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Effect of Codeine and Loperamide on Upper Intestinal Transit and Absorption in Normal Subjects and Patients with Postvagotomy Diarrhoea

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Effect of Codeine and Loperamide on Upper Intestinal Transit and Absorption in Normal Subjects and Patients with Postvagotomy Diarrhoea Gut: first published as 10.1136/gut.29.3.312 on 1 March 1988. Downloaded from Gut, 1988, 29, 312-318 Effect of codeine and loperamide on upper intestinal transit and absorption in normal subjects and patients with postvagotomy diarrhoea J D O'BRIEN, DG THOMPSON, A McINTYRE, W R BURNHAM, AND E WALKER From the Department ofGastroenterology, The London Hospital, Whitechapel, London, Oldchurch Hospital, Romford, Essex, and Hope Hospital, Salford SUMMARY Patients with chronic severe diarrhoea after truncal vagotomy and pyloroplasty are often difficult to treat using conventional antidiarrhoeal drugs and remain severely disabled. We examined the effect of two drugs, codeine phosphate and loperamide, on upper intestinal transit and carbohydrate absorption, measured non-invasively by serial exhaled breath hydrogen monitoring, in patients with postvagotomy diarrhoea who had previously failed to gain relieffrom drug therapy. Orocaecal transit was consistently faster in these patients than a group ofcontrols and was associated with malabsorption ofglucose. Codeine phosphate 60 mg significantly delayed transit in patients and controls and was associated with a reduction in glucose malabsorption and improvement in symptoms. Loperamide also delayed transit and improved symptoms, but the doses required for this effect (12-24 mg) were higher than usually considered necessary in secretory diarrhoea. These studies indicate that rapid intestinal nutrient transit and associated malabsorption is a factor in the development of diarrhoea postvagotomy and that symptomatic relief can be achieved in most patients by more rational use of existing drugs. http://gut.bmj.com/ Until the introduction of effective antisecretory Because of incomplete understanding of the drugs, truncal vagotomy with pyloroplasty was a aetiology, therapy remains empirical, involving on October 1, 2021 by guest. Protected copyright. common operation in the United Kingdom for dietary manipulation, bile acid binding agents'' or chronic duodenal ulceration. Its most significant antibiotic therapy, in addition to regular anti- unwanted effect, diarrhoea, was usually short lived, diarrhoeal drugs'2 such as codeine phosphate or although for a minority of patients (2-8%) the loperamide. Many patients, however, do not obtain problem has continued and remains severely satisfactory benefit from such antidiarrhoeal disabling. 1-3 therapies despite their use at doses which have The exact cause for the diarrhoea in an individual measurable effects on other diarrhoeal states.`131 patient is often difficult to ascertain. While several After the referral to our unit of several patients mechanisms have been proposed' including bile with severe postvagotomy diarrhoea, which had acid malabsorption, and bacterial overgrowth,5` the apparently been unresponsive to large doses of major factor seems to be rapid gastric emptying and codeine and loperamide we wondered whether there upper gastrointestinal transit which results in might be differences in the pharmacological activity reduced digestion and absorption in the small of these drugs in such patients requiring a different intestine, and osmotic overload of the colon.9 approach to therapy. We therefore decided to investigate the effects of codeine phosphate and loperamide on upper gastrointestinal nutrient transit Address for correspondence: Dr D G Thompson, Department of Medicine, and absorption in patients with postvagotomy diarr- Hope Hospital, Eccles Old Road, Salford M6 8HD. hoea, in an attempt to determine their efficacy and Received for publication 4 September 1987. optimal therapeutic regimens. 312 Gut: first published as 10.1136/gut.29.3.312 on 1 March 1988. Downloaded from Effect ofcodeine and loperamide on upper intestinal transit in patients with postvagotomy diarrhoea 313 80 tion, for at least three years. Of the 14 patients studied, 10 were regarded by their physicians as being severely incapacitated with frequency of defecation between six to eight times daily on most days. In addition to being given standard advice on ingestion of small, dry meals and avoidance of sugary liquids, all patients had been prescribed loperamide - and codeine phosphate. None, however, admitted to 60 having derived any appreciable benefit from either drug. Therapeutic regimens used by patients varied widely in total dosage and timing of administration. 405 Therapies advised had ranged from 2 mg loperamide to be taken in the event of diarrhoea, to large doses of 0 both drugs taken with or after meals. Maximum daily doses of codeine were 180 mg and loperamide 12 mg. E SELECTION OF PATIENTS FOR THE STUDIES 240 Patients were recruited for the two experiments in the order of their referral to the unit and their availability for repeat study. The first eight patients carried out the initial experiment, and six agreed to return for the second experiment by which time a further six patients had been recruited. UPPER INTESTINAL TRANSIT This was determined by the technique of serial exhaled breath hydrogen sampling.` After an over- night fast of at least 15 hours, each individual came to the clinical study area where, after a period of 15 http://gut.bmj.com/ minutes, a series of basal exhaled breath hydrogen samples were collected using a previously described Fig. 1 Time to the breath hydrogen rise after test meal technique.'` After this basal period a standard test ingestion in normalsubjects andpatients with postvagotomy meal (400 ml chicken soup, HJ Heinz Ltd, 255 kcal, diarrhoea (PVD). PVD is associated with an earlier breath plus 30 ml lactulose, Duphalac, Duphar Ltd) was hydrogen rise compared with normalsubjects, indicating ingested. In a previous study'7 this meal reliably accelerated orocaecal transit. produced a breath hydrogen rise in eight normal on October 1, 2021 by guest. Protected copyright. subjects who ingested the meal on three separate Methods occasions with a mean individual coefficient of varia- tion'8 of 9%. After meal ingestion breath samples PATIENTS AND SUBJECTS were collected at five minute intervals and then more Fourteen patients, 10 men, four women (mean age frequently (two to three mins) once values appeared 38, range 35-67 years) with severe, chronic diarrhoea to become raised. As previously reported'67 a after truncal vagotomy and pyloroplasty took part in sustained rise in breath hydrogen by more than twice the studies, together with 12 normal volunteers (age the mean baseline value was taken to indicate the 19-55 years), drawn from the medical personnel and caecal arrival of the meal, this value being selected as student population of the hospital. All protocols in earlier studies because it offered a simple, con- were submitted to and approved by the London servative endpoint which reduced possibility of Hospital Ethics Committee, and patients and con- erroneous interpretation because of baseline varia- trols gave their informed consent before participa- tion. When compared in our laboratory with other tion. Postvagotomy diarrhoea was defined as a previously reported end points such as time for postoperative change in bowel habit with the baseline values to rise by 10 ppm,'9 it provided a value development of at least three or more loose motions a which was consistently earlier by two to five minutes. day, exacerbated by food. All patients had also The normal subjects each carried out six transit suffered from repeated episodes of food related studies on separate days, receiving either no drug, lower abdominal discomfort, and urgency of defeca- codeine phosphate (30 and 60 mg) or loperamide (4, Gut: first published as 10.1136/gut.29.3.312 on 1 March 1988. Downloaded from 314 O'Brien, Thompson, McIntyre, Burnham, and Walker 8, 12 mg). To avoid bias, the order of experiments or absence of a breath hydrogen rise after carbohy- was randomised between individuals, and the estima- drate ingestion can be used as an index of the tion of the time to hydrogen rise from the serial data completeness ofits absorption in the small intestine.20 was made by one of the research team who was While others have reported that the area under the unaware of the drug given. breath hydrogen curve can be used as a guide to Based on the results of the normal subjects, carbohydrate malabsorption2` this method neces- repeated transit studies were done on eight patients sarily assumes a constant relationship between using an identical method. Each patient undertook quantity of carbohydrate arriving at the caecum and four studies in random order, receiving either no size of breath hydrogen rise. Because carbohydrate drug, loperamide (4 mg and 12 mg) or codeine fermentation products reduce caecal pH, which can phosphate (60 mg). autoinhibit hydrogen genesis22 this method can only Because of an apparent lack of effect of lopera- be approximate. In an attempt to avoid such assump- mide on transit in the patients, seven of them tions we recorded the presence or absence of a breath consented to be restudied after ingestion of 24 mg hydrogen rise after ingestion of a glucose solution loperamide. (50 g in 250 ml water) which is completely absorbed in normal subjects but malabsorbed in those with post- GLUCOSE ABSORPTION STUDIES vagotomy diarrhoea. The 12 normal subjects and 12 Since fermentable carbohydrate that escapes absorp- patients participated in this experiment. tion in the small intestine induces a rise in breath After ingestion of the test solution serial exhaled hydrogen upon its arrival at the caecum, the presence breath hydrogen measurements were taken until at least four hours had elapsed or until a definite rise 80. was observed (using the same criteria as the transit studies). The studies were then repeated in the ± patients on separate days after oral administration of Mean SEM either loperamide (4, 12, 24 mg), or codeine (60 mg) (n-12) one hour before the glucose. The order of adminis- r tration was randomised between individuals, and as in the transit studies, the interpretation of the presence and timing of a hydrogen rise was made by 60O http://gut.bmj.com/ * one individual unaware of the drug used.
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