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7.0 cg 33#3 200J Clin Gastroenterol 2001;33(3):206–209.
2001 Lippincott Williams & Wilkins, Inc.
Does Short-term Treatment With Proton PumpInhibitors Cause Rebound Aggravationof Symptoms? Per G. Farup, Ph.D., P.H. Juul-Hansen, M.D., and A. Rydning, Ph.D.
cussed.4,9 This trial compares symptoms before, during, and Background: Rebound acid hypersecretion might occur after
after 5 days’ treatment with lansoprazole 60 mg once daily treatment with proton pump inhibitors. This study looks for a in patients with reflux symptoms. More symptoms after rebound aggravation of symptoms after short-term treatment with treatment than before would indicate a rebound aggravation lansoprazole. Study: Sixty-two patients (19 men and 43 women;
mean age, 54 years; range, 32–77 years) with heartburn and re-
of symptoms. The treatment duration was chosen because it gurgitation and normal upper endoscopy findings were studied in is an appropriate period for use of PPIs as a confirmatory a randomized, double-blind, placebo-controlled trial with a cross- test for acid-related disease in these patients.
over design. There were two 5-day treatment periods with lanso-prazole 60 mg once daily or placebo in random order, separated by MATERIALS AND METHODS
a 9-day washout period. Reflux, total, and antacid scores werecalculated for each of the treatment periods. Higher scores during Patients
the placebo period in the group given lansoprazole first than in the Two gastroenterologic units recruited consecutive outpatients group given placebo first indicated a rebound aggravation of aged 18 years and older who had been referred for an upper gas- symptoms. Results: The mean symptom scores during the placebo
trointestinal endoscopy. All patients had symptoms indicative of period in the groups given lansoprazole first and placebo first were gastroesophageal reflux disease (heartburn and acid regurgitation) as follows: reflux score, 21.5 and 17.6, respectively (not signifi- and normal findings at endoscopy (esophagitis grade, 0 [Savary cant); total score, 11.2 and 10.3, respectively (not significant); and Miller]). Patients with previous peptic ulcer disease or reflux antacid score, 8.2 and 7.2, respectively (not significant). Conclu-
esophagitis were excluded, as were patients who had undergone sions: There is no indication of a rebound aggravation of symp-
operations in the upper abdomen and those who had been on drug toms 12 to 14 days after a 5-day treatment with lansoprazole 60 mg treatment of gastrointestinal symptoms during the previous weeks.
once daily in patients with reflux symptoms.
Patients with other complicating diseases (including irritable Key Words: Proton pump inhibitors—Rebound aggravation—
bowel syndrome), who misused drugs or alcohol, who were preg- Symptoms—Gastroesophageal reflux disease.
nant, and from whom poor cooperation was expected were alsoexcluded.
At inclusion, a medical history of past and current disorders Proton pump inhibitors (PPIs) are effective in the treat- was obtained; demographics, alcohol, and smoking habits were ment of heartburn and gastroesophageal reflux, inde- recorded; a physical examination was performed; and the patients’ pendent of severity.1,2 Clinical experience shows that recent and concurrent medications were noted. An upper gastro-intestinal endoscopy was performed, and two biopsies from the withdrawal of the drugs leads to rapid relapse of symptoms, gastric mucosa were analyzed with a rapid urease test for Helico- and a substantial proportion of patients need maintenance treatment.2–4 Rebound acid hypersecretion occurs after The study was double-blind and placebo-controlled, with a treatment with both H -receptor antagonists and PPIs.5–8 crossover design. There was a 14-day run-in period, followed by The rapid relapses and the difficulties in withdrawing the two 5-day treatment periods, separated by a 9-day washout period.
Only antacids were allowed during the run-in period. The patients drugs might be related to rebound hypersecretion; whether were randomized at the end of the run-in period to start treatment the rebound hypersecretion also results in an aggravation of with lansoprazole 60 mg once daily or placebo. Every day during symptoms after withdrawal of treatment has been dis- the treatment periods, the patients filled in diary cards that hadthree 120-mm visual analogue scales for registration of acid re-gurgitation, heartburn, and total dyspeptic symptoms. At the ran-domization visit, the patients were supplied with ample antacid Submitted November 28, 2000. Accepted April 25, 2001.
tablets (Link 1100 [Alpharma, Oslo, Norway] chewing tablets, From the Unit for Applied Clinical Research (P.G.F.), Norwegian Uni- containing aluminium hydroxide/magnesium carbonate 1,100 mg ) versity of Science and Technology, Trondheim, Norway; the Rasta Medi- for symptomatic relief. At the end of the first treatment period, cal Center (P.H.J-H.), Lørenskog, Norway; and the Department of study drugs and antacids were collected, the patients’ levels of Medicine (A.R.), Akershus Central Hospital, Nordbyhagen, Norway.
antacid consumption were calculated, diary cards were collected, Funding source: Wyeth-Lederle provided the drugs and gave financial and the patients were given study drugs for the last treatment period, as well as antacid tablets. The antacids were in two sepa- Address correspondence and reprint requests to Dr. Per G. Farup, Unit for Applied Clinical Research-NTNU, Kreftbygget 5 etg., RiT, N-7006 rate packages: one for the washout period and one for the last Trondheim, Norway. E-mail: Per.Farup@medisin.ntnu.no treatment period. At the end of the second treatment period, diary cards, study drugs, and antacids were collected, and the patients’ variables between the two treatment groups. The results levels of antacid consumption were calculated separately for the were analyzed separately for Hp-positive and Hp-negative washout and the last treatment periods.
patients. The small number of Hp-positive patients makes the results in this group unreliable. Table 2 shows the results Three symptom variables were calculated for each of the two for the Hp-negative patients. The results in the Hp-negative treatment periods. The symptom variables were defined as follows: patients did not differ significantly from the overall results “reflux score” was the sum of the visual analogue scales scores (in or from the Hp-positive patients (results not shown). There mm) for acid regurgitation and heartburn the last 3 days of each ofthe treatment periods, “total score” was the sum of the visual were no serious or clinically significant adverse events.
analogue scales scores (in mm) for total dyspeptic symptoms thelast 3 days of each of the treatment periods, and “antacid score”was the total use of antacid tablets during each of the treatment DISCUSSION
periods. The antacid score was also calculated for the washout It has been known for many years that a rebound acid The symptom variables were compared between the groups hypersecretion follows treatment with acid secretion inhibi- given lansoprazole first and placebo first. If a rebound aggravation tors, which was first demonstrated for H -receptor antago- of symptoms occurred, the group of patients given lansoprazole nists and was later demonstrated for PPIs.5–8 It is a well- first would have more symptoms during the placebo and washout known clinical observation that symptoms reappear shortly periods than those given placebo first. Correspondingly, if a re- after treatment with these drugs and that a substantial pro- bound phenomenon occurred, the differences between symptomsduring the active and placebo treatment periods would be higher in portion of patients with acid-related diseases are in need of the group given lansoprazole first than in the group given placebo long-term treatment.2,4 It is unknown whether the rapid re- lapses and the high proportion of patients on long-termtreatment are caused by the natural courses of the diseases Statistics
or whether they are induced by a rebound hypersecretion The results are reported as number and proportion or mean with SEM if not otherwise indicated. Fisher exact test and Mann- after withdrawal of treatment. The use of potent acid- Whitney U test were used for comparisons of the groups, and p secretion inhibitors has given rise to concerns related to values less than 0.05 were regarded as statistically significant.
potential side effects, including physical dependency.9 Although the rebound phenomenon has been known of Informed consent was obtained from each patient. The study for years, little is known about the clinical consequences.
was performed according to the Declaration of Helsinki and ap- Two months’ treatment with ranitidine is reported to cause proved by the Regional Ethics Committee at the University of dyspepsia after withdrawal in previously asymptomatic vol- unteers, and in a small study, 3 months’ treatment with omep-razole resulted in an insignificant increase in acid reflux, as measured with 24-hour esophageal pH monitoring.10,11 Seventy-eight patients were included in the trial at the The rapid recurrence of symptoms is clearly shown in time of their endoscopies. Six patients did not meet for the this trial. The symptoms 12 to 14 days before and after the randomization visit, nine had incompletely filled in diary treatment period were rather similar between the two treat- cards, and one had no symptoms throughout the run-in ment groups, as were the differences in the symptoms be- phase and the treatment periods. Thus, 62 patients went tween the treatment and the placebo periods. The results are through the trial according to the protocol and were avail- not indicative of any rebound aggravation of symptoms. A able for the analysis. Table 1 shows the patients’ character- type II error could not be excluded because of the limited istics. The treatment groups were well balanced.
number of patients and the rather great range in the severity The results of the study are shown in Table 2. There are of symptoms. Whether other methods for registration of no statistically significant differences in any of the symptom symptoms are more accurate than the visual analogue scales TABLE 1. Patient characteristics for the two treatments groups
The results are given as number (no.) of patients with proportion in percentage and J Clin Gastroenterol, Vol 33, No. 3, 2001 TABLE 2. Symptom variables during the placebo period, differences in symptom variables between the placebo and active
treatment periods, and antacid score in the washout period Differences in symptoms between the placebo and active periods There are no statistically significant differences between the two groups. The results are given as mean (SEM).
NS indicates not significant.
is unknown. The fact that there was no tendency toward a an effect. The finding that the intake of antacids in the rebound effect makes a type II error less likely.
washout period did not differ between the treatment groups The 12- to 14-day interval used in this trial was chosen indicates that an earlier appearing rebound effect is unlikely.
for several reasons. First, it is the appropriate interval for Despite the fact that drug-induced hypergastrinemia rebound hypersecretion after long-term treatment with is more marked in Hp-positive patients than in Hp-nega- PPIs.7,8 The rebound acid hypersecretion reported after tive patients, rebound hypersecretion is more marked in long-term treatment is probably partially caused by the hy- Hp-negative patients.6,8 This study is not indicative of any perplasia of the enterochromaffin-like cells and the parietal differences between Hp-positive and Hp-negative patients.
cells, which is induced by the trophic effect of the drug- In conclusion, this trial confirms the rapid recurrence of induced hypergastinemia.4 But the 5-day treatment period in reflux symptoms after the end of treatment, but it gives this trial is probably too short to induce enterochromaffin- no indication of any rebound aggravation of symptoms in like cell and parietal cell hyperplasia. Secondly, 5-day treat- the first 2 weeks after short-term treatment with high-dose ment with high-dose PPI leads to a hypergastrinemia, with a significant increase in 12-hour integrated meal-stimulated Acknowledgment: The authors thank Wyeth-Lederle, Nor-
daytime plasma gastrin and a doubling of the mean serum way, for providing the drugs and for financial and admin- gastrin concentration.12,13 Most serum gastrin values nor- malize 10 to 14 days after the end of treatment, but somepatients have elevated gastrin levels for a longer period of REFERENCES
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a. bahwa negara berkewajiban melayani setiap warga negara dan penduduk untuk memenuhi hak dan kebutuhan dasarnya dalam kerangka pelayanan publik yang merupakan amanat Undang-Undang Dasar Negara Republik Indonesia Tahun 1945; b. bahwa membangun kepercayaan masyarakat atas pelayanan publik yang dilakukan penyelenggara pelayanan publik merupakan kegiatan yang harus dilakukan seiring dengan harap