Recognizing Doxycycline-Induced Esophageal Ulcers in Dental Practice
A Case Report and Review
Stuart L. Segelnick, DDS, MS and
Mea A. Weinberg, RPh, DMD, MSD
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ABSTRACT
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Background. Doxycycline-induced esophageal ulcer is a documented adverse drug reaction. Unfortunately, many health care professionals are not familiar with this particular drug reaction. Because doxycycline frequently is prescribed in the clinical practice of periodontics, it is important for dentists to be aware of this potential drug reaction.
Methods. The authors describe the case of a patient who was taking doxycycline after undergoing periodontal surgery and experienced a complication. The diagnosis revealed that the patient had developed an esophageal ulcer as a result of taking the doxycycline.
Results. The patient’s esophageal ulcer resolved with the aid of dietary changes and a prescription of rabeprazole, a proton pump inhibitor.
Conclusions and Clinical Implications. The etiology of doxycycline-induced esophageal ulceration is complex, and proper diagnosis is essential for its resolution. Dentists should be aware of the potential for this adverse drug reaction.
Key Words: Drug injuries; doxycycline; esophageal ulcer; patient education; adverse drug reaction; dentistryAbbreviations: GI: Gastrointestinal.
Doxycycline is a commonly used antibiotic in dentistry and especially periodontics. When not taken properly, doxycycline has been implicated in causing ulcers of the esophagus through a combination of drug factors, including acidity and dissolution rate.
The risk of esophageal injury can be minimized by being cognizant of the early symptoms and by taking the drug in an upright position. Doxycycline should be taken well before lying down; at least a few sips of water should be drunk before taking the drug, and a full glass of water should be drunk when the drug is swallowed. An overview of the uses, formulations and adverse effects of doxycycline follows, along with a case report of doxycycline-induced esophageal ulcer.
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DOXYCYCLINE
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Doxycycline, a member of the tetracycline class of antibiotics, frequently is used in medicine and in dentistry for its antibacterial properties. It is effective against a wide range of bacteria, including those found in dental infections. Many adverse effects have been reported, including esophageal ulcers, gastrointestinal distress, xerostomia and exaggerated sunburn when the patient is exposed to sunlight or ultraviolet rays.
Indications.
Doxycycline is a semisynthetic derivative of oxytetracycline invented and clinically developed in the 1960s. Tetracyclines are among the most important broad-spectrum antibiotics used in medicine and periodontics.1 Doxycycline frequently is used to treat chronic prostatitis, sinusitis, syphilis, chlamydia, pelvic inflammatory disease, acne and rosacea. In addition, it is used in the treatment and prophylaxis of Bacillus anthracis (anthrax), Lyme disease, and Rocky Mountain spotted fever and in prophylaxis against malaria. Tetracyclines have been used in periodontics for more than 25 years; in 1981, Gordon and colleagues2 published an article documenting that tetracycline was detectable in gingival fluid at least 19 hours after a single dose but rarely was detectable at 24 hours. Tetracyclines continue to be used for a wide range of periodontal indications.3–9
Description.
In pharmaceutical formularies, doxycycline is described as a light-yellow crystalline powder. Once absorbed, it generally is very stable in normal body fluids, where it forms an acidic solution (pH 3.0) that can account partially for its toxic effects. This pH, however, also is beneficial. An acidic solution of doxycycline at 100 milligrams per milliliter, when applied to root surfaces, is effective in eliminating the smear layer and demineralizing the root surface to facilitate the formation of a new attachment through exposure of collagen fibrils.10
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ADVERSE DRUG REACTIONS
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Several adverse effects have been reported with the use of doxycycline and tetracycline: esophageal ulceration and heartburn, gastrointestinal (GI) distress (because of doxycycline’s almost complete absorption from the GI tract, diarrhea is less common than with tetracycline use), tooth and soft-tissue staining, photosensitivity, black hairy tongue (due to superinfection) and xerostomia. The use of tetracyclines during tooth development in the last half of pregnancy and in children to the age of 8 years may cause permanent discoloration of the teeth (yellow-gray-brown). Also, widespread emergence of bacterial resistance to the tetracyclines has diminished their effectiveness.
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CASE REPORT
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In October 2007, a 42-year-old woman was examined by S.L.S. in our private practice in Brooklyn, N.Y. Her medical history included gastric bypass surgery for weight loss in November 2004 and an allergy to penicillin. At the clinical examination, severe recession of the maxillary right canine of 5 millimeters, Miller Class III, was noted by S.L.S. The treatment plan consisted of placement of an acellular dermal matrix graft (Alloderm, Biohorizons, Birmingham, Ala.). The surgery was uneventful. The patient was given postoperative instructions by S.L.S. and prescriptions for 11 capsules of doxycycline 100 mg, two to be taken immediately and the rest once daily until finished. The patient also received a 16-ounce bottle of chlorhexidine gluconate for twice daily rinsing.
On the day of surgery, the patient took two capsules of doxycycline with a small amount of water in the evening two hours before going to sleep. On the following days, she took one capsule every morning.
The patient returned one week later, and the dentist determined that her postprocedure healing was uneventful. She reported that she had a sore throat and odynophagia and that she was going to see her physician about her symptoms. After leaving the dentist’s office and without reporting any other untoward effects, she went to her physician and reported severe sharp painful spasms down her throat. These tightening spasms transpired approximately six times an hour and lasted for a few seconds each. Her throat felt sore when she swallowed saliva, food and even liquids. The physician thought it might be thrush and esophageal ulcers. He recommended that she stop taking the doxycycline and prescribed nystatin, an antifungal agent, and omeprazole, a GI proton pump inhibitor agent.
Three days later, there was no improvement, and the physician referred her to a gastroenterologist. The gastroenterologist performed endoscopy with the patient under intravenous conscious sedation and found three ulcers in the middle of the esophagus (Figure 1
). Concurrently, he performed a biopsy of the area, the results of which confirmed his diagnosis of esophageal ulcer (Figure 2). His diagnosis was ulceration of the middle of the esophagus secondary to doxycycline use. He found no evidence of thrush. He prescribed rabeprazole 20 mg orally every morning and advised the patient to avoid consuming acidic and spicy foods until the ulcer healed. Four days after seeing the gastroenterologist, the patient felt a complete resolution of symptoms. She continued taking the rabeprazole for another eight weeks.
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Figure 1. Endoscopic views of esophageal ulcers caused by doxycycline. A. Endoscopic view of esophageal ulcer located 25 centimeters from the epiglottis. B. Endoscopic view of superficial linear ulcer of surface mucosa with surrounding erythema. C. Esophageal ulcer located 28 to 30 cm from the epiglottis.
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Figure 2. Photomicrograph of biopsy specimen of esophagus (hematoxylin and eosin stain, original magnification X200) showing stratified squamous cell epithelium with hemorrhage and granulation tissue in the lamina propria in response to an adjacent ulcer.
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DISCUSSION
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The reported incidence of doxycycline-induced esophageal ulceration is approximately four in 100,000,11 and most likely it is underestimated because of the failure to report the adverse drug effect by the patient or the physician or failure of the clinician to diagnose it properly. Tetracyclines, particularly doxycycline, have been implicated in about 70 percent of all reported drug-induced esophageal ulcerations.12 There is a possibility that this also may occur with doxycycline 20 mg. This long-term low dosage of doxycycline is used to treat periodontal disease nonsurgically, but, to date, no cases of induced esophageal ulcers have been reported. However, as a precaution, the clinician should advise the patient that the drug be taken at least two hours before going to sleep.
The patient took the initial loading dose of 200 mg as a single dose. Many periodontal studies have used this single loading dose regimen.13–17 In addition, doxycycline has been used with the same and higher dosages for other infections.18,19 Spacing the initial doses apart by eight to 12 hours might have prevented this complication.
We believe that the physical contact of the capsule with the epithelial lining of the esophagus likely caused the ulceration. Doxycycline is available in tablets and capsules, with capsules being dispensed more frequently. Esophageal ulceration can occur with either form,11,12,20–24 although the incidence possibly is greater with capsules than with tablets,12 because of a number of factors that make them more prone to causing ulcerations. When a capsule is swallowed, it enters the esophagus and then the upper part of the stomach, where it is disintegrated (opened) before the drug can be dissolved. Then it passes down into the upper part of the duodenum, where most of it is absorbed through the GI mucosal lining into the blood. On the other hand, when a tablet is swallowed, it enters the esophagus and then the upper part of the stomach, where it disintegrates before entering the duodenum.
After the capsule, which is sticky and gelatinous, is swallowed, it may linger in the esophagus or stick to the mucosa if too little water is taken; as it opens up, the acidic powder may come into direct contact with the esophageal nonkeratinized epithelium.11,25 Doxycycline capsules remain in the esophagus three times longer than do doxycycline tablets.11
The esophagus is a muscular canal about 23 to 25 centimeters long, extending from the pharynx to the stomach. It is the narrowest part of the digestive tube and is most contracted at its beginning and at the point where it passes through the diaphragm. The esophagus has four layers: external or fibrous, muscular (smooth muscle), submucosal (contains mucous secreting glands called esophageal glands) and internal or mucosal. The mucosa layer (tunica mucosa) is thick and is arranged in longitudinal folds, which disappear when the tube distends. Its surface has small papillae, and it is covered throughout with a thick layer of nonkeratinized stratified squamous epithelium. This layer is turned over rapidly and plays a protective role because of the high-volume movement of food, saliva and mucus.
In most cases, ulcers initiated by doxycycline are superficial, whereas ulcers resulting from use of nonsteroidal anti-inflammatory drugs or other therapeutics are more deeply involved.21 In this case report, the ulcer was located in the middle of the esophagus. The area of ulceration involved in this case is similar to findings in other case reports11,21,26,27 in which the middle one-third of the esophagus, at the aortic arch level or above the lower esophageal sphincter—the narrowings where the capsules or tablets often stick—was the most common site.
We agree with the conclusions of several studies28–31 that improved clinical outcomes often do not result from the use of antibiotics in general; this indicates that antibiotics may not be necessary as supplements for usual and customary periodontal and oral surgical procedures. However, in cases in which bone or tissue grafts are placed, antibiotics may be considered part of pre-or postsurgical care because these newly placed grafts have not yet established a blood supply (revascularization) with the host bone or tissue.32 This antibiotic regimen is used to reduce the potential for infection until a blood supply (and hence inflammatory cells) is established, which takes about seven to 14 days.32 In addition, a meta-analysis9 of reported literature has shown a slight statistically significant improvement in periodontal surgery results with prophylactic use of antibiotics. However, the complexity in selecting the appropriate antibiotic, dosage and patient is not identified in the meta-analysis.
Most case reports of esophageal ulcer resulting from doxycycline use indicate that patients complained of odynophagia, retrosternal pain and dysphagia.26,33 In this case, the patient’s only symptoms were a sore throat and odynophagia. Symptoms can be useful in leading to a correct diagnosis. However, the diagnosis of doxycycline-induced ulcers is established by means of upper GI endoscopy.33
The first step in treatment of such ulcers is discontinuation of the doxycycline therapy. In some cases, however, it can be continued if proper patient education is initiated. Treatments vary, and it is controversial whether the clinician should administer antacids, sucralfate, histamine H2 receptor antagonists or proton pump inhibitors.22,34 Gastric acid secretion must be controlled to avoid further chemical irritation of the ulcer.22 Some patients may require hospitalization and intravenous administration of fluids.22
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CONCLUSION
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Providing the patient with instructions regarding doxycycline and tetracycline often is overlooked. Proper patient instructions often can reduce the incidence of adverse drug reactions. Doxycycline can be taken with food or on an empty stomach, which is interpreted as one hour before meals or two hours after meals. An empty stomach ensures quicker absorption into the blood. Doxycycline must be taken with a full glass of water and the patient must stay in an upright position for at least two hours. Both the dentist and the pharmacist are responsible for reviewing instructions with the patient (Box). The patient should report the onset of diarrhea, heartburn or dysphagia to the physician. In addition, the patient should avoid direct exposure to sunlight during therapy and for several days after therapy is terminated to reduce the possibility of photosensitivity reaction, which appears as exaggerated sunburn.
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FOOTNOTES
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Dr. Segelnick is a clinical assistant professor, Department of Periodontology and Implant Dentistry, New York University College of Dentistry, New York City. He also is in private practice, Advanced Periodontal Services, PC, 1603 Voorhies Ave., Second Floor, Brooklyn, N.Y. 11235, e-mail "EperioDr{at}aol.com". Address reprint requests to Dr. Segelnick.
Dr. Weinberg is a clinical associate professor, Department of Periodontology and Implant Dentistry, New York University College of Dentistry.
Disclosure. None of the authors reported any disclosures.
The authors thank Dr. Mike Salkin for his guidance and invaluable editorial assistance in preparing this article and Dr. David Wolfson for the endoscopic views, histologic testing and patient care.
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ABSTRACT
DOXYCYCLINE
