Scandinavian Journal of Gastroenterology

ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20

Sucralfate versus Cimetidine in Reflux Oesophagitis: The Effect on Oesophageal pH and Motility F. Jørgensen & L. Elsborg To cite this article: F. Jørgensen & L. Elsborg (1991) Sucralfate versus Cimetidine in Reflux Oesophagitis: The Effect on Oesophageal pH and Motility, Scandinavian Journal of Gastroenterology, 26:3, 263-268, DOI: 10.3109/00365529109025040 To link to this article: http://dx.doi.org/10.3109/00365529109025040

Published online: 08 Jul 2009.

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Date: 21 March 2016, At: 22:33

Sucralfate versus Cimetidine in Reflux Oesophagitis The Effect on Oesophageal pH and Motility F. J0RGENSEN & L. ELSBORG Dept. of Clinical Physiology and Dept. of Medicine B, Central Hospital, Hiller~d, Denmark

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J0rgensen F, Elsborg L. Sucralfate versus cimetidine in reflux oesophagitis. The effect on oesophageal p H and motility. Scand J Gastroenterol 1991, 26, 263-268 Sixty patients with endoscopically verified oesophagitis entered a double-blind study comparing the effect of 1 g of sucralfate granulate given four times a day and cirnetidine, 400 mg twice a day. Fifty-two patients, 26 treated with cimetidine and 26 with sucralfate, were examined with short-term pH monitoring before and after 12 weeks of treatment. In about half of the patients, 19 treated with cimetidine and 11 treated with sucralfate, the oesophageal motility was studied with a radionuclide test before and after treatment. The sucralfate treatment did not affect either mean p H or the emptying rate but reduced the number of spikes. The cimetidine treatment increased mean pH and reduced the number of spikes but did not affect emptying rates. Both groups had significantly prolonged mean transit time (M'IT) compared with healthy volunteers. M'IT did not change after either treatment. The residual activity in the sitting position was significantly increased after cimetidine. It is concluded that the pharmacodynamic effect on oesophageal motility is different for the two drugs in question. Primary dysmotility might be involved in the pathogenesis of oesophagitis.

Key words: Cimetidine; pH-monitoring; radionuclide transit measurements; reflux oesophagitis; sucralfate Frank [email protected], M. D . , Medical Dept. B, Frederiksberg Hospital, DK-2OOO Copenhagen F, Denmark

Several authors have recognized a delayed acid clearance rate as the single most important factor in the pathogenesis of reflux oesophagitis (1). Decreased peristaltic amplitude in patients with reflux oesophagitis has been demonstrated ( 2 ) , and abnormal motor function has been suggested as significant in the generation of oesophageal symptoms. Delayed oesophageal emptying, and not deficient acid neutralization by saliva, appeared to be the predominant component in abnormal acid clearance in patients with reflux oesophagitis (3). By manometry it has been shown that the severity of peptic oesophagitis is correlated to peristaltic dysfunction (4). In children with reflux oesophagitis nonspecific motor abnormalities were more common than in controls ( 5 ) . After a period of 12 weeks of antacid treatment patients with cured oesophagitis show a marked

regression of motor abnormalities. The effect of cimetidine on oesophageal motility has been investigated by manometry in seven trials (6-11) and reviewed by Dobrilla et al. (12). In two trials with healthy volunteers a significant increase in lower oesophageal sphincter pressure (LOSP) was found (6,8). No controlled studies of oesophageal motility before and after treatment with sucralfate are on record. The aim of the present study was to evaluate the oesophageal motility and changes in pH in patients with reflux oesophagitis before and after treatment with cimetidine and sucralfate. PATIENTS AND METHODS The study was performed as a randomized doubleblind controlled study with two parallel groups,

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using a double-dummy technique. Sixty patients, age 18-75 years, suspected of having reflux oesophagitis because of dyspepsia were included in the study when endoscopy showed oesophagitis grade 11-111 in accordance with Savary-Miller (13). In the patients treated with cimetidine 37% had endoscopic grade I1 and 63% grade 111; in the sucralfate group 43% had grade I1 and 57% grade I11 before treatment. Pregnancy, lactation, concomitant peptic ulcer, previous gastric surgery, and concomitant cardiac, hepatic, or renal diseases and malignancy were also used as exclusion criteria. Patients treated with drugs affecting oesophageal motility or with cimetidine or sucralfate within 2 months before the initial examination were omitted. The patients were randomly allocated to treatment with 1g of a sucralfate granulate four times a day, taken before meals and at bedtime, or 400 mg of cimetidine twice daily. The patients were treated for 12 weeks. All patients were asked to participate in pH measurements and the motility studies. Fifty-two patients were evaluated with short-term pH monitoring (Table I). Thirty patients agreed to have their oesophageal motility evaluated by radionuclide transit measurement. Nineteen patients were treated with cimetidine, and 11 were treated with sucralfate. No other medication was allowed during the treatment period. A reference group for the radionuclide measurements consisted of 60 healthy volunteers (Table I) and of 14 young volunteers as controls for pH measurements. When the patients had been examined by endoscopy and included in the study, they were examined by pH monitoring and radionuclide transit studies within the next 7 days. Thereafter the patients entered the study and

started to take the medication. In the 12th week of treatment the patients were examined by endoscopy, asked about symptoms, and monitored by radionuclide transit. By the end of the 12th week medication was discontinued, and within the next 7 days p H monitoring was performed. The time lapse between the double measurements was 30 sec. The study was approved by the Regional Ethics Committee and registered by The Danish Board of Health. Each patient was given written information about the study, and verbal informed consent to participation was obtained before inclusion. Methods Oesophageal transit. Oesophageal transit time was calculated by means of a radionuclide technique as presented in a recent paper (14). The oesophageal transit time was measured with the patients in the supine and sitting positions, using single swallows of 15ml of water containing 5 MBq of 99mTc-pertechnetateand a gamma-camera (GE-Maxi) and a computer (Digital-PDP-11). By means of a computer program the mean transit time (MTT) for the rapid part of the bolus was calculated, and the residue of the bolus remaining in the oesophagus after the swallow was estimated from the activity curves, The MTT and the residual activity in the supine and sitting positions were measured twice, and the values used were the average of the two measurements. p H measurements. The pH monitoring was performed in fasting patients on a separate day, starting at 0800 h and using an antimony pH electrode (Ingold, Radiometer GK 282C, Copenhagen, Denmark). The electrode was placed 5 cm above the lower oesophageal sphincter (LOS),

Table I. Demography in the 52 patients evaluated by short-term pH measurement and in the 30 patients evaluated by radionuclide transit measurement (MTT) (in parentheses) ~~~~~~

Initial no. incl. Female, n Male, n Age (mean), years Age (range), years

Sucralfate

Cimetidine

Controls (MTT)

32 14 (6) 12 ( 5 ) 48 (53) 2&75 (27-72)

28 13 (8) 13 (11) 50 (49) 24-73 (24-73)

60 29 31 43 (20-79)

Motility and p H in Reflux Oesophagitis

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week, and symptoms. These data have been presented in a recent paper (16). Statistical methods. The statistics used are nonparametric. When paired data were compared before and after treatment, the Wilcoxon test for paired data was used, whereas the Mann-Whitney U-test was used for unpaired data. When more than two groups were compared, a significance level of 0.05 was corrected by the method of Bonferoni.

15

RESULTS

MTT supine

.-

30 -*-

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10

*s

5

A

B

Sucralfate

A B Cimetidine

C

Fig. 1. The mean transit time (MTT) in the supine position in the two groups of patients, sucralfate ( n = 11) and cimetidine ( n = 19), before (A) and after (B) treatment. In the right column controls (C) are presented ( n = 60). The asterisk marks significantly different groups.

Radionuclide transit measurements Mean transit time. In the supine position before treatment one-third of the patients had prolonged MTT. After treatment only a few were normalized; that is, 23% still had prolonged MTT after both treatments. When MTT were compared within groups before and after treatment, no differences were found. Compared with healthy volunteers the MTT were prolonged both before and after treatment (Fig. 1). In the sitting position we did not find any differences between groups before and after treatment, and again both groups had significantly prolonged MTT before and after treatment. Residual activity. In the supine position the residual activity was equal in healthy volunteers and patients before treatment. In the sitting position the residual activity increased significantly in the cimetidine group (p 2/h, and k < 0.5) are present significantly by both treatments. The clearance (15). From the recordings the mean pH, number k was accelerated by both treatments, but no rate of reflux episodes (spikes), defined as a drop in statistically significant difference was found in the pH to s 4,and mean acid clearance rate ( k ) were cimetidine group. calculated. The calculation of k was defined as Cimetidine significantly increased pH after the mean value of the descending slopes of all the treatment, whereas sucralfate did not have any spikes. The patients were checked with pH monitoring effect on pH. In both groups the pH values were at the start and at the end of treatment after 12 significantly lower than in the healthy volunteers before and after treatment. weeks. All patients ( n = 26) treated with cimetidine Clinical assessment. The patients were evaluated by medical history, endoscopy every 4th had reduced clearance rate ( k ) before treatment.

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'3

Residual activity

7

.-

Cirnelidine

-

A

0

Sucrollate -ns-

A

.

9

I:

B

C

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Spikes

30{

- -

-*-

A

A

20 10

k

B

-nsI

A

8

Sucralfate

A

B

C

3.0

Cimetidine

Fig. 2. The residual activity in the sitting position in the two groups of patients, sucralfate (n = 11) and cimetidine (n = 19) before (A) and after (B) treatment. Controls are presented in C (n = 40). The asterisk marks significantly different groups.

*'OI 1.5 1.0

Twenty-four patients had pH < 6.3, but the two patients with normal pH had > 3 spikes. All cimetidine-treated patients had a pH monitoring indicative of GOR. After treatment all still had a reduced clearing rate, whereas six patients had their pH elevated above 6.3. Of these six patients five had fewer than three spikes. This means that five patients (20%) no longer met the criteria for GOR. All the sucralfate-treated patients also met the pH-monitoring criteria before treatment. All had reduced clearing rate ( k ) ,and 23 had reduced pH. The three patients with normal pH had more than three reflux episodes. After treatment with sucralfate the clearing rate was still delayed in all patients, and all had a pH < 6.3. This indicates that no patient really improved from the pHmonitoring criteria. Yet eight sucralfate-treated patients (40%) had their reflux episodes reduced to less than three.

0.5

A B Cimelidine

A B Sucrollate

C

Fig. 3. Results of the pH monitoring before (A) and after (B) treatment with cimetidine and sucralfate. Controls are presented in C (n = 14). The upper values represent the median oesophageal pH, the middle values the number of spikes, and the bottom values the clearance rate (k). The asterisk marks significantly different groups.

DISCUSSION The diagnosis of reflux oesophagitis has to be defined by certain criteria, since everybody occasionally experiences symptoms of regurgitation (15). Reflux episodes occur when the gastric content is present and a dysfunction or

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Motility and pH in Rejlux Oesophagitis

incoordination of the LOS occurs. In spite of episodic regurgitation most people do not have reflux oesophagitis. It is not known when and why some persons do get oesophagitis. The prolonged MTT before and after treatment in one-third of the patients suggests a primary motility disorder in some patients with reflux oesophagitis. Similar results have been obtained by others (17). The results of our pH monitoring show that treatment with cimetidine and sucralfate significantly and to the same extent reduce the number of spikes-that is, reflux episodes of gastric content to the oesophagus. The clearing rate ( k ) was not changed in either group* Cimetidine reduces the production of gastric acid, and median oesophageal pH increased after treatSucralfate did not have any effect On pH. All patients fulfilled the pH-monitoring criteria (criteria in Patients and Methods) for GOR when entering the study, but after the treatment 19 of 26 cimetidine-treated (73%) still met the criteria, and all 26 treated with sucralfate still met 2 of for These differences are not surprising, merely reflecting the different pharmacologic profiles of the drugs and the fact that we are treating symptoms rather than the of an illness, the nature of which is still a puzzle. Cimetidine reduces the intraoesophageal acid load but in most patients (Fig. 2). Oral cimetidine has been reported to increase (6, 8), which is consistent with our data showing a significant increase of the residual activity in the distal oesophagus after cimetidine. This primary inhibitory influence on oesophageal motor function may explain why cimetidine is not more effective in the treatment of oesophagitis than sucralfate, which does not have any negative influence on the motor action. The effect of SUCralfate may solely be caused by the local healing effect Of the mucoSa restoring Some motor activity of the distal oesophagus. The mechanism of the reduced oesophageal 'learance by "Inetidine might be to a nonspecific, anticholinergic effect of cimetidine (18) or to a weak ganglioll-blocking effect (19). What-

ever mechanism > combined therapy with a prokinetic drug like cisapride and cime-

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tidine in severe reflux oesophagitis is better than cimetidine alone (20). Our data show that the pretreatment MTT is prolonged in one-third of the patients and remains abnormal after either treatment in most patients. It is therefore suggested that a primary motility disorder reducing the ability to clear the oesophagus may be responsible for some cases of oesophagitis.

REFERENCES 1 . Orr WC, Robinson MG, Johnson LF. Acid clearance during sleep in the pathogenesis of reflux esophagitis. Dig Dis Sci 1981, 26, 423-427 2. Burns m,Venturatos SG. Esophageal motor function and response to acid perfusion in patients with symptomatic reflux esophagitis. Dig Dis Sci 1985, 30, 529-535 3. Ferguson MK, Ryan Jw, Little AG, Skinner DB. Esophageal emptying and acid neutralization in patients with symptoms of esophageal reflux. Ann Surg 1985, 201, 728-736 wJ, Hogan wJ, Kern M, 4. Kahrilas pJt Arndorfer RC, Reece A. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterol 1986, 91, 897-904 5. Cucchiara s, Staniano A, Di Lorenzo c, et al. Esophageal motor abnormalities in children with gastroesophageal reflux and peptic esophagitis S. J Pediatr 1986, 108, 907-910 6. Roesch w , LUX G, Schittenhelm w , DemPling L. Stimulation of lower oesophageal sphincter pressure (LESP) by cimetidine-a double blind study. Hepatogastroenterology 1976, 23, 422425 7. Freeland GR, Higgs RH, Castell DO. Lower oesophageal sphincter response to oral administration of cimetidine in normal subjects. Gastroenterology 1977, 72, 28-30 8. Siewert RG, Lepsien R, Arnold W, Creutzfeldt W. Effect of cimetidine on lower esophageal sphincter pressure, intragastric pH and Serum levels of immunoreactive gastrin in man. Digestion 1977, 15, 8184 9. Krawitz JJ, Snape WJ, Cohen S. Effect of histamine and histamine antagonist on human lower oesophageal sphincter function. Gastroenterology 1978, 74, 435-440 10. Behar J, Brand DL, Brown FG, et al. Cimetidine in the treatment of symptomatic gastroesophageal reflux. Gastroenterology 1978, 74, 441-448 11. Wesdorp E, Bartelsman J, Pape K, Dekker W, Tytgat GN. Oral cimetidine in reflux oesophagitis: A double-blind controlled trial, Gastroenterology 1978, 74, 821-824 12. Dobrilla G , Pretis de G , Comberlato M, Amplatz S. H,-antagonists and motility of the upper gastrointestinal tract in man. Hepatogastroenterology 1988, 35, 30-33

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13. Savary M, Miller G. In: Savary M, Miller G, eds. The esophagus. Handbook and atlas of endoscopy. Verlag Gassman, AG, Solothurn, Switzerland, 1978, 119-205 14. J0rgensen F, Hesse B, Grdnbak P, Fogh J, Hauns0 S. Abnormal oesophageal function in patients with non-toxic goiter or enlarged left atrium, demonstrated by radionuclide transit measurements. Scand J Gastroenterol 1989, 24, 11861192 15. Jdrgensen F, Elsborg L, Hesse B. The diagnostic value of computerized short-term pH-monitoring in suspected gastro-oesophageal reflux. Scand J Gastroenterol 1988, 23, 363-368 16. Elsborg L, Jdrgensen F. Sucralfate versus cimetidine in reflux oesophagitis. A double-blind clinical study. Scand J Gastroenterol 1990, 25, 146150

Received 3 May 1990 Accepted 8 August 1990

17. Eriksen CA, Sadek SA, Cranford C, Sutton D, Kennedy N, Cushieri A. Reflux oesophagitis and oesophageal transit: evidence of a primary oesophageal motor disorder. Gut 1988, 29, 448-452 18. Bertraccini G , Scarpignato C. Histamine H2-antagonists modify gastric emptying in the rat. Br J Pharmacol 1982, 77, 443-448 19. Gwee MCE, Chea LS, Lee HS. Ganglion blocking activity of cimetidine in the anaesthetized cat. Clin Exp Pharmacol Physiol 1985, 12, 475-480 20. Galmiche JP, Brandstatter G , Evreux M, et al. Combined therapy with cisapride and cimetidine in severe reflux oesophagitis: a double blind controlled trial. Gut 1988, 29, 675-681

Sucralfate versus cimetidine in reflux oesophagitis. The effect on oesophageal pH and motility.

Sixty patients with endoscopically verified oesophagitis entered a double-blind study comparing the effect of 1 g of sucralfate granulate given four t...
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