Saudi Journal of Gastroenterology
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Year : 1998  |  Volume : 4  |  Issue : 1  |  Page : 20-24
Doxycline-induced esophageal ulcerations


1 Department of Gastroenterology, Dr. Al Mofarreh Polyclinic, King Fahd Quarters, Riyadh, Saudi Arabia
2 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Date of Submission19-Oct-1997
Date of Acceptance24-Nov-1997
 

   Abstract 

Over a period of six years 16 patients presented to Dr. Al Mofarreh's polyclinic with drug­-induced esophageal ulcerations. One patient had esophagitis without ulcerations and two patients, who declined endoscopy were not included in this analyzis. The mean age of the remaining 13 patients was 28.92 ± 10.39 years. The mean ulcers number was 3.69 ± 2.76. The ulcers were located at the mid-esophagus, 29.23 ± 3.94 cm from the incisors teeth. Odynophagea, retrosternal pain and dysphagea in 13 (100%), 12 (92%) and 9 (69%) patients, respectively, were the most frequent presenting symptoms. All patients took a doxycycline preparation at bed time with little water. The mean elapse between the drug intake and endoscopy was 7.85 ± 9.96 days. The symptoms resolved within a maximum of one week of antireflux treatment despite the continuation of doxycycline therapy in three patients with brucellosis. The current data confirmed the role of oral doxycycline intake, the timing and the amount of concurrent fluid in the etiology of esophageal ulcerations.

How to cite this article:
Al Mofarreh MA, Al Mofleh IA. Doxycline-induced esophageal ulcerations. Saudi J Gastroenterol 1998;4:20-4

How to cite this URL:
Al Mofarreh MA, Al Mofleh IA. Doxycline-induced esophageal ulcerations. Saudi J Gastroenterol [serial online] 1998 [cited 2019 Feb 21];4:20-4. Available from: http://www.saudijgastro.com/text.asp?1998/4/1/20/33903


Esophagitis is the most frequent esophageal disorder. Chemical esophagitis due to reflux disease is the commonest form. Corrosives and drugs are other causes of chemical esophagitis. Around 90% of drug-induced esophagitis occur after use of emopronium bromide, tetracyclin and derivatives, potassium chloride and quinidine [1] . Other incriminated drugs include ferrous sulfate [2] , aspirin and other nonsteroidal anti-inflammatory drugs, (NSAIDs) [2],[3] , clindamycin, lincomycin, erythromycin, penicillin-V, potassium chloride, ascorbic acid [2] , theophyllin [4] and alendronate [5] . Retrosternal pain, odynophagea and dysphagea are the most frequently reported symptoms [1],[2] .

The diagnosis is established by upper gastrointestinal endoscopy, which is recognized as the method of choice [1] . Double contrast studies detect also superficial ulcers and subtle mucosal changes [6],[7] . History alone may also be sufficient to establish a clinical diagnosis [1],[8] . Ulcers occur often at the level of the aortic arch and occasionally at the distal esophagus [7],[9] . Histopathological changes are non-specific and constitute necrosis and inflammatory exudate with eosinophils and lymphocytes predominance [8] .

The clinical course is usually uneventful and severe complications are rare [1],[10] . However, serious sequelae including mortality may complicate potassium induced injuries. Severe complications have also been associated with iron, quinidine and NSAID s . The disease is usually self-limiting. Symptoms frequently disappear within 10 days of symptomatic treatment and discontinuation of injurious drugs[1],[11]. It can be prevented by avoiding drug intake at bed time and ingestion of an adequate fluid amount.

The aim of this article is to increase the awareness of physicians and endoscopists on drug-induced esophageal ulcerations and to discuss endoscopic features, drugs implicated, prevention and treatment.


   Patients and Methods Top


In a retrospective analyzis of 4818 upper gastrointestinal (UGI) endoscopies performed by the same endoscopist in a private clinic over a period of six years, 16 patients had drug-induced esophageal ulcerations. In this analyzis only 13 patients with ulcerative esophagitis were included. The remaining three patients, one had non-ulcerative esophagitis and two declined endoscopy were not included. Endoscopy was performed after a 12 hours fasting utilizing 10% xylocaine spray or 2% xylocaine viscous (Astra, Sweden) for local anesthesia. Pentax EG 2901 UGI-endoscope (Pentax EPM-3000 videoscope system) was used. Hard print photodocumentation was performed in all patients utilizing color video printer (UP-5000 P, Sony). The number of ulcers and the distance from the incisors teeth was estimated. Biopsy material was initially obtained in two patients to determine the etiology of ulcerative esophagitis. After endoscopic diagnosis, patients were asked to bring the drugs correlated with the development of the current symptoms. They were also asked about the timing of drug intake and the amount of concurrent fluid ingested. The diagnosis in all 13 patients included and in the patient with non-ulcerative esophagitis was based on history and endoscopy. In the two patients who declined endoscopy the diagnosis was based on history alone. The patients were managed with proton-pump inhibitors and prokinetics and when feasible, the injurious drug was withdrawn. All patients were requested to give a feedback on their response after a week of treatment initiation.


   Results Top


Over a six years period 4818 UGI-endoscopies were performed. Esophagitis was diagnosed in 1084 patients. Majority (1015) were due to gastroesophageal reflux and 65 patients had esophageal moniliasis. Drug-induced esophageal ulcers were found in 13 patients with almost equal gender distribution (six males and seven females). Another female patient had esophagitis without ulceration was excluded. The age ranged between 14 and 55 (mean 28.92 ± 10.39) years. All patients presented with odynophagea. Other symptoms and patients characteristics are as shown in [Table - 1]. Doxycycline was the only drug incriminated in all patients. It was prescribed for acne in five,  Brucellosis More Details in three and miscellaneous indications in the remaining patients. Doxycycline was combined with rifambicin to treat brucellosis in one patient. The elapse between drug ingestion and endoscopy was 3-8 days in 12 patients and 42 days in one patient (mean 7.85 ± 9.96 days). The ulcers were found at 18 - 36 (mean 29.23 ± 3.94) cm from the incisors teeth. The surrounding mucosa appeared normal. The ulcers were variable in size, depth and number. The number ranged from one to ten (mean 3.69 ± 2.76) ulcers [Figure - 1],[Figure - 2],[Figure - 3],[Figure - 4],[Figure - 5],[Figure - 6]. The histopathological findings in two patients, including the patient who was symptomatic for 42 days, revealed non-specific ulcerations with inflammatory cells and edema. Repeat endoscopy four weeks after treatment revealed healed ulcers.

All patients,except one,adhered to followup. Initial improvement occurred as early as 24 hours after treatment initiation in some patients. After one week, all patients reported a complete resolution of symptoms including the three patients in whom doxycycline therapy for brucellosis was continued.


   Discussion Top


The prevalence of drug-induced esophageal ulcerations in this analyzis was 0.0027. Several drugs including antibiotics, NSAIDs, potassium chloride, quinidine, ascorbic acid and iron preparation may induce ulcerative esophagitis [2] , Doxycycline [2],[12] and alendronate [5] are the two more frequently incriminated drugs.

The only drug incriminated in our patients was doxycycline. The risk factor was drug intake at bedtime with little fluid in all patients. During recumbency and sleep, salivation and swallowing are reduced and esophageal transit time is prolonged, which causes drugs retention in the esophagus [2] Pre-existing esophageal disease and external esophageal compression, due to left atrial enlargement, precipitate also drug-induced esophageal ulceration[3] . None of our relatively young patients had a history of a pre-existing esophageal or cardiac disorder.

Drug retention and the acidic property of a drug such as doxycycline and ferrous compounds, may explain its injurious esophageal mucosal effect [2],[5] . Esophagitis associated with NSAIDs is linked with a mucosa altered protective function due to decreased prostoglandine synthesis [13] . Other drugs may produce hyperosmotic solution with noxious effect [2] .

The ulcers were located mainly at the mid­esophagus. This agrees with other reports where the mid-esophagus was found to be the commonest site [7],[9] . The ulcers number and size were variable. They were small and/or large, single or multiple, mostly facing each other with apparently normal surrounding mucosa. Extensive ulcers involving a large portion or the entire esophagus reported in association with alendronate use, are atypical for drug-induced esophageal injury [14] . We have not encountered such a severe and extensive esophageal injury.

The main presenting symptoms of our patients were odynophagia, retrosternal pain and dysphagia in 100, 92% and 69% of patients, respectively. This is in agreement with other reports, where retrosternal pain, odynophagia and dysphagea are the most frequently reported symptoms [1] . Heartburn in 62% of patients ranged as the fourth commonest symptom.

Drug-induced esophageal ulcerations were verified in all patients included by endoscopy. Endoscopy is the method of choice for confirming the clinical diagnosis. Double contrast barium swallow is also accurate and may detect even subtle mucosal changes, but single contrast study may give wrong negative results [1],[2] . Complications were not encountered in this analysis. However, serious sequelae such as hemorrhage strictures and perforations with fatalities have been reported usually in association with potassium chloride, NSAIDs, quinidine and ferrous preparations but not with antibiotics [2],[15] . Complications due to alendronate have occured during the first month of treatment [5] . Drug-induced esophagitis is usually a self-limiting disease and symptoms resolve within 10 days [1] .

We agree with other authors, who have considered injurious drug withdrawal as the main step of management [1],[2],[5],[11] . However, we feel doxycycline therapy can be continued when required with emphasis on patients education in regard of timing of medication and the amount of fluid required. All patients became asymptomatic within the first week of treatment with proton-pump inhibitors and prokinetics despite the maintenance of doxycycline therapy in patients with brucellosis.

The benefit of commonly used medications including antacids, sucralfate, H 2 -receptors antagonists and proton-pump inhibitors for treatment of drug-induced esophageal injuries remain questionble unless associated with gastroesophageal reflux [5],[14] . We noticed that ulcers have not healed completely in a patient reendoscoped after a month of treatment and doxycycline withdrawal. In addition another patient who presented to us six weeks after completing a course of doxycycline continued to be symptomatic and endoscopy revealed esophageal ulcerations. His symptoms improved soon after initiation of treatment and ulcers healing was confirmed by endoscopy. Hence, we think proton-pump inhibitors and prokinetics may be required and even extended over a longer period in some patients.

In conclusion, in the current study, doxycycline was responsible for all drug-induced esophageal ulcerations. The presence of odynophagea and retrosternal pain should raise the suspicion and necessitate exploration of drugs history and endoscopy to confirm the diagnosis. Withdrawal of doxycycline is the main step of management when feasible. Patients education and the use of alternative drugs in patients at risk are important to prevent drug-induced esophageal ulcerations. Proton-pump inhibitors and prokinetics may be indicated, especially in patients who require doxycycline therapy and in those who continue to have symptoms, despite drug withdrawal.

 
   References Top

1.Bott S, Prakash C, McCallum RW. Medication-induced esophageal injury: Survey of the literature. Am J Gastroenterol 1987;82:758-63.  Back to cited text no. 1  [PUBMED]  
2.Kikendall JW, Friedman AC, Oyewole MA, et al. Pill induced esophageal injury: Case reports and review of the medical literature. Dig Dis Sci 1983;28:174-82.  Back to cited text no. 2  [PUBMED]  
3.Coates AG, Nostrant TT, Wilson JAP, Elta GH, Agha FP. Esophagitis caused by nonsteroidal anti-inflammatory medication; Case reports and review of the literature on pill­induced esophageal injury. South Med J 1986;79:1094-7.  Back to cited text no. 3    
4.Enzenauer RW, Bass JW, McDonnell JT. Esophageal ulceration associated with oral theophylline. N Engl J Med 1984;310:261.  Back to cited text no. 4  [PUBMED]  
5.Castell DO. "Pills esophagitis" The case of alendronate. N Engl J Med 1996;335:1058-9.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Creteur V, Laufer I, Kessel HY, et al. Drug-induced esophagitis detected by double-contrast radiography. Radiology 1983;147:365-8.  Back to cited text no. 6    
7.Agha FP, Wilson JA, Nostrand TT. Medication-induced esophagitis. Gastrointest Radiol 1986;11:7-11.  Back to cited text no. 7  [PUBMED]  
8.Ramirez RA, Valladares G, Barreda CC. Esophageal ulcers induced by doxycyclin: evaluation of 4 cases. Acta Gastroenterol Latinoam 1981;11:309-13.  Back to cited text no. 8    
9.Jeffery PC, Cullis SN. Drug-induced esophagitis. S Afr Med J 1983;64:1081.  Back to cited text no. 9  [PUBMED]  
10.Kato S, Komatsuk, Harada Y. Medication-induced esophagitis in children. Gastroenterol Jpn 1990;25:485-8.  Back to cited text no. 10    
11.Mason SJ, O'Meara TF. Drug-induced esophagitis. J Clin gastroenterol 1981;3:115-20.  Back to cited text no. 11  [PUBMED]  
12.Amendola MA, Spera TD. Doxycycline-induced esophagitis. JAMA 1985;253:1009-11.  Back to cited text no. 12  [PUBMED]  
13.Heller SR, Fellows IW, Ogilvie AL, et al. Non-steroidal anti­inflammatory drugs and benign esophageal stricture. Br Med J 1982;285:167-8.  Back to cited text no. 13    
14.de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996;335:1016-21.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Spera TD, Amendola MA. Drug-induced esophagitis. JAMA1985;254:508.  Back to cited text no. 15    

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Correspondence Address:
Mohammad Abdullah Al Mofarreh
Dr. Al Mofarreh Polyclinic, King Fahd Quarters, P.O. Box 9789, Riyadh 11423
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


PMID: 19864782

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