BRlEF COMMUNICATION

Treatment of severe odynophagia with long~acting topical nitroglycerin ointment

in a patient with acquired immune deficiency syndrome

YOUNG-IN KIM, MD, FRC PC, FRrn SAIBIL, MD, FRCPC, ANITA RACIILIS, MD, FRCPC

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.

Key Words: Acquired immune deficiency syndrome , Dysphagia, Esophagitis, Nitro­~ycenn, Odynophagia, Spasm

Traitement de l'odynophagie severe a l'aide d'onguent de nitro­glycerine topique a longue action chez un patient atteint de SIDA

RESUME: L'odynophagie ec la dysphagie sonc Jes symptomes gastro-incestinaux frequents chez les patients atteints de SIDA. Ces symptomes peuvent diminuer nettement l'apport alimentaire et ainsi aggraver l'etat nutrinonnel, cc qu i predis-

Divisions of Gascroemerology and lnfecuous Disease, Sunnyhrook Healch Science Cemre, l mcers11y of Toronw, Toronw, Onrano

Corres/>0ndence and re/,rims: Dr Fred Saihil , Sunnylmx>k Heahh Science Cemrc, 2075 Bayview Avenue, Room H-52, Tornnw, OnrarioM4N 3M5. Telephone (416) 480-4727, Fax (416) 480-5977

Receiml for publicauon ( kwher 21 , 199 2. Acceptd October 29, 199 2

Co\l\ j GASTROENTEROL VOL 7 Nl14 M AY/JUNE 1993

ODYNOPI IAGIA AND DYSPHAGIA

are common gastrointestinal symp­toms experienced by patients with the acquired 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 worsening 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 factors ( I l - L 4) but often symptoms persist or recur after Lreatments have been d iscontinued. T he exact pathoge­netic pathway for 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 (Nitro­Bid [Hoescht-Rousscl Canada, Incl), a smooth muscle relaxant.

349

KIM etal

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'odynophagie et la dysphagie chez les pat ien 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 patient sideen qui presentait une candidose orale refractaire au ketoconazole oral et une odynophagie grave qui restreignaient serieusemenc son apport alimentaire. Ce patient a repondu d'un e fa~on phenomenale a un onguent de nitroglycerine a longue action (N itropasce) avec un traitement concomitant d'amphotericine B intraveineuse. Les auteurs suggerent qu'un spasme oesophagien pourrait e tre en partie responsable de l'odynophagie e t de la dysphagie chez certains patien ts sideens et que les relaxants des muscles lisses, comme la nitroglycerine ou les inhibiteurs calciques, pourraient constituer des traitements 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 acyclovir. The pat ient had been recently diagnosed with cyto­megalovirus retinitis and chis was treated wi th intravenous foscamet (Astra Pharma Inc) initia 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 marrow 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, he was unable to take anything by mouth and had significan t weight loss. He had no pyrosis, regurgitation, nausea, vom­iting, abdominal pain, fever or signs of gastrointestinal hemorrhage. His oral candidiasis had been noted co be worse over the week prior to admission and had been treated with oral ketocona­zole 200 mg daily for two weeks with no significant improvement. The patient had never had dysphagia or odyno­phagia 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 and oral cavity. There was severe oral candidiasis but no aphthous ulcers were noted. O ther systems were unre­markable. He had severe neutropenia ( white blood cell count was 0.9x109/L) and absolute neutrophil counts were less than 500xl06/L; this 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 diagnos­tic 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 for 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 completely within 24 h that he was able to resume his oral intake. The nitroglycerine ointment was continued and amphotericin B was d iscontinued after five days (oral keto­conazole 200 mg daily was then given).

The patient was d ischarged on day 9 without odynophagia or dysphagia on keroconazole 200 mg daily and N itro­Bid l " tid.

DISCUSSION Odynophagia and dysphagia are

very common in patients with AIDS ( 1 ). Although the exact frequencies have

not been established since nor all pa­tients with esophagitis are symptomatic ( 15), odynophagia anJ dysphagia may be the most common symptoms experi­enced by paticnrs with AIDS (1). These symptoms can significantly decrease food intake, thereby worsening the nu­tritional sta tus of AIDS patients ( l ) and are responsible for significant morbidity in these patients.

The most common cause of odyno­phagia/dysphagia in patients with AID~ is esophageal candidiasis ( l ). le has been estimated that at King's County Hospital in Brooklyn, New York, more than 75% of patients with AIDS had symptoms of oroesophageal candidiasis during their hospital course ( 2 ). O ppor­tunistic infect ions of the esophagus with cytomegalovirus (3,4) and herpes simplex virus, both types l and 2 (6), are other well known causes for odyno­phagia/dysphagia in AIDS patients. A recent report from Canadian investiga­to rs described o ra l and esophageal ulcerat ions in associat ion with electron microscopic evidence of viral particles occurring coincident with HIV sero­conversion (7). Other conditions which may cause odynophagia/dyspha­gia arc cryptosporidiosis (8), esopha­geal lymphoma (9) and oropharyngeal Kaposi's sarcoma ( 10). It appears that acid-peptic reflux esophagitis may not make a significant contribution to odynophagia/dysphagia in AIDS pa­tients. Interest ingly, a recent study (16) has shown that achlorhydria or hypo­chlorhydria and decreased pepsin in gastric juice may be common in pa­t ients with AIDS.

The relationship between ora l and esophageal 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 involvement of the esophagus, regardless of the presence of odynopha­gia/dysphagia. Therefore, these investi­gators advocated char a patient with AIDS, odynophagia/Jysphagia and oral candidiasis could be presumed to have esophageal candidiasis without radio­logical or endoscopic confirmation, and the patient could be treated with appropriate anti fungal therapy. lt was

350 CAN J 0ASTROENTEROL VOL 7 No 4 M AY/JUNE 1993

suggested that further diagnostic eva lu­ation could be reserved for nonrcspo n­Jcrs or for patienls with clinical and laboratory evidence of an esophageal Jisorder othe r than esophageal can­JiJiasis. While ora l thrush ofLen pre­dicts concurrent csophagitis, iL is clearly established tha t the absence of thnish docs not exclude the possibility of esophageal candidiasis (22,23 ).

The treatment of oclynophagia/dys­phagia in AIDS pa Licnts depends on the specific etio logy. In esophageal can­didiasis, nystatin suspension and clotri­mazole lozenges a rc gene rally consid­ered to be inadequate therapy, even though they may be benefic ial for treat­ing oral candidiasi ·. Ketoconazole has been the mainstay of the rapy for esophageal candidiasis ( l ). This imida­:ole compound increases fungal mem­brane permeability by interfering with ,rerol synthesis (I ). Even though oral kcroconazole 200 mg da ily is an cffec­ttve therapy for esophageal candidiasis in patients with immunode ficiency states other than AIDS ( 11 ), this dose often is ineffective for e radicating esophageal candidiasis in some patients with AIDS (1 2). Therefore, a J ose of kcroconazole up to 600 mg a Jay has been suggested (1) to eradicate esopha­geal candidiasis wi tho ut causing hepa­tcicellular tox icity. Patients who fail to

respond to high dose ke toconazole may respond to the newly developed flu­conazole or low J ose intravenous am­photericin B.

Herpes csophagitis will respond to acyclovir, a lthough resolution often is followed by re lapses. Cytomegalovirus csophagitis has been successfully treated with ganciclovir (13 ,14), a l­though large, randomized controlled scuJies with confirmatory endoscopic examinations arc lacking.

Reduction of esophageal symptoms t1 an important goal since it leads to

REFERENCES I Raufman J-P. O<lynophagia/J ysphagia

m AIDS. Gastroentcrol Clin North Am 1988; 17:599.

2. FarmanJ , Tavit ian A, Ro~emhal LE. Focal esophageal candiJias1~ in .icquircJ immumxlcficiency syndrome (AIDS). Gastroincesr RaJilll 1986;1 l:213.

grcmcr comfort, increased o ral intake, better nutritional status anJ ability to take medications. Eradication of these opportunistic infectio ns docs not nec­essarily prolong survival and suppres­sion only may be achieved. The odyno­phagia, in particular, may have multifactoria l causes, such as invas ion beyond the mucosa by the organism, inflammatory reactions, 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 esophageal spasm may contribute to

od ynophagia/ dysphagia in these AIDS patients.

In uncontrolled trials (25-29), short- and long-acting ni trates reduced symptoms and improved mano metric and radiographic patte rns in some pa­tients with spastic disorders of smooth muscle segments of the esophagus. These agems are thought rn be benefi­cial because of the ir re laxant effect on smooth muscle, a lthough the effect on manometric paramete rs may actually be minimal. Calcium channel blockers, in some anecdotal cases (30-33), have shown po tential benefit in the manage­ment of spastic disorde rs of the esopha­gus. Calcium channel 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 for con­t raction . However, evidence support­ing the uniform efficacy of calcium channel blockers is lacking in cont rol­led studies (34 ). Successful management of symptoms of esophageal spasm has a lso been anecdota lly reported using psychoactive drugs, including the anti­depressant trazodonc hydrochloride (35).

T he presented patien t had severe odynophagia associated with oral ca n­didiasis re fractory to oral ketoconazole.

3. Balthazar EJ, Mcgibow AJ, I lulonick DI l. Cytomcgalovirus esophagitis anJ gastritis in AIDS. Am J RaJiol l 985; 144: 120 1.

4. Sr Ongi G, Bczahlcr OH. Giant esophageal 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

The patient also had severe neutro­pen ia which precluded defin itive diag­nostic endoscopy because of concern for aspiration and infectious complica­t ions. Most likely, however, th is pa­tient d ic.J h ave severe esophageal can­Jidiasis as suggested by the above discussion. A lthough opportunistic in­fect ions of the esophagus by cytomega­lovirus or herpes virus were possibil i­ties, he had been on ganc iclovir and ncyclovi r for some time prior to his presentation. I ncravcnous amphoteri­c in B was ini tiated soon afte r admission but the time interval between the start o f amphoteric in Band his dramatic re­sponse make amphOLericin very un­like ly as the benefic ia l agent. T opical nitroglycerin was selected rather than the sublingual or 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 oral in take for both pleasure and nutritional support, with clear-cut improvement of his qua lity of life.

CONCLUSIONS Esophageal spasm may he a sign ifi­

cant factor in the odynophagia/J yspha­gia common ly expe rienced by AlDS patients. N itroglycerin - topically, sub­lingual ly or orally - may provide rapid amelioration of these symptoms wh ile specific ant i-infect ive treatments a re institu ted. The symptomatic re lief may a llow improved nu trient intake in these patients anJ enhance their gen ­eral nutri tiona l sta tus and qua lity of life. Othe r smooth muscle relaxants, such as calc ium channel blockers or psychotropic medications, may have an adjunc tive role in the treatment of these esohagcal sympto ms.

G,1slrointestinal complications of AIDS: RaJ iologic features. RaJ1ology 1986;158:597.

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7. Rabeneck L, Boyko WJ, McLean DM,

35 1

KIM eial

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9. Fkrnal A, del Junco GW. Emh,scnp1c 18. Tavit ian A, Raufman J- P, Rosenth al 1981;15:806. ,md pathlllogk fc.1tures uf e,llph ageal LF. Orn I candidinsis rn, u marker 28. Mclk1w Ml I. Effect of isosmhide and lymphnma: A rcp,lrt of fnur C;tM:s in for esoph:1gcal cnndidias1s in the h ydrn la:inc in painful primary pat ients with ,1Lq u1rcd acquired immunodeficiency esoph ageal 111oti l11 y dborder. immunodeficiency syndrome. syndru mc. Ann Intern Mcd Gast n >L'nternlogy 1982;8 3:364. Gastrointcsr Endnsc 1986; 32:96. 1986; I 04:54. 29. Kikemhill JW, Mrcllow M l I. Effect of

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11. F.iz10 RA, WiLknemc,mghc PC, Arsun The· diagnnsis nf csnphageal Singleton RT, c t a l. Primary EL, ct .ii. Keto.:,,naznle trc:urnent llf c mdidiasis 111 patients with acquired csophageal motor d isorder: C linical candida esophagi, is a pnbp~clive immunodeficiency syndr11mc: Is response to N ifcdipine. Snu t h Med J study n f 12 c,1sc,. Am J Gastn,enternl endmcopy ,ii ways ncn·ssary? A m J 1985;78:3 I 2. I 983;78:261. Ga,t roc.:n rcrol 1989;84: 14 "l. l 1. Cargill G, Theodore C, Pan lagg, JA.

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14. C h ad1mm A, Dictench l), ct a l. 9- oppo nun b tic infection in .icqu1red ct al. Ornl nifcdipinc in the treatment ( I , 3-dihydroxy-2-propoxymcth yl) immunodeficiency syndrome. Dig Dis of nonrnrdiac ch c,1 patn 111 patients gunn inc (g:111.:ic lnv ir) m the t rc:itmcnt Sci 1986;3 I :328S. with the nut c racker esophagus. of cytllmcgalovirus g.istmimcstin :11 24. Gould E, Kory UP, Raskin JP, c t al. Gast ruentcmlogy 1987;93:2 I . d isease w11h t he :icquircd Esoph ageal hiopsy findings in the 35. C lause RE, Lusuw111 PJ. Eckert T C, immunodeficiency ,yndro mc. A nn acquired immunod eficiency syndrome ct al. Low dose T razmlnnc fur Intern Med 1987; 107: I 3l. (AIDS). C linicopathologic correlation sympto matic patients with

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352 CAN J GA:-;TROI.NTl:R~ll VOi 7 N~14 MAY/JL'NE 199l

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