Pathology

Treatment of aphthous stomatitis with saturatedpotassium nitrate/dimethyi isosorbideMiiton Hodosh, DMDVSteven H. Hodosh, DMDVAlex J. Hodosh,

Concentrated potassium nitrate has been used tc lessen the pain caused by aphthous stomatitis. Theproblem with this approach is that if can have difficuity penetrating into the deeper iayers of mucosae orskin, and for this reason, its beneficial affects are not routinely predictabie. When dimefhyl isosorbide isadded to potassium nitrate in an aqueous hydroxyethyi celluiose gei, if enhances fhe capacity of potas-sium nitrate fo more compiefely permeate fhese tissues and predictabiy promote rapid pain controi andaphthae healing. (Quintessence Int 2004:35:137-141)

Key words: action potentiai, dimethy isosorbide, potassium nifrafe, recurrenf apthous ulcer, resfingmembrane potentiai

Recurrent aphthous ulcers (RAU) are extremelycommon, and the clinician is often asked to estab-

lish a diagnosis and suggest a treatment to alleviatethe painful symptoms.' The most common form isRAÜ minor (70% to 90% of all RAU cases).'-^ RAUmajor have a similar appearance but are usually larger,last from several weeks to months, and may heal withscarring.^ The least common type of RAU is calledherpetiform, and these appear in clusters (approxi-mately 10 to 50) found most frequently in the poste-rior aspects of the oral cavity. All three forms of RAUare confined to the nonkeratinized mucosae, specifi-cally, the vestibules, the floor of the mouth, thetongue, the soft palate, or buccal mucosa.'-^ Occa-

'Private Practice, Providence, Rhode Island, formerly. Associate Professor,Scrtooi ol Dentistry, Harvard University, Boston, f^assaohusetts; AssociateProfessor, Scfiool of Bjomedicine, Brown University, Providence, RhodeIsland; and Assistant Professor, Scfiooi of Dental Medioine, TuftsUniversity, Boston, fulassacusetts.

^Private Practioe, Providence, Rhode Island,

Reprfnt requests; Or Miiton Hodosh, 243 Elmwood Avenue, Providence,RI 03907. Fa^i: + 401-781-9854.

sionally, there may be submandibular lymphadenopa-thy with associated pain on palpation without thepresence of other systemic symptoms.'"^

Many etiologic factors were at one time thought tocause aphthous ulcérations. Heredity had been sug-gested as one, and aphthous lesions frequently bavebeen observed in several members of the same family.The disease had sometimes been thought to be viral;and although herpes simplex ulcers are often similarin appearance to the aphthous ulcer, there is no evi-dence that this virus (herpes) is the etiologic factor inaphthous stomatitis. Tissue cultures have been uni-formly negative for herpes simplex in aphthous le-sions. Bacterial factors (Bacillus crosses) have beentbought to cause "canker sores," but no one bacterialagent bas ever heen consistently associated with apht-hous ulcérations. Furthermore, there is no evidence ofcross infection. Protozoa had sometimes been sug-gested as a cause of this disease,^ but no conclusive ev-idence has establisbed this to be true. While it is sus-pected that trauma may contribute to the developmentof the aphthous lesion, it is not considered the cause.The tissue sensitized and made susceptible to the aph-thous lesion by a traumatic injury does not usually

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resuit in canker sores in people not prone to developsuch lesions. Another observation is tbat the eruptionof apbtbous lesions is frequently associated witb tbeonset of menstruation and bas been associated witbmenopause.^ It also bas been observed tbat recurrentapbtbae completely subside during pregnancy in otb-erwise highly susceptible women.' Regardless of tbisapparent relationsbip, tbere is no definite explanationof tbe mecbanism of this pbenomenon. Add to tbis tbefact that apbtbae are frequently seen in men, and tberole of hormones in tbis disease becomes even moresuspect. Apbtbae outbreaks can follow tbe ingestion ofcertain drugs or foods.' Tbere is, bowever, little evi-dence tbat tbese eruptions are due to hypersensitivereactions in more patients.

It also bas been noted tbat acute psycbologic fac-tors appear to precipitate aphtbous ulcers. Altboughpsycbologic factors are difficult to analyze, it nevertbe-less has been popularly concluded that mental stressand psycbologic disturbances act as precipitatingmechanisms to the disease, altbougb tbey are not theactual causes.''

Gastrointestinal (GI) factors also bave beentbougbt to be related to apbtbous lesions.^ It is fre-quently difficult to separate Gl disturbances from psy-chosomatic factors. The GI tract is extremely suscepti-ble to emotional disturbances, and lesions of thestomacb and lower intestinal tract often coexist witbapbtbous stomatitis lesions.

It is helieved tbat apbtbae are related to a focal im-mune effect in wbicb T-lympbocytcs play an early role.Before ulcération, an intense T-lympbocyte infiltrate isseen at the connective tissue interface. This suggests thatdestruction of the epithelium is the result of cell-medi-ated immunity, but tbe triggering event is unknown.

Apbtbous stomatitis is tbe most common oral mu-cosal disease in the United States, hut little is under-stood of its etiology or patbogenesis.' Tbis report pre-sents a new and effective treatment for apbthous ulcers.

CLINICAL APPEARANCE OF APHTHOUS ULCERS

Clinically, aphtbous ulcers are classified into major,minor, and berpetiform types.* Major apbtbae repre-sent a larger, more severe form of tbe disease, gener-ally over 1.5 to 2 cm in diameter. Tbe ulcers aredeeper, often have a raised irregular border, and usu-ally last for more tban a montb.' Herpetiform'" (her-pes-like) aphtbae are multiple, usually appearing incrops. Minor apbtbae appear as single or multipleround or oval ulcérations and range in size from 1 to40 mm in diameter. Tbey occur on mucous mem-branes of the tongue, cheek, inside the lips, soft palate,pharynx, and floor of the moutb,'" Aphthae can be ex-

tremely painful, and tbey flrst appear as small wbiteareas or raised red papules. Tbese areas quickly un-dergo necrosis, leaving a sbarply defined, roundedulcer, Tbe ulcération can be deep, with a yellow-wbitebase representing necrotic tissue at the surface. Themargins of tbe ulcer are somewbat indurated, and themarginal mucosa has a surrounding erytbematouszone. The marginal erytbema ranges from slight to ex-tensive. The lesion undergoes gradual bealing, and asa general rule, tbere is no scarring. Tbere is no vesicu-lar stage with minor aphthae, and tbe lesions aremostly found on movable tissues. The bard palate andgingivae are rarely involved. Minor and berpetiformapbthae are usually less than 0,5 cm in diameter andrepresent a more mild form of the disease.'

Characteristically, tbere is a recurrent pattern ofone or more of tbese ulcers." Tbe lesions may recuras often as one month apart; and tbere are caseswhere for periods of years, an individual is not with-out aphthous lesions, with new ones forming as theolder ones heal. In other cases, aphtbous attacks mayoccur two to tbree times during a year. Tbe lesionsoften appear to follow some intense emotional stress,hut tbey may flrst appear following a cbange in envi-ronment or following an emotional situation, sucb asthe adjustment period in a'marriage, new school, oremployment in a nonfamiliar environment. Aphthoussores have been found to occur in cyclic patterns infemales,'^ and tbere is a tendency for a greater fre-quency of tbese lesions in females than in males. Tbeyoccur most often in teenagers and young adults. Theinter-relationship between smoking and RAU hasbeen of interest for many years, and in a study of20,000 adult Swedes, Axell and Henricsson'^ reportedthat people wbo smoke do not experience apbtbae ordo so witb less frequency tban nonsmokers, as smok-ing alters tbe mucosa.

From a symptomatic standpoint, it has heen foundtbat approximately 24 to 28 hours prior to the onset ofan aphthous lesion, there is a vague prodromal dis-comfort, sometimes described as a tingling sensationin the area. As the tissues undergo necrosis and anulcer forms, the lesion becomes very painful.

PREVIOUS TREATMENT REGIMES

Many different substances and agents bave been usedto treat apbtbous lesions. Cauterizing drugs (escharoticagents), such as pbenol, chromic acid, alum, and silvernitrate have been used for many years. These sub-stances alleviate pain by destruction of the nerve end-ings. Tbe bealing time of tbe lesion is prolonged due totbe destructive action of these drugs on the surface ep-ithelium and tbe active fibrosis at the base and sides of

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the ulcerated areas. Different vitamins" have been tried,with inconsistent results, and various antibiotics alsobave been used with mixed results. Temporary ease ofpain is sometimes achieved by rinsing with milk ofmagnesia or various heavy syrups. The transient natureof their benefits renders these preparations impractical.Orábase (Squibb), a mucous membrane adhering com-pound, has been used without predictable success.Recently, 2-octyl cyanoacrylate bioadhesive has beenproposed as a new treatment modality for pain relief ofaphthous ulcers, and it appears to be helpful.'Vaccinations with cowpox virus, lactobacillus-contain-ing materials, and nutrient supplements bave beentried. Corticosteroids have been used in several waysfor treating aphthous ulcers. These agents suppress in-flammatory processes in the skin and mucous mem-branes. Topical steroids must be frequently and thor-oughly applied to the ulcers, usually in lotion, cream,ointment, or gel forms. It is thought, however, that theirpenetration through the skin is minimal. Attempts havebeen made to use intraiesional steroid injections totreat aphthous ulcers. This treatment methodology pro-duees significant discomfort, especially when there aremultiple lesions. In addition, patients with gastric ulcersmay absorb enougb steroid to complicate their condi-tion. Daily dosages of systemic corticosteroids may betaken but must be gradually reduced, as it is bazardousto suddenly stop systemic cortisone. Recently, nons-teroidal, anti-inflammatory agents and oral antihista-mines have been tried, but have not been consistentlyeffective,'' as they do not provide immediate pain relief.Benadryl (diphenhydramine) (Pñzer) with Kaopectate(Pfizer) or Maalox (Novartis) used as oral rinses arehelpful for reducing pain and discomfort.

It is the primary objective of this article to presentthe current findings, which appear to provide a pre-dictable, reproducible, noninvasive method to success-fully treat aphthous ulcers by eliminating the painsooner and shortening the duration of the disease.

METHOD AND MATERiALS

inclusion/exclusion criteria

Parficipants were seiected based on the following criteria:

• Must not have used a potassium nitrate (KNO3)dentifrice for 3 weeks prior to the study

• Must be IS years of age or more• Must not use a commercial mouthrinse during the

course of the study

• Must not use antibiotics, nonsteroidal, anti-inflam-matory medications, or systemic corticosteroidsduring the course of the study

• Must have professionally confirmed painful minor,major, or herpetiform aphthous lesions

A gel was prepared using 35% KNO; aqueous hy-droxyethyl cellulose to which was added 25 drops ofdimcnthyl isosorbide (DMI) per ounce of gel. Tbis geiwas labeled No. I. The positive control preparation.No. 2, was composed of 35'>'Ü KNO, aqueous hydrox-yethyl cellulose. Gel 2 differed fi-om gel 1 only in thatit did not contain DMI. The negative controi was gel 3and contained aqueous hydroxyethyl cellulose only. Akey hsting the composition of each gel was sealed inan envelope and placed in a locked drawer to only beopened upon completion of the study. The cliniciansexamined each patient and professionally establishedthat they had aphthous ulcers (major, minor, or her-petiform), and they recorded pertinent informationconcerning the patient and their lesions. Each patientwas asked to describe their degree of pretreatmentpain as (1) none, (2) slight, (3) moderate, (4) severe, or(5) intense. The clinicians applied the designated gelinitially to the appropriate pafient's lesions with a cot-ton swab and 3 to 5 minutes later, recorded pafientpain assessment based on tbe above numerical ver-bally reported scale. The pafients were given their des-ignated gel in one-oimce plastic bottles for home self-help usage. They were told to apply their assigned gei(1, 2, or 3) to their lesions before meals and at bedtime(four times daily). The patients were asked to recordwhen they were free from pain. They continued apply-ing their assigned gel to the lesions until the ulcershealed.

Weekly clinical examinations were performed tocheck their progress, and they also were told to comeinto the office at any fime that their pain or lesion dis-appeared (Table 1).

Fifty-four randomly cbosen pafients with aphthousulcers volunteered for the study. Eighteen pafients re-ceived gel 1; 18 patients received gel 2; and 18 pa-tients received gel 3. The three gels had an identicalappearance, and neither the clinicians nor the patientswere aware of which gel they were receiving. A mastersheet was provided to the clinician for treatment geldistribufion (ge! 1, 2, or 3). A second sheet lisfing gelcomposition was sealed in an envelope and placed ina locked drawer only to be opened on the complefionof the study when the key was to be broken. Any localor systemic untoward finding reported or observedwas recorded.

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TABLE 1 Mean values of the three outcomemeasures by gel preparation group

Gelpreparation

Pain rating Days toafter appiication' no pain"

Days toheal ulceri

1 Active preparation2 Positive control3 Negative control

1,003,004,17

4.0012,1722.11

8.0015,1130,33

•Gel 1 signiticanily outpertormsd the other two preparations. Patients whcreceiued gel 1 unitormly raporled no pair aHsr 3 minutes, white the meantor gels 3 and 3 indicated moderate to severe pain {F == 941,8,degrees of freedom [df] - 2.51, P < 001 )"Get 1 significanlly outperlormed the olher two preparations. Patients whcreceived gel 1 reported notably less than 1 week to freedom trorîi pain,white tlie other two preparations were closer to 2 and 3 weeks, respec-tiveiy (F = 58.53, df = 2,51, P< .001).'Get t atso signHicantly outperformed the other two preparations in thisoutcome. Patients who received get 1 reported |ust over 1 week to heaithe uicer, whiie the means for geis 2 and 3 were just over 2 weeks and 4weet(s, respectivety [F = 309,77, df = 2.51, P < ,001),F = tesutt of statistLoai lest comparing the three group means conductedby araiysls ot variance atter treatment,

RESULTS

Gell

The key was broken at the end of the study, and it re-vealed that all 18 patients receiving ge! 1 experiencedpronounced relief from their pain within 3 to 5 min-utes of the gel application. Where pain returned fol-lowing the first application, self-application caused thepain to quickly disappear again. The ahility of the pa-tient to self-treat with immediate positive pain controlgave the patients assurance that with self-help theycould continue their daily activities in comfort. Gel 1rendered complete pain relief for at least 4 to 8 hours,and continued applications kept patients functionaland free of pain. All 18 patients using gel 1 were freeof pain by the end of day four. Ulcer healing tookplace, on average, 8 days following the initial applica-tion of gel 1,

Gel 2

Eighteen patients having painful aphthous ulcers re-ceived an initial office application of 35% KNOj aque-ous hydroxyethyl cellulose gel {gel 2 without DMI) totheir lesions. The clinicians applied it with a cottonswab and left the gel on for 3 to 5 minutes. None ofthe 18 patients receiving gel 2 said that the pain wascompletely gone with the office application (as seenwith gel 1), However, all of these patients did notice alessening of their pain. They continued to apply gel 2qid, and 3 patients were free of pain in 6 days; 12 pa-tients were free of pain in 12 days; and 3 were free ofpain in 19 days. The ulcers of 10 patients had healedwithin 12 days, and the remaining 8 patients' ulcershealed in 3 weeks.

Gei3

None oí the 18 patients in the gel 3 group (aqueous hy-droxyethyl cellulose without KNOj/DMI) had notablepain relief from the office application. Their meanbaseline value was severe. Two patients became painfree in 4 days; six patients became free of pain in 19days; eight patients became free of pain in 27 days; andtwo hccame free of pain in 30 days. Eight patients' le-sions healed in 27 days, and 10 patients' lesions healedin 33 days. Gel 3 showed no evidence of hasteninghealing, or predictably controlling the ulcer pain.

RATIONALE FOR POTENTIATING KNO3WITH DWllTOTREAT APHTHOUS ULCERS

KNO3 has been used to treat aphthous ulcers (USpatent 4,191,750), This remedy has lessened pain andmade the healing period shorter. The prohlem with thisapproach, however, is that it is not always able to pen-etrate the deeper basal layers of mucosa or skin. WhenDM! is added to the KNO, hydrox 'ethyl cellulose gel,it enhances the capacity of KNOj to penetrate tissues.It routinely and predictably promotes pain control, andhealing is hastened. It does this hy bathing the apht-hous lesions' nerves with potassium ions changingtheir -85 vs resting membrane potential to a 0 or apositive, preventing an action potential from takingplace and inhibiting these central nervous systemnerves from emitting and conducting pain, and the au-tonomie nerves from initiating an inflammatory tissueresponse. These tissues include both central nervoussystem and autonomie nervous system neurons. Theautonomie nervous system fibers provide neurogenicmodulation of the local circulatory system. The classicinflammatory response of histamines, bradykinines,ieukotrienes, prostaglandins, and edematous fluids arenot stimulated to bring inflammatory components tothe aphthous ulcers. Redness, swelling, tenderness, andtissue warmth are eliminated and/or ameliorated, al-lowing healing to proceed at a faster rate, DMI locatedoutside the celis osmotically shrinks the adjacent cellsand membranous-contained tissues hy drawing waterout of them. It raises the osmotic pressure of ñuid sur-rounding cells and membranous structures, shrinkingthem in volume, DMI along with KNO, are better ahleto flow readily Into the targeted tissues by travelingthrough the openings and spaces created by the loss ofcellular voiume, widened bridge spaces (between cells},cell junctions, and enlarged openings. Osmotic cell andmembranous tissue shrinkage is a strong stimulus forthe uptake of potassium hy the shrunken cells.Potassium is necessary to restore cell volume. Aftertiewly captured potassium has entered into the

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shrunken cells to restore its normal equilihrium, theexcess potassium escapes from the inside of the nervesand other fissues. It leaves them strongly negative andhyperpolarized. Nerves so influenced cannot executean acfion potential, as they are unable to return totheir resting membrane potential from which nerveconducfion takes place. Potassium located outside thenerves, as well as, potassium combined witb DMI solu-tion by lining up in quantity outside its membrane,slows the escape of potassium from within the cells.This provides the unique situation whereby the nerve isfirst depolarized and then hyperpolarized. The DMIworking in eonjunction with KNOj disturbs tbe func-fions normally attributable to cells that have not losttheir volume (size). When KNOj/DMI exert their ef-fects on autonomie nerves, they lose their ability tostimuäate an inflammator i response. In this marmer, itacts as an anti-inflammatory agent.

CONCLUSION

It is apparent that DMI significantly potentiates theahility of KNOj to eliminate the pain associated withaphthous lesions. The healing time of ulcers treatedwith KNO/DMI was significantly shorter tban thosetreated witb the positive and negative control (seeTable 1), KNO3 witbout DMI is beneficial for tbetreatment of aphthous ulcers, but when combinedwith DMI, it hecomes roufinely and predictably veryeffective and safe. Patients acbieve true comfort witbinminutes of its application, Debilitafing effects causedby painful aphthae are eliminated allowing patientsthe ability to eat, talk, and readily conduct their dailyfuncfions and activifies in comfort.

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2, Rees DT, BInnie WH. Recurrent aphthous stomatitis.Dermatol Clin 1996;14:243-256.

3, Woo SB, Sonis ST, Recurrent aphthous uleers: A review ofdiagnosis and treatment [review]. J Am Dent Assoc 1996;127 (8): 1202-1213,

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11. Pedersen A, Homsleth A. Recurrent aphthous ulcération. Apossible clinical manifestation of reactivation of varicellazoster or cytomegalovirus infection. J Oral Pathol Med1993^22:64-68,

12. Brice SI, Kester JD, Huff JC. Recurrent aphthous stomatitis.Curr ProbI Dermatol 1991;3:107-127,

13. Axell T, Henricsson V Tbe occurrence of recurrent apht-hous ulcers in an adult Swedish population. Acta OdontolScand 1985;43:121-125.

14. Nolan A, Macintosh WB, Allan BF, Lamey RJ, Recurrentaphthous ulcération: Vitamin Bl, B2, and B6 status and re-sponse to replacement therapy, J Oral Pathol Med1991;20:389-391,

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