Hatlebakk Department of Medicine, Suite 501 Pepper Pavillion, Allegheny University Hospitals—Graduate, 1800 Lombard Street, Philadelphia, PA 19146, USA. firstname.lastname@example.org
On chronic intake of omeprazole, most healthy volunteers and patients still have nocturnal acid breakthrough (NAB), defined as night-time periods with gastric pH < 4.0 lasting for longer than 1 h. Gastro-oesophageal reflux during NAB may be particularly injurious to the oesophageal mucosa, contributing to the chronic lesions complicating the condition.
To compare the effect of three different dosing regimens of omeprazole 40 mg daily with regard to suppressing nocturnal gastric acidity and avoiding NAB.
Eighteen healthy volunteers were given three different regimens of omeprazole for 7 days each in randomized order: 40 mg before breakfast (qAM), 40 mg before dinner (qPM) and 20 mg before breakfast and dinner (b.d.). On day 7, 24-h intragastric and intra-oesophageal pH-metry was performed. Tracings were analysed for the period from 22.00 h until 06.00 h with regard to the percentage of time at which gastric pH was below 4.0, 3.0 and 2.0, and also the occurrence and duration of NAB.
Nocturnal acid breakthrough was significantly more common on qAM than on qPM and b.d. (P < 0.05) dosing. The percentage of time gastric pH was less than 4.0 overnight was significantly lower on qPM (median 31.3) and b.d. (median 20.5) than on qAM (median 66.3) dosing (P = 0.01 and P < 0.02, respectively). A pH threshold of 3 and 4 showed the same differences, as did median 24-h gastric pH. Daytime acidity was not significantly different.
In healthy volunteers, dinner time or split dosing of omeprazole 40 mg daily is significantly more effective than dosing before breakfast in preventing NAB and controlling gastric acidity. These regimens should be preferred in patients in whom suppression of nocturnal gastric acidity is desirable.
In some patients with gastro-oesophageal reflux disease (GERD), nocturnal symptoms dominate, interrupting sleep and leaving the patient tired during the following day. In addition, nocturnal oesophageal acid exposure can contribute to the development of oesophagitis1 and complications such as Barrett’s metaplasia, ulcerations or peptic strictures.2 Nocturnal acid reflux is also related to airways disorders such as bronchial asthma.3 Reflux episodes are of longer duration at night due to loss of drainage by gravity and absence of primary peristalsis and salivation during sleep. Therefore, acidity in the distal oesophagus may approach that of the gastric contents for extended periods.
The primary method of alleviating manifestations of nocturnal reflux is the control of gastric acidity. Healing of reflux oesophagitis with antisecretory medication is statistically correlated to maintaining gastric pH above 4.0 for 20 h or more of a 24-h period.4 Nocturnal gastric acidity and acid reflux can be difficult to control, even with potent antisecretory medication, as has been shown in recent studies.5–7 The phenomenon of nocturnal acid breakthrough (NAB), defined as an intragastric pH continuously below 4 for 1 h or more, could jeopardize treatment goals in GERD.
Because many patients with GERD require increased doses of proton pump inhibitors, our study was designed to compare the effect of administering omeprazole 40 mg in different ways to control NAB and gastric acidity during the night-time period.
SUBJECTS AND METHODS
Study subjects were all healthy volunteers recruited from employees in a university hospital. They were required to have infrequent dyspeptic symptoms and to use no medication on a regular basis and, in particular, to use no medication whatsoever during the study period. Before entering the study, a complete medical history was taken and a physical examination was performed.
The study was a three-way crossover pharmacodynamic study. Each subject was studied using 24-h intragastric pH-metry on four occasions, once on entering the study and then again on day 7 of each of three different omeprazole regimens, which were administered openly and in a randomized order. A period with no medication, lasting for 1–3 weeks, was inserted between each period of medication.
Medication was given as capsules of omeprazole (Astra Merck Inc., Wayne, PA, USA): 40 mg before breakfast (qAM), 40 mg before dinner (qPM) or 20 mg before breakfast and dinner (b.d.). The study subjects were instructed to take the capsules with at least half a glass of water (75 mL). Medication was given in an open fashion and compliance was monitored with a diary, in which intake of capsules and any adverse experiences were recorded.
A manometric examination of the lower oesophageal sphincter (LES) and oesophageal body served as a guide to correct placement of the pH-sensitive probe. Manometry was performed with a 5-channel solid-state catheter (Koenigsberg Inc., Pasadena, CA), with a station pull-through method.8 The proximal border of the LES was defined by the pressure inversion point just distal to the stable oesophageal baseline.9
For simultaneous recording of oesophageal and gastric pH, a 2.1 mm catheter was used (Synectics Inc., Minneapolis, MN) with two separate monocrystalline antimony electrodes 5 and 155 mm from the tip, and a separate skin reference electrode. Calibration was performed prior to each recording as per the recommendations of the manufacturer, in buffers of pH 1.07 and 7.01 at room temperature, and an adjustment for body temperature was introduced.
The probe was passed transnasally and swallowed with a minimal amount of water. The pH catheter was passed to the stomach, then retracted to the estimated position, to ensure that it was not curled up. The proximal electrode was placed with its tip 5.0 cm proximal to the upper margin of the LES, as identified manometrically. The distal electrode was thereby located in the proximal stomach, about 5–7 cm distal to the cardia, in the fundic or upper body region. Sampling rate was 0.25 Hz and recorded data were stored in a multichannel solid-state datalogger (Digitrapper Mark III, Synectics Inc.).
Recordings started in the morning and lasted for 23–24 h. The subjects were allowed to return to work and follow their daily routine. They were instructed to take meals at 08.00, 12.00 and 18.00 h, with a composition and calorie content they were accustomed to and to repeat this closely on each pH recording day. They were instructed to avoid acid and alcoholic beverages. A diary was kept recording the exact timing and composition of meals, and time spent in a recumbent position. We defined the nocturnal period as being from 22.00 h to 06.00 h, regardless of whether the subject was recumbent or not. The daytime period was defined as the period between 06.00 h and 18.00 h, to exclude the dinner meal and the extended postprandial period after dinner.
At the end of the recording, digital values were transferred to an IBM-compatible computer for processing and editing in a dedicated software program (EsopHogram release 5.70, Gastrosoft Inc., Irving, TX). Meal periods were omitted from analysis to avoid erroneous recording of oesophageal acidity.10 From the gastric recordings we calculated the percentage of the nocturnal recording period during which gastric pH was less than 4.0, and also the percentage of time at which pH was less than 3.0 and 2.0. Acid breakthrough was defined as periods when gastric pH was less than 4.0 for 1 h or longer. Occurrence of nocturnal acid breakthrough (NAB), duration of the longest such episode and the time elapsed from dinner (18.00 h) until the first episode occurred were calculated. From the oesophageal recordings, the percentage of the total recording period during which pH was less than 4.0 (reflux time) was calculated for each regimen.
All comparisons were carried out using non-parametric statistics, to reflect the commonly skewed distribution of gastric and oesophageal pH variables. The percentage of the nocturnal period during which gastric and oesophageal pH were less than 4.0, 3.0 and 2.0 on the three different omeprazole regimens was compared using a Friedman non-parametric analysis of variance for paired data to detect any significant differences, followed by a Wilcoxon matched pairs test to localize such differences. The proportion of subjects with nocturnal acid breakthrough on each regimen was compared using a chi-squared test. A Bonferroni correction for multiple comparisons was carried out. A P-value of less than 0.05 was considered to indicate statistical significance.
Nineteen healthy male volunteers were recruited and started study medication. Mean age was 25 years (range 20–30 years). One subject was excluded from data analysis because of a technical failure in a pH recording.
Nocturnal acid breakthrough occurred in all 18 subjects at baseline, in 14 on qAM dosing, and in only 8 on both qPM and b.d. regimens. Thus, NAB was significantly more common if omeprazole was given in the morning than on each of the two other regimens (P < 0.05).
Other variables of gastric acidity and gastro-oesophageal reflux on each regimen are shown in Table 1. All regimens reduced the percentage of the nocturnal period when gastric pH was less than 4.0 from the baseline recording ( Figure 1), whereas the qPM and b.d. regimens were significantly superior to the qAM regimen (P < 0.01 and P < 0.05, respectively). There was a marked degree of intersubject variability in acid control, as can be seen from the figure. The median percentage of the nocturnal period during which gastric pH was less than 4.0, 3.0 and 2.0 is shown in Figure 2.
Table 1. . Parameters of gastric and oesophageal acidity in 18 volunteers treated with three different regimens of omeprazole 40 mg daily
The median percentage of time during the total 24-h recording for which gastric pH was less than 4.0 was 43.4 in subjects with NAB, compared to 12.7 in those without NAB on omeprazole medication (P < 0.0001). Time from dinner (18.00 h) until onset of acid breakthrough was not significantly different among regimens (if it occurred). Duration of the longest NAB was significantly shorter with qPM dosing than with qAM (P < 0.01).
The percentage of the daytime period when pH was less than 4.0 is shown in Figure 3, and was found to be not significantly different among the three omeprazole regimens␣(P = 0.06), although a trend towards an improved effect with b.d. dosing was observed. The percentage of daytime pH < 4.0 was significantly lower during the day than at night on the baseline (P < 0.05) and qAM recording (P < 0.001), but not on the two other regimens.
The median nocturnal gastric pH and percentage of the nocturnal period when pH was less than 4.0 showed a strong linear correlation (r = – 0.933, P < 0.0001).
Oesophageal acid exposure during the night-time period was not significantly different among the three omeprazole regimens (P = 0.38). The values were all within normal values in our laboratory, reflecting very little nocturnal reflux in healthy young subjects ( Figure 4).
The present study demonstrates that omeprazole, even at the moderately high dose of 40 mg daily, does not control gastric acidity throughout 24 h in most subjects. Nocturnal re-acidification of the stomach occurring on the customary morning dosing of omeprazole can be markedly reduced, however, by either dividing the dose or giving the drug before dinner only.
In GERD patients, omeprazole has traditionally been prescribed for intake in the morning for a variety of reasons. Pharmacokinetic studies have shown a greater bioavailability of a morning dose compared with an evening dose.11 Compliance with medication is better in the morning. Intake before a meal such as breakfast may be important for optimal acid suppression.12 Most GERD patients have predominantly postprandial reflux, which also makes a single morning dose, or at least dosing with a meal, a logical choice. In these patients with primarily postprandial upright reflux, nocturnal gastric acidity may be of little importance.
A large subgroup of patients, including those with Barrett’s oesophagus and patients with airways manifestations of GERD, can have a considerable amount of acid reflux during the night. In certain complications of GERD, in particular Barrett’s oesophagus, it may be important to verify that gastric acidity and acid reflux are well controlled.7 Persisting high levels of gastric acidity during the night is a potential source of nocturnal gastro-oesophageal reflux, particularly after late or fatty meals or if the position in the bed favours reflux.13
In a recent study, Hendel and co-workers found that a morning dose was most effective in reducing gastric acidity during the working day, whereas a late evening dose (taken between 21.00 and 23.00 h) was more effective in controlling night-time gastric acidity.14 Patients with nocturnal symptoms consistently preferred the evening dose. In our study, acid suppression during the night seemed to be more variable on b.d. than on dinner time dosing, suggesting that as a single evening dose, 20 mg was too small in some subjects, reflecting the highly variable absorption of small doses of omeprazole.15 The variation in gastric acid suppression between subjects on each regimen of omeprazole was considerable, as shown in Figure 1. Recent data indicate that dosing before meals is important to obtain the most effective acid suppression.12 Because the evening dose in our study was given in relation to dinner, the largest meal, this may partly explain the beneficial effect on night-time acidity.
While the frequency of nocturnal acid breakthrough has not been extensively studied in GERD patients, the available evidence indicates that it is no less common than in normal volunteers.6 Gastric acid secretion and response to acid-suppressive drugs is largely similar in GERD patients and normals,16,17 and gastric acid hypersecretion is not usually found in GERD patients.16 The potential importance of nocturnal acid breakthrough is that it may place the GERD patient at risk of repeated episodes of acid reflux at a time when it is likely to produce mucosal injury.
In the present study, nocturnal acid breakthrough occurred significantly more often if overall acid control was low and more often on qAM medication. Time from the evening meal until acid breakthrough was extended on omeprazole from a median of 3.8 h to 5.5–6.5 h, but breakthrough was still common on all regimens. The cause of the phenomenon is unknown. Because NAB is more common with a single morning dose, there is reason to argue that it relates simply to the duration of action of omeprazole. Omeprazole inhibits meal-induced daytime acid secretion more effectively and for longer than fasting acid secretion,11 whereas the opposite is true for H2-receptor antagonists.18 Gastric acid secretion in a fasting subject is maximal at the time when we found NAB, independent of gastrin values.19,20 As shown by Waldum and co-workers, gastric mucosal histamine concentration is appreciably increased in patients on 40 mg omeprazole daily,21 and in animal studies omeprazole has been found to stimulate histidine decarboxylase, indicating an increased capacity for histamine synthesis.21,22 Our recent observation that a histamine H2-receptor antagonist controls NAB better than an increased dose of a proton pump inhibitor,23 supports the notion that a high nocturnal histamine concentration contributes to nocturnal acid breakthrough in subjects taking proton pump inhibitors.
Gastric acidity can be expressed and analysed in different ways.24,25 We found that the percentage of time during which pH is less than 4.0 correlated well with median pH during the period studied. Median pH was less sensitive to treatment effects at both ends of the gastric pH range. The percentage of time at which the pH is less than a defined threshold is a logical parameter to use, but the threshold chosen should have a biological correlation. The accumulated time with a caustic level of acidity would be expected to correlate with severity of tissue damage. Animal studies have shown that microscopic tissue damage appears only when exposing oesophageal mucosa to acid below pH 3.26 We furthermore know from studies in humans that the threshold for sensing reflux varies within this area in most patients.27
New insight into the clinical pharmacodynamics of omeprazole and other proton pump inhibitors should allow us to individualize and optimize the treatment given to each patient. Nocturnal acid breakthrough and gastro-oesophageal reflux is a particular challenge which may be mastered by targeting the medication to this particular time period, with little loss in daytime acid control.
This study was partially funded by Astra-Merck Inc., Wayne, Pennsylvania, USA. Dr Jan G. Hatlebakk was supported by a grant from The American College of Gastroenterology.