Omeprazole

Paul N. Maton, M.D.

N Engl J Med 1991; 324:965-975April 4, 1991DOI: 10.1056/NEJM199104043241406
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OMEPRAZOLE is the first of a new class of drugs that inhibit gastric secretion by
altering the activity of H+/K+ATPase,1 2 3 the final common step of acid secretion, in
gastric parietal cells. The discovery of omeprazole has led to new insights into the
mechanism of gastric secretion, knowledge of the genesis of certain gastrointestinal
tumors, and the development of new treatments for acid-peptic diseases. In the United
States, omeprazole has been approved only for short-term use in certain patients with
reflux esophagitis and for patients with the ZollingerEllison syndrome, because of
concerns raised by the results of long-term studies of toxicity in animals, but in many
countries the approved uses are much wider. This review will discuss the pharmacologic
features of omeprazole and the results of trials of the drug in patients with duodenal ulcer,
gastric ulcer, reflux esophagitis, and the ZollingerEllison syndrome.

Pharmacology
Gastric Acid Secretion, H+/K+ATPase, and the Action of Omeprazole
The secretion of hydrochloric acid by gastric parietal cells ultimately depends on the
function of the proton (hydrogen ion) pump.1 , 2 This pump is H+/K+ATPase, a
membrane-spanning enzyme that uses the energy released by the metabolism of ATP to
move protons (actually, hydronium ions) across the membrane in exchange for potassium

ions4,5 (Fig. 1Figure 1

Schematic Diagram of the Action of Omeprazole
on a Gastric Parietal Cell.). H+/K+ATPase consists of two subunits: the 111,000-dalton
subunit, which catalyzes the hydrolysis of ATP and transports ions, and the smaller
subunit, whose function is unknown. In the nonsecreting state, H+/K+ATPase is situated
in vesicles in the cell cytoplasm. Since the vesicles contain no potassium and the
vesicular membranes are impermeable to potassium ions, the pump is inactive.4 , 5 On

activation of parietal cells by the appropriate stimulus, such as histamine, the H+/K+
ATPase translocates to the plasma membrane of the secretory canaliculus of the parietal
cell.6 , 7 The extracellular aspect of H+/K-ATPase is thus exposed to potassium ions,
and because there is an associated increase in the permeability of the membrane to
potassium,5 the cells are able to secrete acid at a pH of about 1.0. Omeprazole has been
shown in several species to inhibit acid secretion by inhibiting H+/K+ATPase.8 9 10
Omeprazole is a lipophilic, weak base with a pK of 4.0. It is absorbed in the intestine and
reaches the parietal cells of the stomach through the bloodstream. At a pH of
approximately 7 omeprazole is not charged and can cross cell membranes (Fig. 1).
However, in the secretory canaliculus of actively secreting gastric parietal cells, where
the drug is exposed to a pH of less than 2.0, omeprazole becomes protonated. It therefore
ceases to be lipophilic and is trapped and concentrated. Omeprazole itself is inactive, but
under acidic conditions it is converted to the active form, a sulfenamide11 , 12 that reacts
covalently with the sulfhydryl groups of cysteine residues on the extracellular surface of
the subunit H+/K+ATPase and inhibits the activity of the enzyme (Fig. 1). The
resumption of acid secretion after the administration of omeprazole almost certainly
requires synthesis of new H+/K+ATPase protein.13 The half-life of H+/K+ATPase is
approximately 18 hours.

Pharmacokinetics and Pharmacodynamics

Exposure to gastric acid degrades omeprazole and leads to poor oral bioavailability.14
The drug has therefore been formulated in pH-sensitive granules that release omeprazole
only when the pH is above 6. With this formulation the bioavailability of omeprazole is
about 50 percent.14 Peak plasma concentrations occur two to four hours after oral
administration15 and tend to increase during the first few days of treatment, probably
because the increasing inhibition of gastric acid secretion results in less degradation of
omeprazole in the gastric lumen. The plasma half-life of omeprazole is about 60
minutes,16 but because it is linked covalently to H+/K+ATPase, the duration of action
of a single dose exceeds 24 hours.17 The degree of inhibition of acid secretion thus does
not correlate with the plasma concentration of the drug, but it does correlate with the area
under the plasma concentrationtime curve.18 A single 20-mg dose of omeprazole
inhibits acid secretion by 65 percent after 4 to 6 hours and by 25 percent after 24 hours,18
but with subsequent doses inhibition increases, reaching a plateau after four doses.18
This increased activity is due both to increased bioavailability and to inhibition of more
H+/K+ATPase molecules. The steady-state inhibition of acid secretion during treatment
with 20 mg of omeprazole per day varies widely from person to person: ranges of 35 to
65 percent, based on measurements of acid secretion 24 hours after drug
administration,18 19 20 and 30 to 100 percent, based on measurements of 24-hour gastric
acidity determined by intragastric pH,21 , 22 have been reported. Indeed, in some
subjects 150 mg of ranitidine twice a day inhibited gastric acidity more effectively over a
24-hour period than 20 mg of omeprazole a day. With larger doses of omeprazole,
variation between patients diminishes and acid secretion is inhibited more profoundly.18 ,
21 When treatment is stopped, it takes at least three days for acid secretion to return to
pretreatment levels.18 , 21 Rebound hypersecretion does not occur.21 , 23

Metabolism
Two major metabolites of omeprazole found in plasma are the sulfone derivative and
hydroxyomeprazole.16 Neither inhibits the secretion of gastric acid,14 15 16 and both are
further metabolized before being excreted. Eighty percent of the metabolites is excreted
in the urine, and the other 20 percent is excreted in the feces after biliary secretion.
Because omeprazole is extensively metabolized by the hepatic cytochrome P-450 system,
interactions with other drugs may occur (see below). The pharmacokinetics of
omeprazole are not altered in patients with impaired renal function,24 , 25 but in elderly
patients16 and those with impaired liver function,16 , 26 metabolism of the drug is slower
and bioavailability is greater than in control subjects.16 However, no dose adjustment is
required.

Other Actions of Omeprazole

Omeprazole does not inhibit the secretion of intrinsic factor,27 , 28 and the absorption of
crystalline vitamin B12 is normal.28 The absorption of vitamin B12 that is bound to protein
is decreased,29 but long-term omeprazole therapy does not appear to cause vitamin B12
deficiency. Omeprazole reduces the secretion of pepsinogen slightly,20 , 27 probably
because it decreases gastric acidity and volume, and serum pepsinogen concentrations
rise during omeprazole therapy.20 Omeprazole has no effect on esophageal pressures30
or gastric emptying.31 Enzymes similar to gastric H+/K+ATPase may exist in the colon
and the kidney,32 but since such enzymes are not in an acidic environment, omeprazole is
not trapped or activated at these sites.
Because the release of gastrin by antral G cells is inhibited by a fall in gastric pH and
stimulated by an increase in pH,33 any drug capable of profoundly inhibiting gastric acid
secretion should lead to an increase in plasma gastrin concentrations. Rats repeatedly
given large doses of omeprazole had increased plasma gastrin concentrations,34 an
increase in gastrin-immunostaining of antral G cells, and a reduction in somatostatin
immunostaining of D cells.35 , 36 More importantly, in the initial two-year toxicity
studies, administration of omeprazole to rats (but not mice) resulted in carcinoid tumors
of the body of the stomach and hyperplasia of certain oxyntic mucosal endocrine cells,
the enterochromaffin-like cells.37 The carcinoid tumors occurred more frequently in
female rats given four different doses of omeprazole; they developed in 2 percent of rats
given 1.7 mg of omeprazole per kilogram of body weight per day and in 40 percent of
those given 140 mg per kilogram per day.37 Tumors did not develop in any of the control
rats. These results led the Food and Drug Administration to restrict the length of
omeprazole treatment to eight weeks, except in patients with the ZollingerEllison
syndrome. Extensive work has since been performed to elucidate the mechanism by
which omeprazole causes these changes in rats. There was a close correlation between
omeprazole-induced hypergastrinemia and hyperplasia of enterochromaffin-like cells,
and these changes were reversible after administration of the drug for as long as one
year.35 36 37 38 39 Antrectomy abolished omeprazole-induced hypergastrinemia and
hyperplasia of enterochromaffin-like cells,36 whereas intravenous infusions of gastrin for
four weeks produced hyperplasia of enterochromaffin-like cells.40 Other studies have

shown that a variety of drugs that inhibit gastric acid secretion can induce
hypergastrinemia, hyperplasia of enterochromaffin-like cells, and gastric carcinoid
tumors in rats. They include the H2-receptor antagonists ranitidine41 and loxtidine,42 and
ciprofibrate and related hypolipidemic compounds43 that inhibit the secretion of acid by
an unknown mechanism. Furthermore, in untreated rats subjected to a 75 percent
fundectomy, hyperchlorhydria occurs, with the consequent development of
hypergastrinemia, enterochromaffin-like-cell hyperplasia, and gastric carcinoid tumors.44
On the basis of these studies, most45 , 46 but not all47 investigators believe that
omeprazole is not a direct carcinogen in rats, but causes gastric carcinoid tumors through
its ability to inhibit the secretion of gastric acid and so cause hypergastrinemia, and it is
the latter that stimulates tumor formation. The occurrence and possible risks of
omeprazole-induced hypergastrinemia in humans are discussed in the section on side
effects.

Omeprazole in Acid-Peptic Diseases

Duodenal Ulcer
Several early studies examined the efficacy of various oral doses of omeprazole on the
healing of duodenal ulcer and relief of ulcer symptoms.48 49 50 51 52 53 54 55 56 57 58
59 Two weeks of treatment with 10 mg per day of omeprazole produced healing rates of
50 percent, and the respective healing rates with doses of 20, 30, 40, and 60 mg per day
were 63 to 79 percent, 73 to 88 percent, 93 percent, and 57 to 100 percent. After four
weeks, all doses of more than 10 mg per day resulted in rates of healing of 90 to 100
percent. Therefore, a dose of 20 mg per day was used in most subsequent studies. All
doses produced rapid relief of symptoms.
At least 16 randomized, controlled trials of omeprazole and H2-receptor antagonists have
been performed.60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 After two weeks of
therapy ulcers healed in 42 to 83 percent of the patients treated with 20 mg of omeprazole
per day and in 34 to 65 percent of those given 300 mg of ranitidine per day a
therapeutic advantage for omeprazole of 2 to +30 percent in individual studies. After
four weeks the ulcer healed in 82 to 97 percent of the patients given omeprazole and in
63 to 96 percent of those given ranitidine, a therapeutic advantage for omeprazole of 5
to +19 percent. The results of a meta-analysis76 that I performed indicate that the pooled
difference in healing for the eight studies in which 20 mg of omeprazole per day or 300
mg of ranitidine per day was given for two weeks was 14.1 percent (95 percent
confidence interval, 8.2 to 20.2), a significant advantage for omeprazole (Fig. 2Figure 2

Differences in the Rates of Healing of Duodenal Ulcers in Patients

Treated with Omeprazole (O), Ranitidine (R), or Cimetidine (C), Expressed as
Therapeutic Advantage for Omeprazole over the H2-Receptor Antagonists, after Two and
Four Weeks of Therapy.). After four weeks the difference was smaller (8.7 percent) but

still significant. With doses of omeprazole of more than 20 mg per day, there was a larger
difference in favor of omeprazole (Fig. 2). In five studies in which the treatment lasted
six to eight weeks,62 , 66 , 68 , 69 , 72 meta-analysis again demonstrated an advantage for
omeprazole (pooled difference in healing, 5.9 percent; 95 percent confidence interval, 2.5
to 9.4). For both classes of drugs, the rate of healing was slower in smokers than in
nonsmokers,61 , 65 , 72 , 74 , 75 and large ulcers healed more slowly than small ulcers.61 ,
74 , 75 There were also geographic variations in healing rates: rates in patients from the
United States71 and Canada69 were lower than those in patients from Hong Kong.65
Although both classes of drugs were effective in relieving symptoms, in 11 of the studies
more patients taking omeprazole were free of symptoms after two weeks of therapy,60 ,
61 , 65 , 66 , 68 69 70 71 72 73 74 and in 5 studies this difference was significant.60 , 61 ,
65 , 66 , 68 , 71 In two other trials daytime pain was less frequent in patients taking
omeprazole than in those taking ranitidine,67 , 74 and the patients treated with
omeprazole took significantly less antacid in three of six trials.62 , 67 , 69 , 70 , 73 , 75 In
five open studies of a total of 88 patients with resistant duodenal ulcers those that had
not healed after at least two months of treatment with an H2-receptor antagonist in
standard or high doses77 78 79 80 81 82 40 mg of omeprazole per day produced
healing in 98 percent in four to eight weeks. In a randomized comparative trial,83 119
patients with ulcers (88 percent of which were duodenal) resistant to conventional
therapy received 40 mg of omeprazole per day or continued taking an H2-receptor
antagonist. After eight weeks ulcers had healed in 98 percent of the former and 60 percent
of the latter (P<0.001). However, in a double-blind trial of patients whose ulcers had not
healed after six weeks of treatment with H2-receptor antagonists, treatment with 20 mg of
omeprazole per day or 150 mg of ranitidine twice a day for eight weeks resulted in
healing in 80 percent of the patients in each group.84 Thus, in the only study of patients
with resistant ulcers that did not demonstrate an advantage for omeprazole, the daily dose
was 20 mg rather than 40 mg.
In patients with duodenal ulcers that heal after treatment with H2-receptor antagonists, the
relapse rates are 50 to 60 percent for the first six months.85 , 86 After omeprazole therapy
was stopped, ulcers recurred in 41 to 44 percent of patients after 6 months49 , 52 , 87 and
in 88 percent after 12 months.88 In one of four comparative trials the relapse rate after
eight weeks was lower in patients who had received omeprazole,66 but in the three other
studies the six-month relapse rates were similar (41 to 72 percent) for omeprazole and H2receptor antagonists.60 , 62 , 72 Taken together, the results of omeprazole therapy in
patients with duodenal ulcer indicate that a dose of 20 mg of omeprazole per day
produces more rapid healing than standard doses of H2-receptor antagonists, but the
longer treatment is continued the smaller the difference between the treatments. For
patients with resistant ulcers, 40 mg of omeprazole per day is usually effective, but the
rate of relapse after discontinuation of therapy is similar to that after discontinuation of
H2-receptor antagonists. These results are consistent with the thesis that the major
determinants of the healing of duodenal ulcers are the degree of acid inhibition and the
duration of therapy.89

Gastric Ulcer

Early noncomparative studies demonstrated that gastric ulcers healed in 22 to 27 percent

of patients treated with 30 mg of omeprazole per day for two weeks. The rate of healing
in patients treated for four weeks was 69 to 72 percent, and in those treated for six to
eight weeks it was 92 to 100 percent.90 , 94 In one study 40 mg of omeprazole per day
resulted in a higher rate of healing than 30 mg per day after four weeks, but the rates
were similar after treatment for six weeks.92
Various doses of omeprazole and H2-receptor antagonists have been compared in
randomized, controlled trials. In patients with ulcers of the gastric body and antrum93 94
95 96 97 or prepyloric ulcers,98 both types of drug were effective: ulcers healed in 86 to
96 percent of patients treated for six to eight weeks with omeprazole and in 78 to 90
percent of those treated with an H2-receptor antagonist. Meta-analysis revealed that when
the DerSimonian and Laird analysis was used, 20 mg of omeprazole per day was
significantly more effective than H2-receptor antagonists only after eight weeks, and that
30 to 40 mg of omeprazole was more effective than H2-receptor antagonists only after

four weeks (Fig. 3Figure 3

Differences in the Rates of Healing of Gastric
Ulcers in Patients Treated with Omeprazole (O), Ranitidine (R), or Cimetidine (C),
Expressed as Therapeutic Advantage for Omeprazole over the H2-Receptor Antagonists,
after Four and Six to Eight Weeks of Therapy.). However, when the Peto method was
used, all differences were significant. In all these studies, irrespective of the drug used,
healing was slower in patients with large ulcers than in those with small ulcers, but the
healing rate was reduced in smokers in only one study.95 Healing was faster in patients
with prepyloric ulcers than in those with ulcers of the gastric body in one study93 but not
in another.96 In one report the advantage of omeprazole over ranitidine was particularly
marked in patients taking nonsteroidal antiinflammatory drugs concomitantly.96 In most
trials there was no difference in symptomatic response, but in three trials more patients
treated with omeprazole were free of symptoms after one to four weeks,95 , 96 , 98 and in
one trial the patients treated with omeprazole consumed less antacid.95
Among 82 patients with gastric ulcers that had not healed after at least two months of
treatment with an H2-receptor antagonist, therapy with 40 mg of omeprazole per day for
eight weeks resulted in healing in 96 percent.77 , 79 , 82 , 83 Omeprazole was also
effective in patients with resistant anastomotic ulcers.79
The rates of relapse of gastric ulcer after therapy was stopped in two comparative studies
were 35 percent and 47 percent after six months, with no difference in the rates between
patients treated with omeprazole and those given H2-receptor antagonists.96 , 97 , 99
Relapses were more likely in patients who had prepyloric ulcers or in smokers.97 , 99
Overall, the results indicate that the rates of healing of gastric ulcer are only slightly
higher with omeprazole than with H2-receptor antagonists and the rates of relapse are
similar. Thus, for most patients with gastric ulcers, omeprazole offers little or no
advantage. For patients with resistant gastric ulcers, however, 40 mg of omeprazole a day
appears to be more effective than continued treatment with H2-receptor antagonists.

Reflux Esophagitis
Only two dose-ranging studies of omeprazole have been performed in patients with
esophagitis. In one, treatment with 30 mg of omeprazole per day resulted in healing in
seven of eight patients after eight weeks.100 In a subsequent double-blind study, after
four weeks the rates of healing with placebo and 20 and 40 mg of omeprazole per day
were 6, 70, and 82 percent, respectively.101 These results compare favorably with
healing rates of about 60 percent in patients treated with H2-receptor antagonists.102
Both doses of omeprazole were effective for symptom relief, but the 40-mg dose resolved
symptoms in a larger percentage of patients.
In randomized, controlled trials, esophagitis healed in 57 to 74 percent of patients after
four weeks of omeprazole therapy and in 78 to 87 percent after eight weeks; the
comparable values in patients treated with ranitidine were 27 to 43 percent and 28 to 56

percent.103 104 105 106 107 108 109 As shown in Figure 4Figure 4
Differences in the Rates of Healing of Esophagitis in Patients Treated with Omeprazole
(O), Ranitidine (R), or Cimetidine (C), Expressed as Therapeutic Advantage for
Omeprazole over the H2-Receptor Antagonists, after Four and Eight Weeks of Therapy.,
meta-analysis demonstrated a significant therapeutic advantage of 35 to 40 percent in
favor of omeprazole after both four and eight weeks of therapy. Esophagitis can be
classified according to severity. A common classification defines Grade I esophagitis as
mucosal erythema with or without friability, Grade II as superficial nonconfluent
ulceration, Grade III as confluent ulceration, and Grade IV as extensive mucosal damage
or stricture formation, shortening, or Barrett's esophagus. In studies that stratified patients
according to grades of esophagitis, the advantage for omeprazole over H2-receptor
antagonists after both four and eight weeks of treatment was slightly greater in the
patients with more severe disease. Overall, symptoms were completely relieved in 61 to
74 percent of the patients taking omeprazole and in 12 to 33 percent of the patients taking
an H2-receptor antagonist. For relief of heartburn, the figures were 82 to 94 percent for
omeprazole and 31 to 55 percent for the H2-receptor antagonists. All doses of omeprazole
were more effective than H2-receptor antagonists in relieving symptoms, and in two
studies the patients taking omeprazole required significantly less antacid.106 , 107
The efficacy of 40 mg of omeprazole per day in patients with esophagitis that had not
improved after at least three months of treatment with large doses of H2-receptor
antagonists has been described in open studies in a total of 175 patients.79 , 80 , 104 , 110
111 112 113 114 Included in these studies were many patients who had had major
complications of esophagitis and had undergone esophageal surgery before the study
began. Therapy with omeprazole for 4 to 12 weeks resulted in healing in 90 to 100
percent of the patients. In a double-blind comparative trial, 98 patients with resistant
esophagitis received 40 mg of omeprazole per day or 300 mg of ranitidine twice a day for
12 weeks.115 The esophagitis healed in 90 percent of the patients receiving omeprazole
and in 47 percent of those receiving ranitidine (P<0.001).

Irrespective of whether the esophagitis healed during omeprazole101 , 106 or

ranitidine106 therapy, relapse occurred soon after therapy was stopped: 60 percent of the
patients relapsed after three months, and 80 to 90 percent after six months. However, in a
group of patients with resistant esophagitis that healed after omeprazole therapy, who
were given a maintenance dose of 20 mg per day, only 19 percent relapsed in six
months.114
In contrast to the slight advantage of omeprazole for most patients with duodenal ulcer
and the marginal advantage for patients with gastric ulcer, omeprazole is much more
effective than H2-receptor antagonists for the relief of symptoms and mucosal healing in
patients with all grades of reflux esophagitis. In many patients it is the only drug capable
of healing the mucosa. Because of the high rate of relapse, however, long-term therapy is
required, and despite the success of omeprazole, the possible risks to the stomach of longterm treatment have made the management of chronic, severe esophagitis problematic
(see below).

ZollingerEllison Syndrome
Patients with the ZollingerEllison syndrome have hypersecretion of gastric acid and
require large doses of H2-receptor antagonists to reduce the secretion of acid to safe
levels. Treatment with H2-receptor antagonists can prevent the consequences of
hypersecretion of gastric acid, such as severe, complicated peptic ulceration, diarrhea,
and malabsorption, but the doses must be large enough to reduce acid secretion to less
than 10 meq per hour125 (or <5 meq per hour if the patient has severe esophagitis117 or
has had a partial gastrectomy118). Nearly all patients require medication every six hours,
and some need as much as 9600 mg of ranitidine per day.116 Omeprazole has been given
to patients with the ZollingerEllison syndrome who were thought to be resistant to
treatment with H2-receptor antagonists, although in most cases the dose of the drug had
been insufficient. Omeprazole resolved the acid-related problems in nearly all
patients,119 120 121 122 123 124 125 126 127 128 129 130 131 132 including those
who, despite a reduction of acid secretion according to established criteria,116 117 118
still had symptoms or mucosal disease (including recurrent esophageal stricture).
Lowering acid output further with omeprazole produced prompt resolution.116 117 118 ,
132 The doses of omeprazole used ranged from 20 mg per day to 120 mg three times a
day. In patients in whom the dose was adjusted to reduce acid output to less than 10 meq
per hour, the median daily dose was about 80 mg.132 Although 120 mg given once daily
did not control acid secretion in 25 percent of the patients, dividing the daily dose (60 mg
every 12 hours) controlled the secretion of acid in every case.123 , 132 Some patients
with the ZollingerEllison syndrome have taken omeprazole, often at a high dose, for
more than five years.
For patients with the ZollingerEllison syndrome omeprazole has an advantage over H2receptor antagonists fewer tablets and fewer doses are needed per day. In addition,
fewer patients require increases in the dosage during long-term treatment,116 , 123 , 132
and in some patients omeprazole is the only drug that will resolve all symptoms and
mucosal disease. Furthermore, omeprazole does not usually cause achlorhydria in these

patients, and in more than four years of continuous administration has not resulted in
increased plasma gastrin concentrations or changes in the gastric mucosa (see below).
Omeprazole is now the drug of choice for patients with the ZollingerEllison syndrome.

Side Effects and Toxicity

General Effects
More than 19,000 patients have been given omeprazole in clinical trials since 1983, but
only patients with the ZollingerEllison syndrome and those with resistant acid-peptic
disease have received omeprazole for longer than a few weeks. Nevertheless, the
frequency of side effects due to omeprazole has been similar to that for placebo or H2receptor antagonists,17 , 46 , 133 and there have been no consistent abnormalities in
laboratory test results, including tests of thyroid and liver function. Although omeprazole
has a minor inhibitory effect on the synthesis of adrenal steroids,134 it has no clinically
important effect on adrenal or other endocrine function.133 Omeprazole interacts with
the cytochrome P-450 system in the liver135 , 136 and inhibits the metabolism of some
drugs (the R isomer of warfarin,137 phenytoin,138 , 139 diazepam,138 , 140
antipyrine,141 and aminopyrine141) but not others (propranolol,142 the S isomer of
warfarin,137 and theophylline143). Since the elimination of phenytoin and warfarin is
prolonged by omeprazole, patients taking these drugs concomitantly should be monitored
closely. Although omeprazole has proved to be remarkably free of side effects,
postmarketing surveillance will be important to confirm its safety profile.

Effects on the Stomach and Gastrin Secretion

The main issue concerning the safety of omeprazole has been its ability to produce
hypergastrinemia and gastric carcinoid tumors in rats and the implications of these
findings for humans. Chronic hypergastrinemia in humans can lead to hyperplasia of
enterochromaffin-like cells and carcinoid tumors of the body of the stomach, although
gastric carcinoid tumors associated with hypergastrinemia are rare144 145 146 and
generally are of low malignancy.147 148 149 Patients with gastric atrophy and
achlorhydria, whether or not they have pernicious anemia, have hypergastrinemia and
hyperplasia of enterochromaffin-like cells, and gastric carcinoid tumors are found in
approximately 5 percent.150 151 152 Whether in all cases these are truly tumors or
simply hyperplasia is questionable because there are several reports of the disappearance
of gastric carcinoid tumors after antrectomy and the normalization of plasma gastrin
concentrations in these patients.153 154 155 All patients with the ZollingerEllison
syndrome have hypergastrinemia, the majority have hyperplasia of enterochromaffin-like
cells, and about 3 percent have carcinoid tumors.156 , 157 However, more than 90
percent of the carcinoid tumors have occurred in patients with multiple endocrine
neoplasia type 1 a subgroup that includes only about 25 percent of all patients with the
ZollingerEllison syndrome. These data suggest that factors other than gastrin may be
important in the genesis of gastric carcinoid tumors in patients with the Zollinger
Ellison syndrome.156

In humans the increase in plasma gastrin concentrations in response to the inhibition of

gastric acid secretion is not as marked as it is in rats.158 Even so, omeprazole causes a 2fold to 4-fold increase in fasting and postprandial plasma gastrin concentrations, and
occasionally a 10-fold increase20 , 21 , 52 , 56 , 71 , 149 150 151 152 153 154 155 156
157 158 159 160 161 162; plasma gastrin concentrations return to normal two to four
weeks after the discontinuation of omeprazole.20 , 160 Some studies have examined 24hour profiles of plasma gastrin concentrations.23 , 160 , 161 The increase in 24-hour
gastrin profiles in patients given 20 mg of omeprazole a day is much more than that in
patients given 150 mg of ranitidine twice a day23 , 160 but comparable to that in patients
who have had a parietal-cell vagotomy161 and much lower than the increase that may
occur in patients with pernicious anemia.163 The limited data on long-term treatment
with omeprazole (20 to 60 mg per day) in patients with normal levels of gastrin secretion
before treatment79 , 162 , 164 indicate that such treatment results initially in fasting
hypergastrinemia (the increase in plasma gastrin levels is typically 3-fold but
occasionally as high as 10-fold). The plasma gastrin levels may stabilize after three
months165 or continue to rise162; for example, in one study 25 percent of the patients
had plasma gastrin concentrations of more than 500 pmol per liter after one year of
therapy.79 , 162 , 164 , 165
The effect of both short-term and long-term treatment with omeprazole (20 to 40 mg per
day for six weeks) on gastric oxyntic mucosal endocrine cells (which include the
enterochromaffin-like cells) has been studied.121 , 122 , 157 , 158 , 164 165 166 167 168
169 Treatment with omeprazole for 6 weeks158 , 164 , 166 or 16 weeks167 had no effect
on the number of endocrine cells. Some patients,164 but not others,165 with resistant
acid-peptic disease treated with omeprazole for one to two years have had a slight but
significant increase in the number of gastric mucosal endocrine cells. In patients with the
ZollingerEllison syndrome who had hypergastrinemia and hyperplasia of
enterochromaffin-like cells121 , 122 , 157 , 166 167 168 treatment with omeprazole
(which does not change plasma concentrations of gastrin in these patients) for up to four
years did not cause a further increase in the number of enterochromaffin-like cells.157 ,
168 , 169
Overall, although short-term therapy with omeprazole apparently produces slight
hypergastrinemia, it is safe. Long-term treatment may produce sufficient
hypergastrinemia to cause hyperplasia of enterochromaffin-like cells and possibly
carcinoid tumors in
some patients. However, only long-term studies can establish the risk of such an
occurrence and define the risk in relation to the benefit of treatment. For example, in an
elderly patient with severe esophagitis, long-term treatment with omeprazole appears to
be safe, but in a young patient the possible risk of a gastric carcinoid tumor with such
treatment might need to be balanced against the risk of other treatments. Other
therapeutic options in young patients include antireflux surgery, intermittent omeprazole
therapy (in low or full doses), continuous treatment with high doses of H2-receptor
antagonists, and even continuous omeprazole therapy in combination with an antrectomy
to abolish the hypergastrinemia. One possibility being explored now is treatment with

omeprazole three days a week170 , 171; this approach appears to reduce the recurrence of
duodenal ulcers,172 but not esophagitis.173
Because omeprazole, like H2-receptor antagonists, inhibits the secretion of gastric acid,
its administration is associated with a reversible increase in bacterial-cell counts and
nitrosamine levels in the stomach.174 Such changes could theoretically lead to an
increased risk of both gastrointestinal infections175 and gastric cancer.176 It has been
suggested that chronic hypergastrinemia may be a risk factor for carcinoma of the colon
a suggestion that is apparently refuted by the absence of an increased incidence of
colonic carcinoma in patients with pernicious anemia.177 , 178

Probable Role of Omeprazole in Acid-Peptic Diseases

Short-term omeprazole treatment is safe and effective. It heals duodenal and possibly
gastric ulcers more rapidly than conventional doses of H2-receptor antagonists, and it can
heal ulcers that are resistant to conventional or large doses of H2-receptor antagonists.
More importantly, omeprazole is markedly superior to H2-receptor antagonists for the
treatment of reflux esophagitis and is currently the best available drug for patients with
the ZollingerEllison syndrome. In addition, although not yet generally available,
intravenous omeprazole effectively reduces the secretion of gastric acid,179 , 180 and
thus the drug may find a use in intensive care units.181 Nevertheless, in many
circumstances the precise role of omeprazole remains to be clearly defined. Although
omeprazole heals peptic ulcers more rapidly than H2-receptor antagonists, the latter drugs
will heal more than 90 percent of such ulcers if given for a sufficient length of time.
Omeprazole therapy thus offers no clear superiority for most patients with a duodenal or
gastric ulcer. On the other hand, omeprazole is the only drug capable of relieving
symptoms and healing the mucosa in some patients with reflux esophagitis. However,
since the relapse rates after omeprazole therapy are similar to those for other agents,
patients with severe disease are likely to require long-term treatment with omeprazole.
The limited long-term data available are reassuring, but continued surveillance of patients
taking omeprazole will be required before the risks of long-term therapy, if any, can be
quantified.