Treatment of severe odynophagia with long ~ acting topical nitroglycerin ointment in a patient with acquired immune deficiency syndrome

Y-1 KIM, F SAJBIL, A RACHUS, Treatment of severe odynophagia with long, acting topical nitorglycerin ointment in a patient with acquired immune defi, ciency syndrome. Can J Gastroenterol 1993;7(4):349-352. Odynophag1a and dysphagic1 are common gastrointestinal symptoms experienced by patients with the acquired immune deficiency syndrome (AIDS). These symptoms can significantly decrease food intake and thus worsen nutritional status, leading to s1gnificanc morbidity in AIDS patients. Esophageal candid iasis is the most comm.on etiological factor associated with odynophagia and dysphagia in AIDS patients, bur there ;ire ocher infectious and malignant causes for these symproms. Often the standard trealmcnts for these causes are not satisfactory. The authors report a patient with AIDS who had oral can<lidiasis refractory to oral ketoconazole and severe odynophagia which severely restricted his oral intake. This patient responded dramatically to long-acting nitroglycerin ointment (Nitro-BiJ [HoeschtRoussel Canada, Inc]) while imravenous amphotericin B was being initiated. The authors propose that esophageal spasm may be a significanl factor in the genesis l1f odynophagia and dysphagia in certain patients with AIDS and that smooth muscle relaxants, such as nitroglycerin or calcium channel blockers, may be 1mporrnnc adjunctive Lherapies.

O DYNOPI IAGIA AND DYSPHAGIA are common gastrointestinal symptoms experienced by patients with the acqu ired immune Jeficiency syndrome (AIDS) ( L ); these symptoms are the manifcstamms of a host of infections and malignancies commonly associated with human immunodeficiency virus (HIV) infection (2-10).These esophageal symptoms can significantly restrict oral intake, thereby worseni ng the nutritional status of AIDS patients in whom weight loss and tissue wasting may be che most prominent clinical features, especially at end-stage.Treatmencs are available for specific etiological facto rs ( I l -L 4) but often symptoms persist or recur after Lreatments have been d isconti nued.T he exact path ogenetic pathway fo r these symptoms is not well established but certainly both structural and motility disturbances are likely involved.We report a patient with AIDS who had oral camlidiasis and severe odynophagia refractory co oral ketoconazole and in whom esophageal spasm may have played a significant role in the ~ymptoms.This patient promptly responded to long-acting topical nitroglycerin ointmcm (Nitro-Bid [Hoescht-Rousscl Canada, Incl), a smooth muscle relaxant.pose a une morbidite considerable chez les patients sideens.La cand idose a:sophagienne est le facteur eciologique le p lus frequent associe a l'odynoph agie et la dysphagie chez les patien ts sideens, mais il y a d'autres causes infectieuses et malignes a ces symptomes.Souvent, les therapeutiques standard de lutte centre ces causes ne sont pas satisfaisantes.Les auteurs rapportent le cas d'un patie nt sideen qui presentait une candidose orale refractaire au ketocon azole oral et une odynophagie grave qui restreignaient serieusemenc son apport alimentaire.Ce pa tient a re pondu d'un e fa~on ph enomenale a un ongue nt de nitroglycerine a longue action (N itropasce) avec un traitement concomitant d'amph otericine B intraveine use.Les a uteurs suggere nt qu'un spasme oesoph agien pourrait e tre e n partie responsable de l'odyn ophagie e t de la dysphagie ch ez certains patien ts sideens et que les relaxants des muscles lisses, comme la nitroglycerine ou les inhibiteurs calciques, pourraient constituer des traiteme n ts d'appoint importants.

CASE PRESENTATION
A 42-year-old homosexual male was diagnosed in 1987 with HIV infection when he presented with oral candidias is.Subsequentl y he had three bouts of Pneumocystis carinii pneumonia, Kaposi's sarcoma involving lungs and oral cavity, and herpes-like lesions in the rectal mucosa which were treated with oral acyclov ir.The patie nt had been recently diagnosed with cytomegalovirus retinitis and chis was treated wi th intrave nous foscamet (Astra Pharma Inc) in itia lly, and then 9-( l ,3-dihydroxy-2-propoxymethyl) guanine (ganciclovir).The patient had received zidovudine and 2',3'-dideoxyinosine in the past but these had been discontinued because of bone ma rrow suppression and neurotoxicity, respectively.He had recurrent oral candidiasis treated with nystatin mouth wash with no significant improvement.
The patient had been complaining of sharp pain in upper pharynx, and upper and middle chest with each swallow with both liquids and solids (worse with solids), and this had been progressively worsening over the two weeks prior to admission.At aJmission, h e was unable to take anyth ing by mouth and h ad significan t weight loss.He had no pyrosis, regurgitation, nausea, vomiting, abdominal pain, fever or signs of gastrointestinal hemorrhage.His oral candidiasis had bee n noted co be worse over the week prior to ad mission and h ad been treated with oral ketoconazole 200 mg daily fo r two weeks with no significant improvement.The patient had never had dysphagia or odyn ophagia in the past and had had no ra-diological or endoscopic examination of the upper gastrointestinal tract.
On examination, the patient was a cachectic appearing male with Kaposi's sarcoma involving his nose, left neck area a nd oral cavity.There was severe oral candidiasis but no aphthous ulcers were noted.O ther systems were unremarkable.He h ad severe ne utropenia ( white blood cell count was 0.9x10 9 /L) a nd absolute neutrophil counts were less than 500xl0 6 /L; t his was thought co be due to ganciclovir which was discontinued.
Because of severe neutropenia, it was fe lt that risks of aspiration and other infectious complications outweighed potential benefi ts of diagn ostic endoscopy.Intravenous amphocericin B was initiated via a Port-a-cath (Pharmacia) within 12 h of presentation.Long-acting nitroglycerin ointment l" tid was started fo r possible esophageal spasm contributing to his odynophagia.The patient had an immediate and d ramatic response to the n itroglycerine o intment and his odynophagia subsided so comple tely within 24 h that he was able to resume his oral inta ke.The nitroglycerine ointment was continued and amphote ricin B was d iscontinued afte r five days (oral ketoconazole 200 mg daily was then given).
The patient was d isch arged on day 9 without odynophagia or dysph agia on keroconazole 200 mg daily and N itro-Bid l " tid.

DISCUSSION
Odynophagia and dysphagia are very common in patie nts with AIDS ( 1 ).A lthough the exact frequencies ha ve not been established since nor all pati ents with esophagitis are symptomatic ( 15), odynophagia anJ dysphagia may be the most common symptoms experienced by pa ticnrs with AIDS (1).These symptoms can signifi cantl y decrease food intake, t he reby worsening the nutritional sta tus of AIDS patie nts ( l ) and a re responsible for signifi cant morbidity in these patients.
T h e most common cause of odynophagia/dysph agia in patients with AID~ is esophagea l candidiasis ( l ).le has been estima ted that at King's Coun ty Hospital in Brooklyn, New York, more than 75% of patie nts with AIDS had sympto ms of oroesoph ageal candidiasis during their hospital course ( 2 ).O pportunistic infections of the esophagus with cytomegalovirus (3,4) and herpes simplex virus, both types l and 2 (6), are othe r well known ca uses for odynophagia/dysphagia in AIDS patients.A recent report from Canad ian investigato rs described o ra l a nd esophageal ulcerations in assoc iation with electron microscopic evidence of viral pa rticles occurring coincident with HIV seroconversion (7).Other conditions which may cause odynophagia/dysphagia arc cryptosporidiosis (8), esophageal lymphoma (9) and oropharyngeal Kaposi's sa rcoma ( 10).It appears that acid-peptic reflu x esophagitis may not make a significant contribution to odynoph agia/dysphagia in AIDS patients.Inte restingly, a recent study (16) has shown that achlorhyd ria or hypochlorhydria and decreased pepsin in gastric juice may be common in patients with AIDS.
The relationship between ora l and esoph ageal candidiasis is somewhat unsettled.In prospective studies (17-2 1) of patients with AIDS or AIDS-related complex and oral candidiasis, almost 100% had endoscopic evidence of candidal involve ment of the esoph agus, regardless of the presence of odynophagia/dysphagia.The refore, these in vestigators advocated char a patient with AIDS, odynophagia/Jysphagia and oral candidiasis could be presumed to have esoph ageal candidiasis without radiological or e ndoscopic con firmation, and the patient could be treated with appropriate a ntifungal the rapy.lt was suggested that further diagnosti c eva luation could be reserved for no nrcspo n-Jcrs or for patienls with clinical and laborato ry evidence of an esophageal Jisorder o the r t han esophageal can-JiJiasis.While ora l thrush ofLen predicts concurrent csophagitis, iL is clearly established tha t the absence of thnish docs no t e xclude the poss ibility of esophageal candidiasis (22,23 ).
The treatment of oclyno phagia/dysphagia in AIDS pa Licnts depends o n the specific etio logy.In esophageal candidiasis, nystatin suspensio n and clotrimazole lozenges a rc gene rally considered to be inadequate therapy, even though they may be benefic ial fo r treating oral ca ndidiasi •.Ketoconazole has been the ma instay of the rapy for esophagea l candidiasis ( l ).This imida-:ole compound increases fungal membrane permeability by interfering with ,rerol synthesis (I ).Even t hough oral kcroconazole 200 mg da ily is an cffecttve therapy fo r esophageal candidias is in patients with immunode ficiency states other than AIDS ( 11 ), this dose often is ineffecti ve for e radicating esophageal candidi asis in some patients with AIDS (1 2).Therefore, a J ose of kcroconazole up to 600 mg a Jay h as been suggested (1) to eradicate esophageal candidiasis wi tho ut causing hepatcicellular tox icity.Patients who fail to respond to high dose ke tocon azole may respond to the newly developed fluconazole or low J ose intraveno us amphotericin B.
Herpes csophagitis will respo nd to acyclovir, a lthough resolutio n ofte n is followed by re lapses.Cytomegalovirus csophagitis has been successfully treated with ganciclovir (13 ,14), a lthough large, randomized controlled scuJies with confirmatory e ndoscopic examinations arc lacking.
grcmcr comfort, increased o ral intake, better nutritional status anJ ability to take medications.Eradication of these oppo rtunistic infectio ns docs not necessaril y prolo ng survival a nd suppression only may be achi eved.The odynophagia, in particular, may have multifacto ria l causes, suc h as invas ion beyond the mucosa by the orga nism, infla mmato ry reactio ns, and tearing of candidal plaque and associated underlying mucosa by combined mechanical shearing forces of food and peristalsis, as suggested by Gould e t al (24 ).Although it is not proven , we suggest that esophagea l spasm may contribute to od ynophagia/ d ysphagia in these AIDS patie nts.
In uncontrolled trials (25-29), short-and lo ng-acting ni trates reduced sympto ms and improved mano metric and radiographic patte rns in some patients wit h spastic disorders of smooth muscle segments of the esophagus.These agem s are thought rn be beneficial because of the ir re laxant effect on smooth muscle, a ltho ugh the effect on mano metric paramete rs may actually be minimal.Calcium channe l blockers, in some a necdotal c ases (30-33), have shown po te ntial be nefit in the manageme nt of spastic disorde rs of the esophagus.Calcium c ha nnel blockers relax the smooth muscle of the esophagus by interfe ring with calcium uptake by smooch muscle cells which a re dependent o n intracellular calcium fo r cont ractio n .H owever, evidence suppo rting the uniform efficacy of calcium channe l blockers is lacking in cont rolled studies (34 ).Successful management of sympto ms of esophageal spasm h as a lso been a n ecdota ll y re ported using psychoactive drugs, including the antidepressa nt trazodo nc hydrochlo ride (35).
T he presented patien t had severe od ynophagia associated with oral ca ndidiasis re fractory to oral ketoconazole.The patient also had severe neutropen ia which precluded defin itive diagnostic e ndoscopy because of conce rn for aspiratio n and infectious complicat io ns.Most likely, however, th is pati ent d ic.J h ave severe esoph agea l can-Jidiasis as suggested by the above discuss io n.A ltho ugh opportunistic infect ions of the esophagus by cy tomegalovirus o r herpes virus were possibilities, he had been on ganc iclovir and ncyc lovi r for some time prior to his presentation.I ncravcnous amphoteric in B was ini tiated soon afte r admission but t he time interval betwee n the start o f a mphoteric in Band his drama ti c response make amphOLericin very unlike ly as the benefic ia l agent.T opical nitroglycerin was selected rather than the sublingua l o r ora l forms because of the patient's extreme cxlynophagia, even o n swallowing h is saliva.His rcspomc to n itroglycerine ointment was immed iate and d ramatic, suggesting esophageal spasm might have been the most significant factor in h is oclynophagia.
The patient immed iate ly was able to resume his o ral in take fo r both pleasure a nd nutritional suppo rt, with clear-cut improvement of his qua lity of life.

CONCLUSIONS
Esophageal spasm may he a sign ificant facto r in the od ynophagia/J ysphagia common ly expe rienced by AlDS patients.N itroglycerin -topically, sublingual ly or orally -may provide rapid ame lioration of these symptoms wh ile specific a nt i-infective treatments a re institu ted.The symptomatic re lief may a llow improved nu trient intake in these patients a nJ enhance their general nutri tiona l sta tus and qua lity of 3. Balthazar EJ, Mcgibow AJ, I lulonick DI l.Cytomcgalovirus esophagitis anJ gastritis in A IDS. Am J RaJiol l 985; 144: 120 1. 4. Sr Ongi G, Bczahlcr OH.Giant esophagea l ulcer associated with cy1omegalovirus.Gastrocnterology 1982;83: 127.S. Frager DI I, Frager JD, Bnmdr LJ, et al.CAN J GASTROENTEROL Vot 7 No 4 MAY/JUNE 1993 Treatment of severe odynophagia life.Othe r smooth muscle relaxants, such as calc ium channe l blockers o r psychotropic medications, may have a n adjunc tive role in the treatment of th ese esohagcal sympto ms.G, 1slrointestinal complications of AIDS: RaJ iologic features.RaJ1ology 1986; 158:597.6. Aghar FP, Horchang I IL, Nostrnnt 1T.l lerpctic c,ophag1tis: A diagnostic challenge in immunocompromized patient.Am J Gastroentcrol l 986;8 l :246.7. Rabeneck L, Boyko WJ, McLean DM,