect is xerostomia, which is usually not severe enough for the patient to stop taking the drug in most cases. Insomnia is somewhat common initially but generally is a tachyphylaxis, so hypnotics are not necessary. Similarly, increased anxiety is generally short lived, though occasionally the drug may be discontinued because of prolonged insomnia or anxiety.
Two cases of refractory RAS are discussed that were successfully treated with dextroamphetamine sulfate. This leads to the hypothesis that hypofunction of the sympathetic nervous system may be an etiologic factor in RAS. The authors hope that this hypothesis and the documentation of the cases presented here will lead to further investigation into the efficacy of sympathomimetic amine therapy in RAS.
The authors had no disclosures to report.
About the Authors
Steven I. Present, DMD
Clinical Associate Professor
Department of Restorative Dentistry
Kornberg School of Dentistry
Jerome H. Check, MD, PhD
Department of Obstetrics and Gynecology
Division Head of Reproductive Endocrinology and Infertility
Cooper Medical School of Rowan University
Camden, New Jersey
Queries to the authors regarding this course may be submitted to email@example.com.
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35. Ryu HJ, Seo MR, Choi HJ, Baek HJ. Infliximab for refractory oral ulcers. Am J Otolaryngol. 2014;35(5):664-668.