A 23 y/o male aircrew member is deployed to your position in South America on a humanitarian mission. He presents to the clinic with complaints of substernal pain. The tech brings him in hooks him up to an ECG which is normal. He has no significant medical history. His vital signs are normal. The only medication he is on is doxycycline 100mg po BID for malaria prophylaxis. The limited number of labs you have drawn are all within normal limits.

What is your diagnosis? Why or why not?

Since you've done a thorough history and physical and all your tests so far are negative, this patient may have pill-induced or drug-induced esophagitis. (FYI - doxycycline is used for malaria prophylaxis in aircrew members instead of mefloquine [Lariam®]. Mefloquine is NOT acceptable for use in aircrew members.)

The esophageal damage can be chemical or mechanical. The drugs most commonly associated with drug-induced esophagitis include potassium chloride, NSAIDs, alendronate, tetracyclines, iron preparations, quinidine (which probably should never be used in anyone anymore!), and clindamycin. Patients with neurological swallowing problems and pre-existing reflux disease may be at greater risk for problems. To minimize the risk, patient should take these (and all) medications with at least 3 ounces of water and
remain upright for at least 15 minutes (alendronate prescribing information recommends remaining upright for an hour).

From MICROmedex:

PILL-INDUCED ESOPHAGEAL INJURY is now considered to be a significant cause of esophageal disease and one for which health professionals should be aware. Usual doses of capsules or tablets that are inadvertently retained in the esophagus may result in an inflamed or ulcerated esophageal mucosa. The
increased recognition of pill-induced ESOPHAGITIS partly reflects the ability of endoscopists to identify mucosal lesions previously undetected by barium contrast studies. It may also reflect the trend to reduce the frequency of dosing by increasing the concentration and, subsequently, the size of the oral dosage form. 

DRUGS 

A relatively small number of drugs are implicated in a majority of the reported cases of esophageal injury. Kikendall et al (1983) extensively reviewed the English and foreign language literature from 1960 to 1981 and reported a total of 221 cases caused by 26 different types of medication (some resulting from combinations). A review of the English language medical literature since 1981 revealed over 107 additional cases (Maconi & Porro, 1995; Carlborg et al, 1983; Ginaldi, 1984; Bliss, 1984; Channer &
Hollanders, 1981; Jeffery & Cullis, 1983; Geschwind, 1984; Hatheway, 1982; Delpre & Kadish, 1984; Amendola & Spera, 1985; Henry et al, 1983; Wilkins et al, 1984; Heller et al, 1982; Bataille et al, 1982; Enzenauer et al, 1984; Israel & Wood, 1979; Coates et al, 1986; Minocha & Greenbaum, 1991).  In a majority of the reported cases, pill-induced esophagitis is due to the tetracycline antibiotics, especially DOXYCYCLINE (Kikendall et al, 1983; Carlborg et al, 1983; Ginaldi, 1984; Bliss, 1984; Channer & Hollanders, 1981; Jeffery & Cullis, 1983; Geschwind, 1984; Hatheway, 1982; Delpre & Kadish, 1984; Amendola & Spera, 1985). Other drugs that have been documented more than once, in decreasing order of frequency, include ASPIRIN and other NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDs) POTASSIUM CHLORIDE (primarily Slow-K(R) and other wax matrix forms), IRON, QUINIDINE, and CLINDAMYCIN (Kikendall et al, 1983; Wilkins et al, 1984; Heller et al, 1982; Bataille etal, 1982; Coates et al, 1986; Henry et al, 1983). EMEPRONIUM BROMIDE, in particular, and several other drugs that are not available in the United States have also been implicated in a number of cases (Kikendall et al, 1983).
Alendronate (Fosamax(R)) has caused esophagitis, esophageal ulcers, and esophageal erosions. The manufacturer recommends that patients take each dose with at least 6 to 8 ounces of water and remain in a sitting or standing position for at least 30 minutes after the dose (Prod Info Fosamax(R), 1996).

There are several reasons why these particular medications cause esophagitis more frequently than other drugs. Mucosal damage from NSAIDs may be theresult of reduced protective mucosal prostaglandin synthesis (Heller et al, 1982). Both doxycycline and FERROUS SULFATE produce an acidic solution once
dissolved (pH less than 3) and may injure the esophageal mucosa through this mechanism (Kikendall et al, 1983). Other drugs may produce hyperosmotic solutions that result in tissue damage (Kikendall et al, 1983). Other important factors include dissolution rate and dosage formulation.

PRESENTATION AND COMPLICATIONS

Although many patients note that they initially feel the tablet or capsule "stuck in their chest," others have no initial subjective sensation that the pill is retained in the esophagus. The most common presenting symptoms of pill-induced esophagitis include odynophagia (painful swallowing of food),
dysphagia, or continuous retrosternal pain. Single contrast barium esophagrams are usually normal; however, double contrast barium esophagrams may have the sensitivity to detect ulceration or mucosal abnormalities. Esophagoscopy is almost always abnormal. The injury may involve discrete ulcers or inflammation with little or no ulceration (Kikendall et al, 1983).

In most of the uncomplicated cases, symptoms resolve within a few days to weeks after discontinuation of the offending drug. However, severe complications such as strictures, bleeding esophageal ulcers and perforation have also been reported and have resulted in several fatalities (Kikendall et al, 1983). These severe complications have only been associated with potassium chloride, iron, quinidine and NSAIDs and not with any of the antibiotics, including the tetracyclines (Kikendall et al, 1983; Spera & Amendola, 1985).

RISK FACTORS

Patients with pre-existing esophageal compression or esophageal reflux may be at a higher risk for pill-induced esophagitis (Coates et al, 1986). For example, severe potassium chloride-induced esophageal injury has occurred most often in patients with esophageal compression due to cardiomegaly or esophageal entrapment following thoracic surgery (Kikendall et al, 1983). Nevertheless, many patients with pill-induced esophagitis have no apparent esophageal transit abnormality or prior esophageal disease. The two risk factors implicated most often in pill-induced esophagitis are taking the pill with little or no fluid and taking the pill just prior to bedtime. Recumbency increases esophageal transit time and sleep further increases transit time by decreasing salivation and swallowing (Kikendall et al, 1983). Pills that are swallowed immediately before the patient reclines, or with little or no fluid, are often retained in the esophagus for at least 5 to 10 minutes; pills have been retained in the esophagus for as long as 2 hours (Channer & Virjee, 1982; Hey et al, 1982; Fisher et al, 1982; Evans & Roberts, 1976). In addition, a recent study demonstrated rapid esophageal transit when subjects swallowed a capsule (with water) after drinking as little as 15 mL of water to lubricate the esophagus, and then followed this
with a 15 mL water chaser (Fisher et al, 1982). Drinking a small amount of fluid both before and after taking a pill may be a practical alternative forpatients who cannot or will not swallow their pills with the recommended amount of fluid.

Dosage form and formulation factors also affect esophageal retention. It is still not known whether tablets and capsules differ in their ability to "stick" in the esophagus (Fell, 1983). However, doxycycline capsules are more likely to dissolve in the esophagus than doxycycline tablets (Carlborg et al, 1983). In general, oval tablets have faster esophageal transit times than round tablets and small tablets have faster transit times than large tablets (Hey et al, 1982). 

CONCLUSION:

Patients should be instructed to take tablets or capsules in an upright or sitting position with at least 100 mL of fluid. Swallowing the medication after a preliminary sip of fluid may also be helpful. If possible, "bedtime doses" should be taken at least ten minutes before actually reclining. These instructions are especially important for patients taking oral solid forms of tetracyclines, NSAIDs, potassium chloride, iron, quinidine and clindamycin, and for elderly or bedridden patients who may have delayed esophageal transit times or esophageal compression due to age or disease. For these patients, a liquid form of medication may be beneficial. A medication history should be obtained in any patient with esophagitis or
symptoms of esophageal injury. 

REFERENCES:

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