J 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. Abstract
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
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. Study Design
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: [email protected]
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
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
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, 2001TABLE 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
time.2–3,13 The acid inhibitory effect of PPIs lasts for less
1. Hatlebakk JG, Hyggen A, Madsen PH, et al. Heartburn treatment in primary care:
than 1 week.14 Thus, in the period shortly after the recovery
randomised, double blind study for 8 weeks. BMJ 1999;319:550–3.
of the H+K+ATPase, the hypergastrinemia is not always
2. Hetzel DJ, Dent J, Reed WD, et al. Healing and relapse of severe peptic esoph-
agitis after treatment with omeprazole. Gastroenterology 1988;95:903–12.
back to normal, and in this period, the hypergastrinemia
3. Klinkenberg-Knol EC, Jansen JB, Lamers CB, et al. Temporary cessation of
could induce acid hypersecretion and rebound symptoms
long-term maintenance treatment with omeprazole in patients with H -receptor-
antagonist-resistant reflux oesophagitis. Effects on symptoms, endoscopy, serum
independent of enterochromaffin-like cell and parietal cell
gastrin, and gastric acid output. Scand J Gastroenterol 1990;25:1144–50.
hyperplasia. It is unknown whether 12 to 14 days after the
4. Kuipers EJ, Klinkenberg-Knol EC. Helicobacter pylori, acid, and omeprazole
revisited: bacterial eradication and rebound hypersecretion. Gastroenterology
end of treatment is the appropriate interval to observe such
5. Frislid K, Aadland E, Berstad A. Augmented postprandial gastric acid secretion
10. Smith AD, Gillen D, Cochran KM, et al. Dyspepsia on withdrawal of ranitidine
due to exposure to ranitidine in healthy subjects. Scand J Gastroenterol 1986;
in previously asymptomatic volunteers. Am J Gastroenterol 1999;94:1209–13.
11. Qvigstad G, Arnestad JS, Brenna E, et al. Treatment with proton pump inhibitors
6. el Omar E, Banerjee S, Wirz A, et al. Marked rebound acid hypersecretion after
induces tolerance to histamine-2 receptor antagonists in Helicobacter pylori-
treatment with ranitidine. Am J Gastroenterol 1996;91:355–9.
negative patients. Scand J Gastroenterol 1998;33:1244–8.
12. Harder H, Teyssen S, Stephan F, et al. Effect of 7-day therapy with different
7. Waldum HL, Arnestad JS, Brenna E, et al. Marked increase in gastric acid
doses of the proton pump inhibitor lansoprazole on the intragastric pH in healthy
secretory capacity after omeprazole treatment. Gut 1996;39:649–53.
human subjects. Scand J Gastroenterol 1999;34:551–61.
8. Gillen D, Wirz AA, Ardill JE, et al. Rebound hypersecretion after omeprazole
13. Blum RA, Hunt RH, Kidd SL, et al. Dose-response relationship of lansoprazole
and its relation to on- treatment acid suppression and Helicobacter pylori status.
to gastric acid antisecretory effects. Aliment Pharmacol Ther 1998;12:321–7. Gastroenterology 1999;116:239–47.
14. Prewett EJ, Hudson M, Nwokolo CU, et al. Nocturnal intragastric acidity during
9. Waldum HL, Brenna E. Personal review: is profound acid inhibition safe? Ali-
and after a period of dosing with either ranitidine or omeprazole. Gastroenter-ment Pharmacol Ther 2000;14:15–22.
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