Drug or pill-induced esophagitis is esophageal mucosal injury caused by the medications and usually refers to a direct toxic effect on esophageal mucosa by the culprit medication. Common symptoms include retrosternal pain, dysphagia, or odynophagia. It was first reported in 1970 by Pemberton when a patient was found to have esophageal ulcers after taking potassium chloride tablets. Drugs can be damaging to the esophageal wall by having a direct toxic effect on the esophageal mucosa, which produces a caustic effect by creating an acidic or alkaline environment. Drug-induced esophagitis can be self-limiting esophagitis, but if persistent, then it can lead to complications such as severe ulceration, strictures, and rarely even perforation. Gastroesophageal reflux disease can aggravate drug-induced esophagitis. This activity will review Drug-induced esophagitis clinical manifestations, etiology, pathophysiology, diagnosis, and management.
There are reports of more than 30 medications as a cause of drug-induced esophagitis. More commonly reported drugs as a cause of drug-induced esophagitis are listed below. Still, it may also be true that any medication can cause drug-induced esophagitis as the mechanism of injury also takes certain other patient-related factors such as inadequate water intake and recumbent position while taking pills. Other patient-related factors include reduced saliva production, which may be due to the ingestion of anticholinergics or other diseases such as Sjogren syndrome etc. Rarely, drug-induced esophagitis can occur due to an anatomical factor or underlying esophageal disorder, for example, undiagnosed vascular ring, scleroderma, etc.
According to a Swedish survey of 700000 patients at medical institutions conducted for four years, the estimated incidence of drug-induced esophagitis is 3.9 per 100000 population per year. Drug-induced esophagitis is more common in females and elderly patients. It is also common in patients using a capsule form of the drug. Another estimate suggested 10000 cases per year in the United States. Other data estimate more than 20 cases in the pediatric population. Among them, the youngest child having drug-induced esophagitis was three years of age.
The pathogenesis of medication-induced esophagitis involves a direct irritant effect and disruption of cytoprotective barriers. Researchers hypothesize that prolonged contact of irritants with the esophageal mucosa can lead to mucosal damage. Some mechanisms have been proposed by which a drug causes esophageal mucosal injury, which includes factors related to both medications and the patient itself.
Drugs related factors
Local acid burn and hyperosmolar properties of a medicine can cause esophageal mucosal injury. A clinical and experimental study which included 40 patients who were taking tetracyclines and developed esophageal ulcer showed similar appearance on endoscopy. The study demonstrated the corrosive effect of tetracycline on the esophagus of a cat in the experimental part of the study. Low PH medicines such as doxycycline, ferrous sulfate, and ascorbic acid cause drug-induced esophagitis with a similar mechanism. Reports also exist of hyperosmolar property-related local tissue destruction and vascular injury of the esophagus as a cause of potassium chloride-induced esophagitis. Sustained-release drugs have higher chances of causing esophagitis as compared to other preparations. Likewise, gelatin capsules are more likely to cause esophagitis because of their hygroscopic nature. They become sticky and adhere to the esophageal wall, probably due to mechanical pressure on the wall of the esophagus or by chemical injury to the mucosa once the drug gets released from the capsule.
Aspirin and other nonsteroidal anti-inflammatory drugs can cause drug-induced esophagitis, albeit with a different mechanism by disrupting the cytoprotective prostaglandin barrier of the esophagus.
Patient-related reasons mainly include factors that cause prolonged transit time of medications in the esophagus. Geriatric-related low saliva production, altered esophageal anatomy, taking a medication just before sleeping, and motility disorder can all result in increased esophageal transit time for drugs, as demonstrated in several studies. The other and probably most important factor is medication ingestion with insufficient water and in the recumbent position. In one study, healthy volunteers showed delayed esophageal transition (defined if transit time is greater than 90 seconds) in subjects taking medications in the recumbent position and with less than 100 ml water. Many preparations stuck to the esophageal mucosa and disintegrated in the lower part of the esophagus. Difficulty in swallowing was reported with one or more medications by sixty percent of the volunteers. The study concluded that patients should take medications with at least 100 ml of water in a standing position to avoid the risk of drug-induced esophagitis, and liquid formulation should be considered in bedridden patients and in patients with swallowing difficulty.
In drug-induced esophagitis, an upper gastrointestinal endoscopy usually reveals pathology in the middle third of the esophagus. Areas of esophageal anatomical narrowing are commonly involved. Mid-esophagus may get externally compressed by the aortic arch or an enlarged left atrium (as in mitral valve disease), thus making it more prone to drug-induced injury. It can also occur at the gastroesophageal junction. Likewise, patients having hiatal hernia are more predisposed to drug-induced esophagitis. The pathology includes erosions, ulcers, mucosal friability, edema, or inflammation. Sometimes pill residues, impacted drugs, or drug coating can also be seen. Endoscopy may show complications like strictures or thickening of the esophageal wall. Other endoscopic findings include bleeding ulcers or kissing ulcers.
Histologically, drug-induced esophagitis may show intraepithelial eosinophilic infiltration. Reflux esophagitis and eosinophilic esophagitis also can have similar findings, and the diagnostic basis is on the clinicopathological picture.
Patients with drug-induced esophagitis typically present with retrosternal chest pain or heartburn, dysphagia, or odynophagia. A retrospective study that included 78 patients with pill-induced esophagitis observed the frequency of chest pain (71.8%), odynophagia (38.5%), and dysphagia (29.5%). The symptoms are generally of sudden onset, intermittent, and self-limiting. Symptoms can develop with hours to 10 days after taking the drug and can be severe enough to cause difficulties even in swallowing saliva. Patients rarely may have melena due to esophageal ulcer related bleeding. The sudden onset of symptoms is probably because the drug releases chemical contents, which then damages the mucosa. There is a history of not taking the medication with an adequate amount of water or taking the medication in the recumbent position. Patients may be taking pills just before going to sleep with little or no water.
Drug-induced esophagitis in children: Children with symptoms of dysphagia, retrosternal chest pain, odynophagia, and vomiting should raise suspicion for drug-induced esophagitis if there is any recent medication administration history. Drug-induced esophagitis can occur in children who take capsules or tablet formulations of medicines. Inadequate water intake and medication administration at bedtime are usually the risk factors associated with children. Severe complications are rare in children having drug-induced esophagitis, but morbidity and mortality have correlated with iron and potassium preparations. Children generally have an uneventful clinical course in drug-induced esophagitis.
It is imperative to make the correct diagnosis to avoid repeated injuries to the esophagus and thus preventing related complications. The determination of drug-induced esophagitis has its basis in both clinical presentation and endoscopic findings. Patients presenting with retrosternal chest pain, dysphagia or odynophagia, and recent history of taking medicines which are known to cause drug-induced esophagitis are diagnosable with history only.
Blood tests, including complete blood count, is not usually needed unless there is an associated history of hematemesis or melena. If a patient presents with severe symptoms including vomiting and unable to swallow, then a metabolic panel also should be done to check for any electrolyte imbalance and to ensure adequate replacement.
Endoscopy usually confirms the diagnosis and remains the gold standard for the evaluation and management of drug-induced esophagitis. It is usually necessary for patients who have either persistent symptoms after discontinuation of culprit medicine for one week or presentation with severe but rather rare symptoms of hematemesis, difficulty swallowing, melena, and abdominal pain. The most commonly observed endoscopic findings in patients with the diagnosis of drug-induced esophagitis are as follows in decreasing frequency:
A barium swallow study is not much useful in evaluating medication-induced esophagitis but usually gets done in the process of evaluation of dysphagia, which can be one of the presenting symptoms at the time of presentation.
Drug-induced esophagitis management involves the discontinuation of culprit medicine and other supportive treatment and lifestyle modification to protect the esophagus from further injury.
Medication-induced esophagitis is usually transient and improves in 1 to 2 weeks after discontinuing culprit medication. In a study, when patients were followed up after two days to 2 months with endoscopy, they showed normal esophageal findings or well-healed scars in the esophagus.
Because retrosternal chest pain and dysphagia or odynophagia are common symptoms shared by many other diseases, differential diagnosis is usually broad. Usually, medication history is vital information in most cases, which helps in differentiating drug-induced esophagitis from other causes.
Drug-induced esophagitis is a self-limiting disease with a good prognosis following conservative treatment. Patients are generally symptom-free within a week of stopping the causative drug and start of symptomatic therapy. Esophageal mucosa also recovers within this time. In most cases, repeat endoscopy or any additional measures are not necessary.
A gastroenterologist consultation is usually needed to confirm the diagnosis with endoscopy. Similarly, a pharmacist can be a good source for both physician and patient to know regarding drug absorption or therapeutic properties of medicines if any liquid preparation is available for the particular medication in a patient who has difficulty swallowing. A nutritionist and pharmacist can also help with parenteral nutrition formulation to meet nutrition requirements in a patient with severe symptoms requiring nothing by mouth status.
Diagnosing drug-induced esophagitis may be challenging because patients tend to underreport the symptoms if they are mild. Clinicians also may not consider it as a cause if missed medication history. Failure in early diagnosis can lead to unnecessary work-up and investigations for these symptoms. A lack of awareness about drug-induced esophagitis can cause persistent injury from the causative drug and eventually lead to complications. It is essential to take the medication with enough water (at least 200 to 250 ml) and to stay in an upright posture for at least 30 minutes.
Healthcare professionals must consider drug-induced esophageal injury while evaluating patients who present with retrosternal pain and dysphagia. The interprofessional healthcare team should also be aware of the importance of prevention strategies, such as recommending the patient to take the medication with an adequate quantity of water and in an upright position. They should create awareness and suggest the patients not to assume the recumbent position after taking drugs. Generally, healthcare professionals such as clinicians and nurses do not always give necessary advice about medicines that can cause esophagitis.
The pharmacist should always be aware of the patient's list of medications and have a suspicion of drug-induced esophagitis in those who present with chest pain. However, because the differential diagnosis of chest pain is large, the first step is to refer the patient to a clinician to rule out an MI and other lung-related disorders. If the workup is negative, the patient should be referred to a gastroenterologist to confirm esophagitis. The pharmacist should educate patients on how to take medications, how much water to drink, and the importance of maintaining an upright position for at least 30 minutes when taking pills. Because there is always the risk of esophageal perforation or bleeding, all clinicians looking after the patient should promptly make the appropriate referral to a surgeon when the pathology is suspected. Nursing staff should always inquire about the patient's medication compliance and ask if there are any issues; this may open the door to finding out about the problem. All members of the interprofessional team must be vigilant to work together to uncover drug-related esophagitis promptly, before it becomes a more significant concern, and prevent it from subverting patient pharmacotherapy through non-compliance. [Level 5]
|||Dağ MS,Öztürk ZA,Akın I,Tutar E,Çıkman Ö,Gülşen MT, Drug-induced esophageal ulcers: case series and the review of the literature. The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology. 2014 Apr; [PubMed PMID: 25003679]|
|||Kim SH,Jeong JB,Kim JW,Koh SJ,Kim BG,Lee KL,Chang MS,Im JP,Kang HW,Shin CM, Clinical and endoscopic characteristics of drug-induced esophagitis. World journal of gastroenterology. 2014 Aug 21; [PubMed PMID: 25152603]|
|||Bigard MA,Pelletier AL, [Esophageal complications of non steroidal antiinflammatory drugs]. Gastroenterologie clinique et biologique. 2004 Apr [PubMed PMID: 15366675]|
|||Zografos GN,Georgiadou D,Thomas D,Kaltsas G,Digalakis M, Drug-induced esophagitis. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus. 2009; [PubMed PMID: 19392845]|
|||de Groen PC,Lubbe DF,Hirsch LJ,Daifotis A,Stephenson W,Freedholm D,Pryor-Tillotson S,Seleznick MJ,Pinkas H,Wang KK, Esophagitis associated with the use of alendronate. The New England journal of medicine. 1996 Oct 3 [PubMed PMID: 8793925]|
|||Guttman OR,Zachos M, Drug-induced esophageal injury with an occult vascular ring. Paediatrics [PubMed PMID: 23115494]|
|||Kim JW,Kim BG,Kim SH,Kim W,Lee KL,Byeon SJ,Choi E,Chang MS, Histomorphological and Immunophenotypic Features of Pill-Induced Esophagitis. PloS one. 2015; [PubMed PMID: 26047496]|
|||Antunes C,Sharma A, Esophagitis . 2019 Jan [PubMed PMID: 28723041]|
|||Carlborg B,Densert O,Lindqvist C, Tetracycline induced esophageal ulcers. a clinical and experimental study. The Laryngoscope. 1983 Feb [PubMed PMID: 6823189]|
|||BOLEY SJ,ALLEN AC,SCHULTZ L,SCHWARTZ S, POTASSIUM-INDUCED LESIONS OF THE SMALL BOWEL. I. CLINICAL ASPECTS. JAMA. 1965 Sep 20 [PubMed PMID: 14338812]|
|||Grossi L,Ciccaglione AF,Marzio L, Esophagitis and its causes: Who is [PubMed PMID: 28533657]|
|||Zezos P,Harel Z,Saibil F, Cloxacillin: A New Cause of Pill-Induced Esophagitis. Canadian journal of gastroenterology [PubMed PMID: 27446834]|
|||Hey H,Jørgensen F,Sørensen K,Hasselbalch H,Wamberg T, Oesophageal transit of six commonly used tablets and capsules. British medical journal (Clinical research ed.). 1982 Dec 11 [PubMed PMID: 6816343]|
|||Hollis JB,Castell DO, Esophageal function in elderly man. A new look at "presbyesophagus". Annals of internal medicine. 1974 Mar [PubMed PMID: 4816179]|
|||Dent J,Dodds WJ,Friedman RH,Sekiguchi T,Hogan WJ,Arndorfer RC,Petrie DJ, Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. The Journal of clinical investigation. 1980 Feb [PubMed PMID: 7356677]|
|||Bordea MA,Pirvan A,Sarban C,Margescu C,Leucuta D,Samasca G,Miu N, Pill -Induced Erosive Esophagitis in Children. Clujul medical (1957). 2014; [PubMed PMID: 26527990]|
|||Abid S,Mumtaz K,Jafri W,Hamid S,Abbas Z,Shah HA,Khan AH, Pill-induced esophageal injury: endoscopic features and clinical outcomes. Endoscopy. 2005 Aug [PubMed PMID: 16032493]|
|||Santos VM,Carneiro MV,Cruz LR,Paixao GT, Drug-induced acute esophageal lesions and use of ciprofloxacin. Anales del sistema sanitario de Navarra. 2012 Jan-Apr; [PubMed PMID: 22552134]|
|||Geraci G,Pisello F,Modica G,Li Volsi F,Cajozzo M,Sciumè C, Herpes simplex esophagitis in immunocompetent host: a case report. Diagnostic and therapeutic endoscopy. 2009; [PubMed PMID: 19750238]|