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2 Drug-induced oesophageal lesions
2 Drug-induced oesophageal lesions MARTIN WIENBECK WILHELM BERGES HEINRICH J. LUBKE
The mouth, pharynx and oesophagus are the first organs to come into contact with drugs and poisons after their ingestion. It is not surprising, therefore, that these organs manifest side-effects if the ingested drugs are damaging to the mucosa. In general, drugs pass rapidly through the oropharynx, whereas the oesophagus may retain tablets of regular size for more than 20 minutes (Evans and Roberts, 1976). The oesophagus is therefore more prone to damage by drugs than the oropharynx. In the stomach, on the other hand, the ingested material is diluted, reducing the risk of direct drug-induced injury. With advances in local drug therapy within the gut, the risk of damage by these drugs increases. It should also be remembered that in oesophageal diseases certain drugs may be particularly badly tolerated. Both these topics are dealt with later in this chapter. OESOPHAGEAL
LESIONS
AFTER
DRUG INGESTION
These lesions comprise all morphological alterations in the mucosa and in deeper layers of the oesophageal wall after oral intake of drugs. The diagnosis is usually made on the basis of the macroscopic appearance of the lesion during endoscopy in connection with a typical history. Pathomorphology Endoscopy may reveal a circumscribed redness and friability of the mucosa, an erosion of about the size of a coin, or an ulcer that may reach into deep layers of the wall. Multiple lesions may occur, and not infrequently one lesion is located directly opposite the other, giving the appearance of ‘kissing ulcers’. Occasionally, remaining particles of the offending drug may be seen adhering to the mucosal lesion. Although the redness and friability are difficult to interpret, overt mucosal defects in connection with a typical history are considered to be sufficient proof of drug-induced injury. The location of the mucosal defects is almost pathognomonic. The majority of lesions are located at the level of the aortic arch, or slightly below or above it (Figure 1). A less common location is the region of the oesophageal entrance, Bailli~re’s
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Figure 1. Location of 25 drug-induced oesophageal ulcers seen by the authors. lesions from the front teeth is indicated in centimetres on the left side.
AND
H. J. LijBKE
The distance
of the
seen in bedridden, decrepit patients. An accumulation of lesions has been reported in the lower centimetres of the oesophagus above the gastrooesophageal junction (Bonavina et al, 1987) and below the aortic arch in patients with mitral valve disease. Histology largely depends on the duration of the lesion at the time of the examination. Acute lesions exhibit mucosal defects and necrosis with little oedema and hyperaemia. As time goes on, there is increasing evidence of leucocyte infiltration and repair processes. The histologic aspect, in general, is not typical of drug-induced lesions; similar alterations may be seen in any type of oesophageal damage. In addition to the mucosal lesions, cicatricial stenosis of the oesophagus may occur as a late sequela. This is apparently much more common than previously thought (Bonavina et al, 1987; Heller et al, 1982). The strictures may be short, but often they may extend over longer distances and exhibit very rigid properties. Because of the lack of access to deeper layers of the oesophageal wall for histologic examination, it is unknown whether specific morphologic changes exist within the cicatrix.
DRUG-INDUCED
OESOPHAGEAL
LESIONS
265
Pathogenesis The exact mechanism of the development of drug-induced oesophageal lesions is still unknown, but two factors appear to be prerequisite: a delay in the passage of a pill down the oesophagus, and the aggressive physicochemical properties of the drug concerned. In 1976 Evans and Roberts showed that an aspirin-sized barium sulphate tablet took longer than 5 minutes to traverse the oesophagus in 57 out of 98 patients who swallowed the tablet with a small amount (15 ml) of water and then lay flat. In 5 subjects, the transit time even exceeded 20 minutes. A more sophisticated study indicated that within the range of commonly used pills, the size and shape of the pill, whether the patient was standing or lying, and the volume of water swallowed, all made significant differences to the incidence of delayed transit (Hey et al, 1982). Oval, small tablets passed most easily, whilst about half the large, round tablets showed delayed oesophageal transit lasting for more than 90 seconds, especially when they were taken with only small amounts of water in the supine position. The region close to the aortic arch appears to be particularly prone to delay the transit of such tablets. Different physicochemical properties of the pills have been suspected to cause damage to the oesophagus. These include a low pH of the drug after its release (Rohner et al, 1982); strong corrosive and hygroscopic properties (Berges et al, 1980; Bonavina et al, 1987); and intracellular invasion of the drug into the basal layer, thus disturbing epithelial regeneration (Giger et al, 1978). The predominantly damaging property may vary from drug to drug, but in each case the extent of the lesion depends on the concentration of the offending agent and on the length of time it acts on the oesophageal mucosa. More than 200 cases of drug-induced oesophageal injury have been reported (Berges et al, 1987; Bonavina et al, 1987); however, these certainly, represent only a minority of the cases that have actually occurred. The majority of cases elude diagnosis, and a small percentage of these eventually end up with a stricture in the oesophagus (Bonavina et al, 1987; Heller et al, 1982). By far the most commonly reported injurious drugs are doxycycline hydrochloride and the anticholinergic agent emepronium bromide, but more than twenty different drugs have been reported to damage the oesophagus, and the list probably will become longer as increasing attention is paid to drugs as a cause of oesophageal injury (Table 1).
Symptoms Most patients are apparently healthy people who are suddenly hit by symptoms of oesophageal injury. Men and women are affected alike, and patients of all ages between 9 and 98 years have been described. The typical history of oesophageal lesions after drug ingestion is exemplified in Figure 2. The patient typically takes a tablet late at night with little or no fluid and then goes to bed. Quite often the patient only remembers to take the tablet when falling asleep, and feels too tired to get up again in order to fetch a glass of water. The patient wakes a few hours later or early in the morning with severe retrosternal pain, which is not relieved by drinking or eating - on the
266
M. WIENBECK,
Table
1. Drugs
No. of cases*
Drug Tetracyclines Emepronium bromide Potassium chloride
97 39 34
Other
26
antibiotics
Aspirin Non-steroidal, anti-inflammatory drugs Ferrous sulphate/ succinate Alprenolol Quinidine 5-Fluouracil Ascorbic acid Paracetamol Mexiletine Theophylline Pinaverium Estramustin Clomethiazol Phenytoin Oral contraceptives Promethazine
reported
No.
of complications
Stricture
Haemorrhage
oesophageal
9
20
14
AND
H.
J. LiiBKE
lesions.
Death
Comments 77
2
3
Deaths due to haemorrhage (2) mediastinitis (1) Pivampicillin, clindamycin, co-trimoxazole, erythromycin, pivmecillinam and others
1
1
Mainly bleeding
3
Deaths
indomethacin; (indomethacin)
death
due
to
5 3
1 together
due to oesophageal
with
necrosis
aspirin
Combination of phenylpropanolamine and thiazinamium
Glibenclamid Thioridazine Pantogar@
Combination of thiamine hydrochloride, calcium pantothenate, aminobenzoic acid, cystine, yeast and keratin Death due to oesophageal perforation
Carbachol Chloral hydrate Bulk laxative Totals
BERGES
Doxycycline 3 12
24
12 9 7 5 2 2 2 2 2 2 1 1 1 1
to induce
W.
295
47
3
8
* Reviewed in Berges et al (1987) Bonavina et al (1987), Borsch et al (1983), Collins et al (1979), Heller et al (1982), Kikendall et al (1983), Rohner et al (1982), Swedish Adverse Drug Reactions Advisory Committee (1986).
contrary, swallowing is painful, and is avoided by the patient. Because of the severity of the pain the patient usually sees a doctor immediately. The doctor prescribes an analgesic agent, a coronary dilator or antacids, having ruled out myocardial infarction. The pain can persist for days, and will only vanish slowly if the patient’s method of taking the drug is changed. The decisive
DRUG-INDUCED
OESOPHAGEAL last pill
pain
267
LESIONS
X-ray
t
endoscopies 2
3
Figure 2. Typical history of a 19-year-old female patient with a drug-induced oesophageal lesion due to emepronium bromide. The drug was first prescribed on day 1. The second day the patient took the tablet with a very small amount of water and immediately fell asleep. She woke up 2 hours later with severe retrosternal pain. Because the pain persisted, the doctor ordered an X-ray examination of the oesophagus two days later. Since this was normal, he ordered the first oesophagoscopy two days later, which revealed two kissing ulcers at the level of the aortic arch. These ulcers were still visible during the second endoscopy one week later, but they were gone another four weeks later.
diagnostic procedure, oesophagoscopy, is usually delayed by several days, and is often only performed after a negative X-ray examination. By the time of endoscopy the lesion in the oesophagus has already lost its acute aspects and is beginning to heal. Depending on the type of the drug and the severity of the injury, there may be some variation to this history. For example, in old, decrepit patients and in those with alcoholic or diabetic neuropathy, the lesion may cause little or no pain, so that bleeding from the lesion or a late stricture may be the first symptom of the injury. In otherwise healthy persons severe bleeding with haematemesis and melaena may occur, but it is rare. The development of a cicatricial stenosis appears to be more common, and severe dysphagia may be the only indicator of the past drug-induced injury (Bonavina et al, 1987). In a few cases lethal complications have been described; they were due to perforation of the oesophageal wall or to severe bleeding. The pain usually subsides within one week provided that further injury is prevented. However, it may take up to six weeks for the ulcer to become fully epithelialized (see Figure 2). Although it is likely that extensive lesions are more prone to develop late strictures, the further course in individual patients cannot be predicted so far. Most lesions certainly heal without sequela.
Functional disturbances Disturbances of oesophageal motor function may facilitate the occurrence of drug-induced oesophageal lesions; conversely, oesophageal injury may completely derange oesophageal motility (Figure 3). In the acute phase it is impossible to distinguish between these two possibilities. Only a repeat examination after complete healing of the lesion will differentiate a secondary from a primary motility disorder. Patients with an underlying motor disturbance must be advised to avoid any drugs in pill form with local
268
M. WIENBECK,
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AND
H. J. LijBKE
.1
-
JL...-A
47 ---JResp. i SW.
W.
-----P---C---*_
__j;
. .
during drug-induced
oesophageal
,
. .
1.
40 days later
ulcer
Figure 3. Oesophageal manometry of a 22-year-old patient, shortly after thioridazine (taken while going to bed) had caused a mid-oesophageal ulcer, and 40 days later when the ulcer was healed. The distance of the four catheters from the teeth is indicated in centimetres on the left side. The tracings each represent 3 minutes of recording. Notice the markedly reduced amplitude of the oesophageal contractions at (a) the first examination, and (b) the completely normal motility 40 days later.
damaging action, so it is essential to identify any pre-existing oesophageal motility disturbance during the patient’s follow-up visit six to eight weeks after the acute injury. Therapy There is no specific therapy for drug-induced oesophageal lesions. It is of the utmost importance that any further intake of the offending agent is avoided. In the treatment of severe retrosternal pain, local anaesthetics (e.g. viscous preparations of lignocaine) are used in addition to systemic analgesic therapy. It is unknown whether antacids are of any benefit, although they are commonly prescribed. Histamine Hz receptor antagonists cannot be considered to be rational treatment. Certainly the best treatment of these lesions is prevention. This requires that any pill should be swallowed only with the patient in an upright position and followed by a fluid ‘chaser’ of at least 120 ml. If different preparations of equal potency are available, the less corrosive one should be prescribed; e.g. liquid drug preparations are preferable to pills, and chewable tablets are preferable to tablets or capsules firmly enclosing the ingredient. The importance of prevention also obliges the pharmaceutical industry to develop better chemical formulations, avoiding damaging concentrations of drugs and enabling pills to pass the oesophagus more readily. First steps in this direction have been taken by some pharmaceutical companies producing doxycycline and emepronium bromide. OESOPHAGEAL
LESIONS
AFTER
LOCAL
DRUG INJECTION
Local injection of sclerosing agents into the oesophageal wall is an established method of treating oesophageal varices. The ensuing inflammation, fibrosis
DRUG-INDUCED
OESOPHAGEAL
LESIONS
269
and thrombosis of the varices are desired therapeutic goals, but often necrosis and ulceration also develop and may cause severe complications (Knauer and Fogel, 1987; Pushpanathan and Idikio, 1986). The type of sclerosing agent and the technique of injection, be it intravascular or paravascular, have little effect (if any) on the nature and extent of these undesired lesions (Ayres et al, 1983). Pathomorphology Most information has been gathered from animal experiments. In rats, the mucosa was found to be oedematous and inflamed two days after intraoesophageal injection of 0.5% and 1% polidocanol, (Metz et al, 1986). These effects appeared to be dose dependent. After one week, necrosis and a granulomatous type of inflammation was seen. An increase of fibrous tissue, located in the granulomatous tissue, did not become evident before the fourth week. Similar observations have been made in autopsies of patients with oesophageal varices (Helpap and Hansen, 1983). Injection of 5% polidocanol produced particularly large ulcerations. Phenol almond oil, however, was associated with less inflammation. Sodium tetradecyl sulphate and ethanolamine also may produce severe inflammation and ulceration (Evans et al, 1982). Again, in animal experiments, sodium tetradecyl sulphate was more effective in occluding oesophageal varices than other sclerosants (Blenkinsopp, 1986). Sclerosing agents An ideal agent causing rapid thrombosis of the varices with little or no inflammation and necrosis of the paravariceal tissue has not been developed so far, and it is doubtful whether it ever will be. Ethoxysclerol and to a much lesser extent phenol peanut oil or phenol almond oil are predominantly used in central Europe. In the phenol solutions the sclerosing agent phenol is slowly released from the oil which acts as a carrier medium. Because these oils have a high viscosity they are difficult to inject through a small needle. Ethoxysclerol, which has been used in the therapy of peripheral varices for a long time, is an aqueous solution of ethanol and the local anaesthetic polidocanol. It is used mainly as a 1% w/v solution, occasionally also as a 0.5% and 2% solution. In Anglo-American countries ethanolamineoleate (5%), sodium tetradecyl sulphate (3%) and sodium morrhuate (5%) are much more popular. These agents contain long-chain unsaturated fatty acids as active ingredients. Pure ethanol has also been used with apparent success(Sarin et al, 1985). However, controlled clinical trials and animal experiments comparing the efficacy and the side-effects of these agents are largely missing. Symptoms In contrast to other drug-induced oesophageal lesions, ulcers due to sclerotherapy of varices rarely produce retrosternal pain. They may, however, be the source of life-threatening bleeding. Four days after sclerotherapy,
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AND
H. J. LijBKE
necrosis may already be seen at the site of the injections (Soehendra et al, 1983). The extent of the necrosis does not appear to be strictly correlated to the volume of the injected agent. During the first days the clot at the surface of the lesion adheres only very loosely. Particles of solid food or endoscopic manipulations may inadvertently rub off part of the clot and cause severe bleeding. In general, after about a week the clot becomes sufficiently adherent and retracted for the patient to resume normal food intake. In a significant proportion of patients, new bleeding mainly due to treatment-induced ulcers occurs (Ayres et al, 1982). In the majority of cases these are silent haemorrhages leading to tarry stools; but if still patent blood vessels are opened, life-threatening haemorrhage may ensue. Considerable fibrosis may develop in the oesophageal wall after sclerotherapy and cause a symptomatic stricture. Bougienage becomes a necessity in about 2% of patients who have undergone sclerotherapy. It has to be performed very carefully in order to prevent bleeding. Transmural necrosis of the oesophagus and perforation are almost lethal complications in these severely ill patients. The occurrence of these complications decreases with increasing therapeutic experience of the endoscopist. Functional disturbances The fibrosis developing within the oesophageal wall may also impair oesophageal motility. The contractions of the oesophageal body may be reduced in amplitude and show an increased occurrence of simultaneous contractions, and the pressure in the lower oesophageal sphincter may decrease (Reilly et al, 1984; Sauerbruch et al, 1982; Siiderlund et al, 1985). An impaired oesophageal clearance and pathological gastro-oesophageal reflux may ensue, but in general, reflux oesophagitis is not a major problem after sclerotherapy. Therapy As with other drug-induced oesophageal lesions, there is no specific treatment for ulcers after sclerotherapy. It is unlikely that any drug accelerates the process of healing. If bleeding from ulcers occurs, it is treated symptomatically by tamponade, systemic application of vasopressin, blood substitution and similar manoeuvers. A new injection of sclerosing agent into a bleeding, druginduced lesion is risky and in most cases unsuccessful; the procedure is avoided by most investigators. POTENTIALLY
HARMFUL
DRUGS
IN OESOPHAGEAL
DISEASE
All diseases that delay transit through the oesophagus increase the risk of drug-induced oesophageal lesions, through decreased clearance of the harmful agent. In addition, it has to be remembered that drugs affecting the motility of the oesophagus and the lower oesophageal sphincter may cause
DRUG-INDUCED
OESOPHAGEAL
271
LESIONS
Table 2. Drugs with motor the human oesophagus. Inhibition Anticholinergic agents Calcium antagonists /Ssympathomimetic agents Oestrogens and progesterones Prostaglandin El
inhibitory
and stimulatory
actions
in
Stimulation Prokinetic agents Parasympathomimetic agents /3-adrenergic blockers cr-sympathomimeGc agents Prostaglandin Fla
unwanted effects, particularly in patients with pre-existing motor disturbances of the oesophagus. They may aggravate the symptoms of the disease. In general, these drugs can be classified into those inhibiting oesophageal contractions, and those stimulating them (Table 2). Drugs causing motor inhibition A number of drugs may inhibit the force of oesophageal contractions and decrease the pressure in the lower oesophageal sphincter (Kilbinger and Weihrauch, 1984; Wienbeck and Berges, 1981). They may thus aggravate or even produce symptoms of gastro-oesophageal reflux such as heartburn, eructation, epigastric pain and dysphagia. These drugs should be withdrawn if such symptoms occur, and replaced by other agents not affecting oesophageal motility. If this is not possible, an antireflux regimen should be added to the offending medication. Drugs causing motor stimulation A series of drugs may stimulate the force of oesophageal contractions and increase the pressure in the lower oesophageal sphincter (Kilbinger and Weihrauch, 1984; McCallum, 1985). Usually these are desirable effects, particularly in the case of the prokinetic agents metoclopramide, bromopride, domperidone, cisapride and bethanechol. These drugs are usually given as a treatment in patients with inadequate oesophageal contractions, e.g. in reflux oesophagitis. Occasionally, however, motor stimulation of the oesophagus may become an undesired effect particularly if painful oesophageal contractions or delayed transit through the oesophagus are induced (Basotti et al, 1987). These drugs should also be avoided in achalasia, diffuse oesophageal spasm and nutcracker oesophagus, although controlled studies on the frequency and severity of drug side-effects in these diseases are absent.
DRUG-INDUCED
BOLUS
OBSTRUCTION
A rare complication of the intake of dietary fibre is bolus obstruction in the oesophagus (Figure 4). Patients with oesophageal motility disorders and organic stenosis are particularly prone to develop this complication, but even
272
M.
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H. J. LtiBKE
04 fibre. 4. X-ray pictures of bolus obstruction of the lower oesophagus due to dietary (a) Obstruction by bran with superimposed food remnants in a 3%year-old healthy man. (b) Obstruction and distension of the lower oesophagus by a guar bolus in a 45-year-old WC six months after gastrectomy and oesophagojejunostomy for gastric cancer. Figure
DRUG-INDUCED
OESOPHAGEAL
273
LESIONS
in healthy subjects an obstruction may occasionally occur. Since dietary fibres such as bran are widely used nowadays in the treatment of chronic constipation and other functional disturbances of the gut, advice should be given on how to take these fibres when they are prescribed. Patients should be advised to soak bran for at least ten minutes in viscous liquids such as yoghurt or apple mash before ingestion, and to swallow it together with plenty of water or other drinks in a sitting position. Guar used to treat dumping syndrome in gastrectomy patients, is particularly dangerous; it may adhere to the lower oesophagus, where it may increase its volume by a factor of three and more within a short time. The swelling of guar is enhanced by the simultaneous intake of alcohol. A very painful-and even dangerous-situation may ensue (Ranft and Imhof, 1983). SUMMARY Persisting retrosternal pain of sudden onset is suggestive of a drug-induced oesophageal lesion, particularly if it starts at night. After exclusion of a myocardial infarction, a carefully taken history and oesophagoscopy will rapidly clarify the cause and severity of the injury. Since almost any pill may produce oesophageal lesions, care has to be taken that tablets, capsules and other pills are always taken in an upright position together with a fluid chaser of at least 120 ml. If possible, less harmful liquid preparations of the drugs should be preferred. Lesions in the oesophageal wall and perioesophageal tissue are almost unavoidable side-effects of sclerotherapy of oesophageal varices. The patient and the doctor should be particularly aware of bleeding from oesophageal ulcers during the first week after sclerotherapy. Numerous drugs may weaken or strengthen contractions of the oesophagus and lower oesophageal sphincter. These potentially unwanted motor effects of the drugs have to be kept in mind, especially in patients with pre-existing gastro-oesophageal reflux disease and hypermotility states. Acknowledgements Part of this work was supported by the Deutsche Forschungsgemeinschaft, (Wi 285). The authors thank MS H. Nickel for her expert secretarial work.
Bonn-Bad
Godesberg
REFERENCES Ayres
SJ, Goff JS, Warren GH & Schaefer JW (1982) Esophageal ulceration and bleeding after flexible fiberoptic esophageal vein sclerosis. Gastroenterology 83: 131-136. Ayres SJ, Goff JS & Warren GH (1983) Endoscopic sclerotherapy for bleeding esophageal varices: effects and complications. Annals of Internal Medicine 98: 900-903. Bassotti G, Gaburri M, Pelli MA & Morelli A (1987) Oesophageal pain exacerbated by propranolol. British Medical Journal 294: 1655. Berges W, Rohner HG & Wienbeck M (1980) ijsophagusulkus nach Einnahme von Emeproniumbromid. Leber Magen Dam 10: 37-40.
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Berges W, Frieling T & Wienbeck M (1987) Medikamentos bedingte ijsophagusgeschwiire. Deutsches drzteblatt-iirztliche Mitteilungen 84: 22-25. Blenkinsopp WK (1986) Comparison of tetradecylsulphate of sodium with other sclerosants in rats. British Journal of Experimental Pathology 49: 191-201. Bonavina L, DeMeester TR, McChesney L, Schwizer W, Albertucci M &Bailey RT (1987) Druginduced esophageal strictures. Annals of Surgery 206: 1733183. Borsch G, Sabin G & Ricken D (1983) Arzneimittelschaden an Mundhdhle Speiserohre, Magen und Zwiilffingerdarm. Medizinische Klinik 78: 758-7’61. Collins FJ, Matthews HR, Baker SE & Strakova JM (1979) Drug-induced oesophageal injury. British Medical Journal 1: 1613-1676. Evans KT & Roberts GM (1976) Where do all the tablets go? Lancet ii: 1237-1239. Evans DMD, Jones DB, Cleary BK & Smith PM (1982) Oesophageal varices treated by sclerotherapy: a histopathological study. Gut 23: 615-620. Giger M, Sonnenberg A, Brlndli H, Singeisen M, Giiller R & Blum AL (1978) Das TetracyclinUlkus der Speiserohre. Deutsche Medizinische Wochenschrift 103: 1038-1040. Heller SR, Fellows IW, Ogilvie AL &Atkinson M (1982) Non-steroidal anti-inflammatory drugs and benign oesophageal stricture. British Medical Journal 285: 167-168. Helpap B &Hansen H (1983) Vergleichende histologische Untersuchungen nach ijsophagusvarizensklerosierung mit unterschiedlichen Substanzen. Leber Magen Darm 13: 215-222. Hey H, Jorgensen F, Sorensen K, Hasselbalch H & Wamberg T (1982) Oesophageal transit of six commonly used tablets and capsules. British Medical Journal 285: 1717-1719. Kikendall WJ, Friedman AC, Oyewole MA, Fleischer D & Johnson LF (1983) Pill-induced esophageal injury. Case reports and review of the medical literature. Digestive Diseases and Sciences 28: 174-182. Kilbinger H & Weihrauch TR (1984) Pharmakologie motilitatswirksamer Medikamente. In Wienbeck M & Siewert JR (eds) Therapie Gastrointestinaler MotilitiitsstBrungen, pp. 1-4. Weinheim: Edition Medizin. Knauer CM & Fogel MR (1987) Pericarditis: complication of esophageal sclerotherapy. A report of three cases. Gastroenterology 93: 287-290. McCallum RW (1985) Review of the,current status of prokinetic agents in gastroenterology. American Journal of Gastroenterology 80: 1008~1016. Metz KA, Erhard J, Gross E & Donhnijsen K (1986) Zur Wirkung unterschiedlicher Sklerosierungsmittel auf den Rattenosophagus. Zeitschrift fiir Gastroenterologie 24: 605611. Pushpanathan C & Idikio H (1986) Pathological findings in the esophagus after endoscopic sclerotherapy for variceal bleeding. American Journal of Gastroenterology 81: 9913. Ranft K & Imhof W (1983) Bolusobstruktion des distalen Esophagus durch pflanzliche Quellstoffe (Guarmehl). Deutsche Medizinische Wochenschrift 108: 1968-1969. Reilly JJ, Schade RR & Van Thiel DS (1984) Esophageal function after injection sclerotherapy: pathogenesis of esophageal stricture. American Journal of Surgery 147: 85-88. Rohner HG, Berges W & Wienbeck M (1982) Clomethiazol tablets induce ulcers in the esophagus. Zeitschrtft fiir Gastroenterologie 20: 469-473. Sarin SK, Sachdeva GK, Nanda R, Vij JC & Anand BS (1985) Endoscopic sclerotherapy using absolute alcohol. Gut 26: 120-124. Sauerbruch T, Wirsching R, Leisner B, Weinzierl M, Pfahler M & Paumgartner G (1982) Esophageal function after sclerotherapy of bleeding varices. Scandinavian Journal of Gastroenterology 17: 745-751. Siiderlund C, Thor K & Wiechel KZ (1985) Oesophageal motility after sclerotherapy of bleeding varices. Acta Chirurgica Scandinavica 151: 249-253. Soehendra N, de Heer K, Kempeneers I & Frommelt L (1983) Morphological alterations of the esophagus after endoscopic sclerotherapy of varices. Endoscopy 15: 291-296. Swedish Adverse Drug Reactions Advisory Committee (1986) Bulletin. Chemotherapie-Telegramm 2: 8. Wienbeck M & Berges W (1981) Die tjsophagusmanometrie. Fortschritte der inneren Medizin und Kinderheilkunde 47: 1 1 1- 152.
The mouth, pharynx and oesophagus are the first organs to come into contact with drugs and poisons after their ingestion. It is not surprising, therefore, that these organs manifest side-effects if the ingested drugs are damaging to the mucosa. In general, drugs pass rapidly through the oropharynx, whereas the oesophagus may retain tablets of regular size for more than 20 minutes (Evans and Roberts, 1976). The oesophagus is therefore more prone to damage by drugs than the oropharynx. In the stomach, on the other hand, the ingested material is diluted, reducing the risk of direct drug-induced injury. With advances in local drug therapy within the gut, the risk of damage by these drugs increases. It should also be remembered that in oesophageal diseases certain drugs may be particularly badly tolerated. Both these topics are dealt with later in this chapter. OESOPHAGEAL
LESIONS
AFTER
DRUG INGESTION
These lesions comprise all morphological alterations in the mucosa and in deeper layers of the oesophageal wall after oral intake of drugs. The diagnosis is usually made on the basis of the macroscopic appearance of the lesion during endoscopy in connection with a typical history. Pathomorphology Endoscopy may reveal a circumscribed redness and friability of the mucosa, an erosion of about the size of a coin, or an ulcer that may reach into deep layers of the wall. Multiple lesions may occur, and not infrequently one lesion is located directly opposite the other, giving the appearance of ‘kissing ulcers’. Occasionally, remaining particles of the offending drug may be seen adhering to the mucosal lesion. Although the redness and friability are difficult to interpret, overt mucosal defects in connection with a typical history are considered to be sufficient proof of drug-induced injury. The location of the mucosal defects is almost pathognomonic. The majority of lesions are located at the level of the aortic arch, or slightly below or above it (Figure 1). A less common location is the region of the oesophageal entrance, Bailli~re’s
Clinical
Gastroenterology-Vol.
2, No.
2, April
1988
263
264
M. WIENBECK,
W.
BERGES
Figure 1. Location of 25 drug-induced oesophageal ulcers seen by the authors. lesions from the front teeth is indicated in centimetres on the left side.
AND
H. J. LijBKE
The distance
of the
seen in bedridden, decrepit patients. An accumulation of lesions has been reported in the lower centimetres of the oesophagus above the gastrooesophageal junction (Bonavina et al, 1987) and below the aortic arch in patients with mitral valve disease. Histology largely depends on the duration of the lesion at the time of the examination. Acute lesions exhibit mucosal defects and necrosis with little oedema and hyperaemia. As time goes on, there is increasing evidence of leucocyte infiltration and repair processes. The histologic aspect, in general, is not typical of drug-induced lesions; similar alterations may be seen in any type of oesophageal damage. In addition to the mucosal lesions, cicatricial stenosis of the oesophagus may occur as a late sequela. This is apparently much more common than previously thought (Bonavina et al, 1987; Heller et al, 1982). The strictures may be short, but often they may extend over longer distances and exhibit very rigid properties. Because of the lack of access to deeper layers of the oesophageal wall for histologic examination, it is unknown whether specific morphologic changes exist within the cicatrix.
DRUG-INDUCED
OESOPHAGEAL
LESIONS
265
Pathogenesis The exact mechanism of the development of drug-induced oesophageal lesions is still unknown, but two factors appear to be prerequisite: a delay in the passage of a pill down the oesophagus, and the aggressive physicochemical properties of the drug concerned. In 1976 Evans and Roberts showed that an aspirin-sized barium sulphate tablet took longer than 5 minutes to traverse the oesophagus in 57 out of 98 patients who swallowed the tablet with a small amount (15 ml) of water and then lay flat. In 5 subjects, the transit time even exceeded 20 minutes. A more sophisticated study indicated that within the range of commonly used pills, the size and shape of the pill, whether the patient was standing or lying, and the volume of water swallowed, all made significant differences to the incidence of delayed transit (Hey et al, 1982). Oval, small tablets passed most easily, whilst about half the large, round tablets showed delayed oesophageal transit lasting for more than 90 seconds, especially when they were taken with only small amounts of water in the supine position. The region close to the aortic arch appears to be particularly prone to delay the transit of such tablets. Different physicochemical properties of the pills have been suspected to cause damage to the oesophagus. These include a low pH of the drug after its release (Rohner et al, 1982); strong corrosive and hygroscopic properties (Berges et al, 1980; Bonavina et al, 1987); and intracellular invasion of the drug into the basal layer, thus disturbing epithelial regeneration (Giger et al, 1978). The predominantly damaging property may vary from drug to drug, but in each case the extent of the lesion depends on the concentration of the offending agent and on the length of time it acts on the oesophageal mucosa. More than 200 cases of drug-induced oesophageal injury have been reported (Berges et al, 1987; Bonavina et al, 1987); however, these certainly, represent only a minority of the cases that have actually occurred. The majority of cases elude diagnosis, and a small percentage of these eventually end up with a stricture in the oesophagus (Bonavina et al, 1987; Heller et al, 1982). By far the most commonly reported injurious drugs are doxycycline hydrochloride and the anticholinergic agent emepronium bromide, but more than twenty different drugs have been reported to damage the oesophagus, and the list probably will become longer as increasing attention is paid to drugs as a cause of oesophageal injury (Table 1).
Symptoms Most patients are apparently healthy people who are suddenly hit by symptoms of oesophageal injury. Men and women are affected alike, and patients of all ages between 9 and 98 years have been described. The typical history of oesophageal lesions after drug ingestion is exemplified in Figure 2. The patient typically takes a tablet late at night with little or no fluid and then goes to bed. Quite often the patient only remembers to take the tablet when falling asleep, and feels too tired to get up again in order to fetch a glass of water. The patient wakes a few hours later or early in the morning with severe retrosternal pain, which is not relieved by drinking or eating - on the
266
M. WIENBECK,
Table
1. Drugs
No. of cases*
Drug Tetracyclines Emepronium bromide Potassium chloride
97 39 34
Other
26
antibiotics
Aspirin Non-steroidal, anti-inflammatory drugs Ferrous sulphate/ succinate Alprenolol Quinidine 5-Fluouracil Ascorbic acid Paracetamol Mexiletine Theophylline Pinaverium Estramustin Clomethiazol Phenytoin Oral contraceptives Promethazine
reported
No.
of complications
Stricture
Haemorrhage
oesophageal
9
20
14
AND
H.
J. LiiBKE
lesions.
Death
Comments 77
2
3
Deaths due to haemorrhage (2) mediastinitis (1) Pivampicillin, clindamycin, co-trimoxazole, erythromycin, pivmecillinam and others
1
1
Mainly bleeding
3
Deaths
indomethacin; (indomethacin)
death
due
to
5 3
1 together
due to oesophageal
with
necrosis
aspirin
Combination of phenylpropanolamine and thiazinamium
Glibenclamid Thioridazine Pantogar@
Combination of thiamine hydrochloride, calcium pantothenate, aminobenzoic acid, cystine, yeast and keratin Death due to oesophageal perforation
Carbachol Chloral hydrate Bulk laxative Totals
BERGES
Doxycycline 3 12
24
12 9 7 5 2 2 2 2 2 2 1 1 1 1
to induce
W.
295
47
3
8
* Reviewed in Berges et al (1987) Bonavina et al (1987), Borsch et al (1983), Collins et al (1979), Heller et al (1982), Kikendall et al (1983), Rohner et al (1982), Swedish Adverse Drug Reactions Advisory Committee (1986).
contrary, swallowing is painful, and is avoided by the patient. Because of the severity of the pain the patient usually sees a doctor immediately. The doctor prescribes an analgesic agent, a coronary dilator or antacids, having ruled out myocardial infarction. The pain can persist for days, and will only vanish slowly if the patient’s method of taking the drug is changed. The decisive
DRUG-INDUCED
OESOPHAGEAL last pill
pain
267
LESIONS
X-ray
t
endoscopies 2
3
Figure 2. Typical history of a 19-year-old female patient with a drug-induced oesophageal lesion due to emepronium bromide. The drug was first prescribed on day 1. The second day the patient took the tablet with a very small amount of water and immediately fell asleep. She woke up 2 hours later with severe retrosternal pain. Because the pain persisted, the doctor ordered an X-ray examination of the oesophagus two days later. Since this was normal, he ordered the first oesophagoscopy two days later, which revealed two kissing ulcers at the level of the aortic arch. These ulcers were still visible during the second endoscopy one week later, but they were gone another four weeks later.
diagnostic procedure, oesophagoscopy, is usually delayed by several days, and is often only performed after a negative X-ray examination. By the time of endoscopy the lesion in the oesophagus has already lost its acute aspects and is beginning to heal. Depending on the type of the drug and the severity of the injury, there may be some variation to this history. For example, in old, decrepit patients and in those with alcoholic or diabetic neuropathy, the lesion may cause little or no pain, so that bleeding from the lesion or a late stricture may be the first symptom of the injury. In otherwise healthy persons severe bleeding with haematemesis and melaena may occur, but it is rare. The development of a cicatricial stenosis appears to be more common, and severe dysphagia may be the only indicator of the past drug-induced injury (Bonavina et al, 1987). In a few cases lethal complications have been described; they were due to perforation of the oesophageal wall or to severe bleeding. The pain usually subsides within one week provided that further injury is prevented. However, it may take up to six weeks for the ulcer to become fully epithelialized (see Figure 2). Although it is likely that extensive lesions are more prone to develop late strictures, the further course in individual patients cannot be predicted so far. Most lesions certainly heal without sequela.
Functional disturbances Disturbances of oesophageal motor function may facilitate the occurrence of drug-induced oesophageal lesions; conversely, oesophageal injury may completely derange oesophageal motility (Figure 3). In the acute phase it is impossible to distinguish between these two possibilities. Only a repeat examination after complete healing of the lesion will differentiate a secondary from a primary motility disorder. Patients with an underlying motor disturbance must be advised to avoid any drugs in pill form with local
268
M. WIENBECK,
BERGES
AND
H. J. LijBKE
.1
-
JL...-A
47 ---JResp. i SW.
W.
-----P---C---*_
__j;
. .
during drug-induced
oesophageal
,
. .
1.
40 days later
ulcer
Figure 3. Oesophageal manometry of a 22-year-old patient, shortly after thioridazine (taken while going to bed) had caused a mid-oesophageal ulcer, and 40 days later when the ulcer was healed. The distance of the four catheters from the teeth is indicated in centimetres on the left side. The tracings each represent 3 minutes of recording. Notice the markedly reduced amplitude of the oesophageal contractions at (a) the first examination, and (b) the completely normal motility 40 days later.
damaging action, so it is essential to identify any pre-existing oesophageal motility disturbance during the patient’s follow-up visit six to eight weeks after the acute injury. Therapy There is no specific therapy for drug-induced oesophageal lesions. It is of the utmost importance that any further intake of the offending agent is avoided. In the treatment of severe retrosternal pain, local anaesthetics (e.g. viscous preparations of lignocaine) are used in addition to systemic analgesic therapy. It is unknown whether antacids are of any benefit, although they are commonly prescribed. Histamine Hz receptor antagonists cannot be considered to be rational treatment. Certainly the best treatment of these lesions is prevention. This requires that any pill should be swallowed only with the patient in an upright position and followed by a fluid ‘chaser’ of at least 120 ml. If different preparations of equal potency are available, the less corrosive one should be prescribed; e.g. liquid drug preparations are preferable to pills, and chewable tablets are preferable to tablets or capsules firmly enclosing the ingredient. The importance of prevention also obliges the pharmaceutical industry to develop better chemical formulations, avoiding damaging concentrations of drugs and enabling pills to pass the oesophagus more readily. First steps in this direction have been taken by some pharmaceutical companies producing doxycycline and emepronium bromide. OESOPHAGEAL
LESIONS
AFTER
LOCAL
DRUG INJECTION
Local injection of sclerosing agents into the oesophageal wall is an established method of treating oesophageal varices. The ensuing inflammation, fibrosis
DRUG-INDUCED
OESOPHAGEAL
LESIONS
269
and thrombosis of the varices are desired therapeutic goals, but often necrosis and ulceration also develop and may cause severe complications (Knauer and Fogel, 1987; Pushpanathan and Idikio, 1986). The type of sclerosing agent and the technique of injection, be it intravascular or paravascular, have little effect (if any) on the nature and extent of these undesired lesions (Ayres et al, 1983). Pathomorphology Most information has been gathered from animal experiments. In rats, the mucosa was found to be oedematous and inflamed two days after intraoesophageal injection of 0.5% and 1% polidocanol, (Metz et al, 1986). These effects appeared to be dose dependent. After one week, necrosis and a granulomatous type of inflammation was seen. An increase of fibrous tissue, located in the granulomatous tissue, did not become evident before the fourth week. Similar observations have been made in autopsies of patients with oesophageal varices (Helpap and Hansen, 1983). Injection of 5% polidocanol produced particularly large ulcerations. Phenol almond oil, however, was associated with less inflammation. Sodium tetradecyl sulphate and ethanolamine also may produce severe inflammation and ulceration (Evans et al, 1982). Again, in animal experiments, sodium tetradecyl sulphate was more effective in occluding oesophageal varices than other sclerosants (Blenkinsopp, 1986). Sclerosing agents An ideal agent causing rapid thrombosis of the varices with little or no inflammation and necrosis of the paravariceal tissue has not been developed so far, and it is doubtful whether it ever will be. Ethoxysclerol and to a much lesser extent phenol peanut oil or phenol almond oil are predominantly used in central Europe. In the phenol solutions the sclerosing agent phenol is slowly released from the oil which acts as a carrier medium. Because these oils have a high viscosity they are difficult to inject through a small needle. Ethoxysclerol, which has been used in the therapy of peripheral varices for a long time, is an aqueous solution of ethanol and the local anaesthetic polidocanol. It is used mainly as a 1% w/v solution, occasionally also as a 0.5% and 2% solution. In Anglo-American countries ethanolamineoleate (5%), sodium tetradecyl sulphate (3%) and sodium morrhuate (5%) are much more popular. These agents contain long-chain unsaturated fatty acids as active ingredients. Pure ethanol has also been used with apparent success(Sarin et al, 1985). However, controlled clinical trials and animal experiments comparing the efficacy and the side-effects of these agents are largely missing. Symptoms In contrast to other drug-induced oesophageal lesions, ulcers due to sclerotherapy of varices rarely produce retrosternal pain. They may, however, be the source of life-threatening bleeding. Four days after sclerotherapy,
270
M. WIENBECK,
W.
BERGES
AND
H. J. LijBKE
necrosis may already be seen at the site of the injections (Soehendra et al, 1983). The extent of the necrosis does not appear to be strictly correlated to the volume of the injected agent. During the first days the clot at the surface of the lesion adheres only very loosely. Particles of solid food or endoscopic manipulations may inadvertently rub off part of the clot and cause severe bleeding. In general, after about a week the clot becomes sufficiently adherent and retracted for the patient to resume normal food intake. In a significant proportion of patients, new bleeding mainly due to treatment-induced ulcers occurs (Ayres et al, 1982). In the majority of cases these are silent haemorrhages leading to tarry stools; but if still patent blood vessels are opened, life-threatening haemorrhage may ensue. Considerable fibrosis may develop in the oesophageal wall after sclerotherapy and cause a symptomatic stricture. Bougienage becomes a necessity in about 2% of patients who have undergone sclerotherapy. It has to be performed very carefully in order to prevent bleeding. Transmural necrosis of the oesophagus and perforation are almost lethal complications in these severely ill patients. The occurrence of these complications decreases with increasing therapeutic experience of the endoscopist. Functional disturbances The fibrosis developing within the oesophageal wall may also impair oesophageal motility. The contractions of the oesophageal body may be reduced in amplitude and show an increased occurrence of simultaneous contractions, and the pressure in the lower oesophageal sphincter may decrease (Reilly et al, 1984; Sauerbruch et al, 1982; Siiderlund et al, 1985). An impaired oesophageal clearance and pathological gastro-oesophageal reflux may ensue, but in general, reflux oesophagitis is not a major problem after sclerotherapy. Therapy As with other drug-induced oesophageal lesions, there is no specific treatment for ulcers after sclerotherapy. It is unlikely that any drug accelerates the process of healing. If bleeding from ulcers occurs, it is treated symptomatically by tamponade, systemic application of vasopressin, blood substitution and similar manoeuvers. A new injection of sclerosing agent into a bleeding, druginduced lesion is risky and in most cases unsuccessful; the procedure is avoided by most investigators. POTENTIALLY
HARMFUL
DRUGS
IN OESOPHAGEAL
DISEASE
All diseases that delay transit through the oesophagus increase the risk of drug-induced oesophageal lesions, through decreased clearance of the harmful agent. In addition, it has to be remembered that drugs affecting the motility of the oesophagus and the lower oesophageal sphincter may cause
DRUG-INDUCED
OESOPHAGEAL
271
LESIONS
Table 2. Drugs with motor the human oesophagus. Inhibition Anticholinergic agents Calcium antagonists /Ssympathomimetic agents Oestrogens and progesterones Prostaglandin El
inhibitory
and stimulatory
actions
in
Stimulation Prokinetic agents Parasympathomimetic agents /3-adrenergic blockers cr-sympathomimeGc agents Prostaglandin Fla
unwanted effects, particularly in patients with pre-existing motor disturbances of the oesophagus. They may aggravate the symptoms of the disease. In general, these drugs can be classified into those inhibiting oesophageal contractions, and those stimulating them (Table 2). Drugs causing motor inhibition A number of drugs may inhibit the force of oesophageal contractions and decrease the pressure in the lower oesophageal sphincter (Kilbinger and Weihrauch, 1984; Wienbeck and Berges, 1981). They may thus aggravate or even produce symptoms of gastro-oesophageal reflux such as heartburn, eructation, epigastric pain and dysphagia. These drugs should be withdrawn if such symptoms occur, and replaced by other agents not affecting oesophageal motility. If this is not possible, an antireflux regimen should be added to the offending medication. Drugs causing motor stimulation A series of drugs may stimulate the force of oesophageal contractions and increase the pressure in the lower oesophageal sphincter (Kilbinger and Weihrauch, 1984; McCallum, 1985). Usually these are desirable effects, particularly in the case of the prokinetic agents metoclopramide, bromopride, domperidone, cisapride and bethanechol. These drugs are usually given as a treatment in patients with inadequate oesophageal contractions, e.g. in reflux oesophagitis. Occasionally, however, motor stimulation of the oesophagus may become an undesired effect particularly if painful oesophageal contractions or delayed transit through the oesophagus are induced (Basotti et al, 1987). These drugs should also be avoided in achalasia, diffuse oesophageal spasm and nutcracker oesophagus, although controlled studies on the frequency and severity of drug side-effects in these diseases are absent.
DRUG-INDUCED
BOLUS
OBSTRUCTION
A rare complication of the intake of dietary fibre is bolus obstruction in the oesophagus (Figure 4). Patients with oesophageal motility disorders and organic stenosis are particularly prone to develop this complication, but even
272
M.
WIENBECK,
W.
BERGES
AND
H. J. LtiBKE
04 fibre. 4. X-ray pictures of bolus obstruction of the lower oesophagus due to dietary (a) Obstruction by bran with superimposed food remnants in a 3%year-old healthy man. (b) Obstruction and distension of the lower oesophagus by a guar bolus in a 45-year-old WC six months after gastrectomy and oesophagojejunostomy for gastric cancer. Figure
DRUG-INDUCED
OESOPHAGEAL
273
LESIONS
in healthy subjects an obstruction may occasionally occur. Since dietary fibres such as bran are widely used nowadays in the treatment of chronic constipation and other functional disturbances of the gut, advice should be given on how to take these fibres when they are prescribed. Patients should be advised to soak bran for at least ten minutes in viscous liquids such as yoghurt or apple mash before ingestion, and to swallow it together with plenty of water or other drinks in a sitting position. Guar used to treat dumping syndrome in gastrectomy patients, is particularly dangerous; it may adhere to the lower oesophagus, where it may increase its volume by a factor of three and more within a short time. The swelling of guar is enhanced by the simultaneous intake of alcohol. A very painful-and even dangerous-situation may ensue (Ranft and Imhof, 1983). SUMMARY Persisting retrosternal pain of sudden onset is suggestive of a drug-induced oesophageal lesion, particularly if it starts at night. After exclusion of a myocardial infarction, a carefully taken history and oesophagoscopy will rapidly clarify the cause and severity of the injury. Since almost any pill may produce oesophageal lesions, care has to be taken that tablets, capsules and other pills are always taken in an upright position together with a fluid chaser of at least 120 ml. If possible, less harmful liquid preparations of the drugs should be preferred. Lesions in the oesophageal wall and perioesophageal tissue are almost unavoidable side-effects of sclerotherapy of oesophageal varices. The patient and the doctor should be particularly aware of bleeding from oesophageal ulcers during the first week after sclerotherapy. Numerous drugs may weaken or strengthen contractions of the oesophagus and lower oesophageal sphincter. These potentially unwanted motor effects of the drugs have to be kept in mind, especially in patients with pre-existing gastro-oesophageal reflux disease and hypermotility states. Acknowledgements Part of this work was supported by the Deutsche Forschungsgemeinschaft, (Wi 285). The authors thank MS H. Nickel for her expert secretarial work.
Bonn-Bad
Godesberg
REFERENCES Ayres
SJ, Goff JS, Warren GH & Schaefer JW (1982) Esophageal ulceration and bleeding after flexible fiberoptic esophageal vein sclerosis. Gastroenterology 83: 131-136. Ayres SJ, Goff JS & Warren GH (1983) Endoscopic sclerotherapy for bleeding esophageal varices: effects and complications. Annals of Internal Medicine 98: 900-903. Bassotti G, Gaburri M, Pelli MA & Morelli A (1987) Oesophageal pain exacerbated by propranolol. British Medical Journal 294: 1655. Berges W, Rohner HG & Wienbeck M (1980) ijsophagusulkus nach Einnahme von Emeproniumbromid. Leber Magen Dam 10: 37-40.
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Berges W, Frieling T & Wienbeck M (1987) Medikamentos bedingte ijsophagusgeschwiire. Deutsches drzteblatt-iirztliche Mitteilungen 84: 22-25. Blenkinsopp WK (1986) Comparison of tetradecylsulphate of sodium with other sclerosants in rats. British Journal of Experimental Pathology 49: 191-201. Bonavina L, DeMeester TR, McChesney L, Schwizer W, Albertucci M &Bailey RT (1987) Druginduced esophageal strictures. Annals of Surgery 206: 1733183. Borsch G, Sabin G & Ricken D (1983) Arzneimittelschaden an Mundhdhle Speiserohre, Magen und Zwiilffingerdarm. Medizinische Klinik 78: 758-7’61. Collins FJ, Matthews HR, Baker SE & Strakova JM (1979) Drug-induced oesophageal injury. British Medical Journal 1: 1613-1676. Evans KT & Roberts GM (1976) Where do all the tablets go? Lancet ii: 1237-1239. Evans DMD, Jones DB, Cleary BK & Smith PM (1982) Oesophageal varices treated by sclerotherapy: a histopathological study. Gut 23: 615-620. Giger M, Sonnenberg A, Brlndli H, Singeisen M, Giiller R & Blum AL (1978) Das TetracyclinUlkus der Speiserohre. Deutsche Medizinische Wochenschrift 103: 1038-1040. Heller SR, Fellows IW, Ogilvie AL &Atkinson M (1982) Non-steroidal anti-inflammatory drugs and benign oesophageal stricture. British Medical Journal 285: 167-168. Helpap B &Hansen H (1983) Vergleichende histologische Untersuchungen nach ijsophagusvarizensklerosierung mit unterschiedlichen Substanzen. Leber Magen Darm 13: 215-222. Hey H, Jorgensen F, Sorensen K, Hasselbalch H & Wamberg T (1982) Oesophageal transit of six commonly used tablets and capsules. British Medical Journal 285: 1717-1719. Kikendall WJ, Friedman AC, Oyewole MA, Fleischer D & Johnson LF (1983) Pill-induced esophageal injury. Case reports and review of the medical literature. Digestive Diseases and Sciences 28: 174-182. Kilbinger H & Weihrauch TR (1984) Pharmakologie motilitatswirksamer Medikamente. In Wienbeck M & Siewert JR (eds) Therapie Gastrointestinaler MotilitiitsstBrungen, pp. 1-4. Weinheim: Edition Medizin. Knauer CM & Fogel MR (1987) Pericarditis: complication of esophageal sclerotherapy. A report of three cases. Gastroenterology 93: 287-290. McCallum RW (1985) Review of the,current status of prokinetic agents in gastroenterology. American Journal of Gastroenterology 80: 1008~1016. Metz KA, Erhard J, Gross E & Donhnijsen K (1986) Zur Wirkung unterschiedlicher Sklerosierungsmittel auf den Rattenosophagus. Zeitschrift fiir Gastroenterologie 24: 605611. Pushpanathan C & Idikio H (1986) Pathological findings in the esophagus after endoscopic sclerotherapy for variceal bleeding. American Journal of Gastroenterology 81: 9913. Ranft K & Imhof W (1983) Bolusobstruktion des distalen Esophagus durch pflanzliche Quellstoffe (Guarmehl). Deutsche Medizinische Wochenschrift 108: 1968-1969. Reilly JJ, Schade RR & Van Thiel DS (1984) Esophageal function after injection sclerotherapy: pathogenesis of esophageal stricture. American Journal of Surgery 147: 85-88. Rohner HG, Berges W & Wienbeck M (1982) Clomethiazol tablets induce ulcers in the esophagus. Zeitschrtft fiir Gastroenterologie 20: 469-473. Sarin SK, Sachdeva GK, Nanda R, Vij JC & Anand BS (1985) Endoscopic sclerotherapy using absolute alcohol. Gut 26: 120-124. Sauerbruch T, Wirsching R, Leisner B, Weinzierl M, Pfahler M & Paumgartner G (1982) Esophageal function after sclerotherapy of bleeding varices. Scandinavian Journal of Gastroenterology 17: 745-751. Siiderlund C, Thor K & Wiechel KZ (1985) Oesophageal motility after sclerotherapy of bleeding varices. Acta Chirurgica Scandinavica 151: 249-253. Soehendra N, de Heer K, Kempeneers I & Frommelt L (1983) Morphological alterations of the esophagus after endoscopic sclerotherapy of varices. Endoscopy 15: 291-296. Swedish Adverse Drug Reactions Advisory Committee (1986) Bulletin. Chemotherapie-Telegramm 2: 8. Wienbeck M & Berges W (1981) Die tjsophagusmanometrie. Fortschritte der inneren Medizin und Kinderheilkunde 47: 1 1 1- 152.