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Therapeutic choices in reflux disease: Defining the criteria for selecting a proton pump inhibitor
Therapeutic Choices in Reflux Disease: Defining the Criteria for Selecting a Proton Pump Inhibitor James W. Freston, MD, PhD
Gastroesophageal reflux disease (GERD) is among the most common disorders of the gastrointestinal tract, with symptoms affecting a substantial proportion of the US population on a daily basis. Heartburn and related symptoms arise from a number of pathophysiologic mechanisms, including dilated intercellular spaces, increased duration of acid reflux, greater proximal extent of reflux, and esophageal sensitivity. Chronic reflux may result in serious complications, such as esophageal erosions or ulceration, stricture, and Barrett esophagus. The goals of GERD therapy are to relieve patients’ symptoms and prevent complications. Proton pump inhibitors (PPIs) represent the most effective treatment option for GERD, relieving symptoms, healing erosions, and maintaining a healed mucosa. Differences in the pharmacokinetics and pharmacodynamics among the PPIs may result in differences in intragastric pH holding time as well as the onset of symptom relief. Lansoprazole and esomeprazole produce similar degrees and onset of symptom relief, with both providing greater symptom relief as compared with omeprazole. Although manufactured as capsules containing enteric-coated granules, lansoprazole, omeprazole, and esomeprazole maintain their high level of pharmacologic efficacy when the capsule contents are emptied into soft foods or various liquids. Lansoprazole and pantoprazole also are manufactured as intravenous formulations, and lansoprazole is available as strawberry-flavored granules for oral suspension and as an orally disintegrating tablet. These alternative routes of administration are particularly beneficial in the management of acid-related disorders in infants, children, the elderly, and patients of all ages who have difficulty swallowing or are unable to swallow intact capsules or tablets and those in the critical care setting. Am J Med. 2004;117(5A):14S–22S. © 2004 by Elsevier Inc.
From the University of Connecticut Health Center, Farmington, Connecticut, USA. Requests for reprints should be addressed to James W. Freston, MD, PhD, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-1111. 14S
© 2004 by Elsevier Inc. All rights reserved.
G
astroesophageal reflux disease (GERD) symptoms are extremely common in the United States, affecting ⬎18 million people, with nearly 10% of individuals having heartburn and regurgitation daily.1,2 In addition to having significant impact on patients’ quality of life, GERD represents a significant burden to the healthcare labor force as well as to financial resources of the healthcare system. Between 2% and 4% of all visits to a primary care provider are because of symptoms of GERD. Of a total estimated disease cost of $9.3 billion, $5.8 billion is spent on acid-neutralizing or antisecretory medications.3 Even among a managed care population in a large city in the United States, the costs of acid-related disorders approached $59 million.4 Left untreated, chronic reflux may result in serious complications, such as esophageal erosion or ulceration, stricture, and Barrett esophagus. In adults and children with reflux disease, the goals of treatment are the same— prompt and sustained symptom relief, healing of the injured esophageal mucosa, and prevention of refluxrelated serious complications, including esophageal adenocarcinoma. An understanding of the pathogenesis of gastroesophageal reflux (GER), specifically, acid exposure that results in heartburn, explains why proton pump inhibitors (PPIs) are considered the cornerstone of GERD management.
PATHOGENESIS OF GASTROESOPHAGEAL REFLUX DISEASE SYMPTOMS The symptoms of GERD and, specifically, heartburn result from mucosal acid exposure5 as well as from the increased stimulation of acid-sensitive sensory nerve endings that exist deep in the mucosal lining of the esophagus.6 It has been documented that patients with GERD symptoms have dilated intercellular spaces.7 These dilated spaces allow acid to have increased access to mucosal nerve endings, thereby eliciting symptoms of heartburn and pain. In addition, there may be other modulating factors that influence the perception of heartburn during an acid reflux event, such as duration of the acid reflux event, proximal extent of the reflux (e.g., reflux episodes of longer duration and greater proximal extent are more likely to elicit symptoms), composition of the refluxate, psychological factors (e.g., stress), and esophageal sensitivity.8 –10 1548-2766/04/$22.00 doi:10.1016/j.amjmed.2004.07.020
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Table 1. Bioavailability of Selected Oral Proton Pump Inhibitors
Lansoprazole 30 mg Esomeprazole 40 mg Omeprazole 20 mg
Day 1 (%)
Day 5 (%)
Relative Change (%)
83 64 40
85 89 65
⫹4 ⫹39 ⫹62
PROTON PUMP INHIBITORS: PHARMACOKINETIC AND PHARMACODYNAMIC CONSIDERATIONS The PPIs provide more effective acid suppression than the H2-receptor antagonists, are more effective at reaching target pH values ⬎4 for ⱖ18 hours per day,11,12 and therefore are considered the drugs of choice for patients with symptomatic GER. Most research supporting PPIs as the mainstay of reflux disease management and as an integral component of Helicobacter pylori eradication regimens pertains to the adult population. However, equally supportive clinical results are emerging in studies involving children, as reviewed by Gold13 and Sherman14 in this supplement. Each of the 5 currently available PPIs has unique pharmacokinetic and pharmacodynamic effects that may have clinical implications with respect to the rate of esophagitis healing, the onset of symptom relief, or the duration of symptom relief. All PPIs are prodrugs that require acid to become protonated and thereby converted to the active form.15 The oral capsule formulations of omeprazole, lansoprazole, and esomeprazole contain enteric-coated delayed-release granules, whereas pantoprazole and rabeprazole use solid tablet formulations to protect the prodrug components from premature activation and degradation in the gastric lumen.16 Once these medications reach the duodenum (pH ⱖ5.6), the enteric coatings and tablets are dissolved, and the unprotonated prodrug is rapidly and extensively absorbed. The prodrug is delivered by the circulatory system to the parietal cell, which it enters; the prodrug then diffuses into the acidic secretory canaliculus where it becomes protonated, trapped, and then covalently binds with H⫹, K⫹-adenosine triphosphatase. This binding irreversibly inhibits the adenosine triphosphatase from exchanging H⫹ for K⫹, the final step in acid secretion.17 Although all PPIs undergo first-pass metabolism to inactive products, differences exist among the agents in bioavailability. Data from pharmacokinetic studies indicate that lansoprazole has the highest day 1 bioavailability (⬎80%) that remains relatively constant (an approximate 4% increase) during 5 days of continuous administration (Table 1).18,19 In contrast, the bioavailability patterns of omeprazole and esomeprazole, 2 closely related molecules, are different from that of lansoprazole. The
bioavailability of omeprazole and esomeprazole is substantially lower after the first dose relative to bioavailability after 5 days of continuous administration (Table 1).18 –23 The bioavailability of omeprazole increases from 40% to 65%, and the bioavailability of esomeprazole increases from 64% to 89%. It has been theorized that this increase in bioavailability is the result of these 2 agents’ emerging effect on gastric pH—as gastric pH increases during the 5 days of administration, a decrease in acid degradation of these agents in the gastric lumen occurs together with an inhibition of the drugs’ metabolism.21,23,24 The differences in bioavailability as well as other pharmacokinetic parameters (e.g., speed of activation, potency, and relative degree of receptor binding) may result in variation in intragastric acidity control among the agents. PPIs are able to inhibit only active proton pumps. Therefore, the degree of acid inhibition is not only related to area under the curve but also to timing of the dose. Specifically, the longer the plasma concentration remains above the threshold concentration necessary to inhibit the proton pumps, the greater the number of pumps that will be inhibited.11,25 For a given PPI, the higher the area under the curve the greater the degree of acid inhibition.11,26 PPIs with a high bioavailability after the first dose are able to inhibit a greater number of active proton pumps. Therefore, they would attain a pharmacodynamic steady-state level more quickly, reflected as the increase in percentage of the day during which gastric pH ⬎4.11 Timing of the dose is critical to achieving maximal acid suppression and therapeutic benefit. Because a greater number of proton pumps are activated with a meal that follows a prolonged fast, PPI therapy should be administered 30 to 60 minutes before breakfast (or the first substantial meal of the day). This timing allows not only increased absorption of the drug but also enables higher levels of drug to reach the parietal cells just at the time that the greatest number of pumps are likely to be activated.27,28 Studies comparing PPIs have determined that differences do exist in the relative degrees of proton pump inhibition as measured by effects on intragastric pH. Tolman et al29 compared the intragastric pH effects on day 1 and day 5 in a crossover trial involving healthy volunteers given lansoprazole 30 mg and rabeprazole 20 mg. Whereas the effects on intragastric pH were similar during the 24-hour evaluation periods, lansoprazole exhibited a significantly (P ⬍0.001) greater effect on intragastric pH during the first 5 hours after administration on day 1 and on day 5 compared with rabeprazole (Figure 1). Studies comparing pH holding times of lansoprazole and pantoprazole have noted similar results. Huang et al30 performed 2 crossover trials of lansoprazole 30 mg and pantoprazole 40 mg and found that the percentages of time 24-hour intragastric pH exceeded 3 and 4 were sig-
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Figure 1. Comparison of lansoprazole and rabeprazole on intragastric acidity in healthy volunteers. In a crossover trial of healthy volunteers (n ⫽ 65), lansoprazole 30 mg produced significantly (*P ⬍0.001) greater percentages of time intragastric pH ⬎4 during the first 5 hours of administration on both day 1 and day 5 as compared with rabeprazole 20 mg. Overall 24-hour percentages of time pH ⬎4 were similar between the treatment groups on both day 1 and day 5. (Adapted from Am J Gastroenterol.29)
Figure 2. Percentage of time 24-hour intragastric pH ⬎3 and 4 on days 1 and 5. In 2 crossover studies of healthy subjects, treatment with lansoprazole 30 mg versus pantoprazole 40 mg produced significantly higher percentages of time that 24-hour intragastric pH was ⬎3 and ⬎4 on day 1. By day 5, the differences in 24-hour intragastric pH narrowed between the 2 proton pump inhibitors. However, lansoprazole produced numerically higher percentages of time that achieved statistical significance for pH ⬎4 in 1 of the 2 studies. *P ⬍0.001 and †P ⬍0.02, lansoprazole 30 mg vs. pantoprazole 40 mg. (Adapted from Aliment Pharmacol Ther.30)
nificantly (P ⬍0.01) greater with lansoprazole as compared with pantoprazole on day 1 in both studies. By day 5, the differences between the 2 PPIs narrowed. However, lansoprazole still produced higher percentages of time that intragastric pH exceeded these thresholds, with significance observed in percentage of time pH ⬎4 in 1 of the 2 studies (Figure 2). In 2 separate studies involving patients with complicated or atypical GERD, Frazzoni et al31,32 noted that normalization of esophageal pH is accomplished more readily with lansoprazole compared with omeprazole31 or pantoprazole.32 Of 36 patients treated with lansopra16S September 6, 2004
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zole 30 mg, significantly fewer had persistently abnormal reflux compared with those treated with omeprazole 20 mg (10 of 36 [28%] vs. 23 of 34 [68%], P ⬍0.001).31 Similar results were observed in the later study of pantoprazole32: esophageal acid exposure was normalized in 100% (26 of 26) of patients treated with lansoprazole 30 mg or 60 mg/day (35% treated with double dose) compared with 75% (18 of 24) of those treated with pantoprazole at a dose of 40 mg or 80 mg/day (P ⫽ 0.008). The stereoselective metabolism of PPIs also may affect intragastric pH. As an example, esomeprazole consists of Volume 117 (5A)
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Figure 3. Speed of heartburn relief with lansoprazole versus omeprazole. A total of 3,530 patients with endoscopically diagnosed erosive gastroesophageal reflux disease were treated with lansoprazole 30 mg or omeprazole 20 mg once daily for 8 weeks. At the end of day 1, a significantly greater percentage of lansoprazole-treated patients reported complete heartburn relief. This significant benefit with lansoprazole persisted throughout the treatment period. *P ⬍0.0001 and †P ⬍0.001, lansoprazole vs. omeprazole. (Reprinted with permission from Am J Gastroenterol.10,38)
only the (S)-enantiomer of the racemic (S)- and (R)-enantiomers of omeprazole. The (S)-enantiomer has a slower clearance compared with the racemic mixture and, therefore, would be expected to attain higher serum levels and thus, greater effects on proton pump inhibition and intragastric pH. In 2 studies comparing the intragastric pH effects of esomeprazole with omeprazole, small but statistically significant differences between the 2 agents were found.33,34 In a double-blind, crossover study of 36 patients with GERD, esomeprazole 20 mg maintained intragastric pH ⬎4 for a mean of 12.7 hours and produced a median intragastric pH of 4.1 compared with pH ⬎4 of 10.7 hours and a median intragastric pH of 3.6 with omeprazole 20 mg (P ⬍0.01 for each comparison).33 In an open-label, crossover study of 130 patients with GERD, the investigators doubled the doses of esomeprazole and omeprazole and found similar numerically small, yet statistically significant differences between the 2 agents.34 On day 1, the mean percentage of the 24-hour period with intragastric pH ⬎4 was 48.6% with esomeprazole 40 mg compared with 40.6% with omeprazole 40 mg, percentages that increased to 68.4% and 62.0%, respectively, on day 5 (P ⬍0.001 for each comparison).
HEARTBURN RELIEF COMPARISONS AMONG PROTON PUMP INHIBITORS The pharmacokinetic and pharmacodynamic differences among the PPIs may impact the main clinical end points: onset and degree of heartburn relief. The speed of symptom relief has been linked to how quickly a pH ⬎4 is achieved in the intragastric compartment,12,35 with several studies finding disparity between omeprazole and lansoprazole and similarity between esomeprazole and lansoprazole. It is important to note that the ability to discern consistent and meaningful clinically differences is limited by the low number of head-to-head PPI clinical
trials that have been performed, as well as by the variability in study design, clinical end point assessments and definitions, and doses used. Clinically, symptom relief may be linked to a patient’s preference of a particular PPI over another.36,37 Huang et al35 performed a meta-analysis of randomized, controlled clinical trials and found a significantly (P ⬍0.001) greater effect on symptom relief after 1 to 2 weeks in patients treated with lansoprazole 30 mg compared with those treated with omeprazole 20 mg. In an 8-week study of ⬎3,500 patients with endoscopically diagnosed erosive GERD, Richter et al38 found a significant difference in favor of lansoprazole 30 mg over omeprazole 20 mg at week 1. In addition, a significantly (P ⬍0.001) higher percentage of patients treated with lansoprazole 30 mg had heartburn relief on day 1 compared with those treated with omeprazole 20 mg (Figure 3). Head-to-head trials comparing symptom relief with lansoprazole 30 mg and esomeprazole 40 mg have found that these 2 PPIs are largely equivalent in controlling heartburn in patients with either erosive esophagitis diagnosed by endoscopy or in patients who present to the primary care physician with uninvestigated heartburn. In a trial involving ⬎5,200 patients with erosive esophagitis treated with lansoprazole 30 mg or esomeprazole 40 mg, Castell et al39 measured symptom relief as complete heartburn resolution at 4 weeks (60% vs. 63%), heartburn-free days (71% vs. 73%), time to first resolution of daytime heartburn (2 days each treatment), and time to first resolution of nighttime heartburn (1 day each treatment). With the exception of complete heartburn resolution after 4 weeks of treatment (P ⬍0.05), there were no statistically significant differences between lansoprazole and esomeprazole. Similar findings were reported in another large (⬎3,000 patients) trial comparing lansoprazole 30 mg and esomeprazole 40 mg performed by Chey
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et al.40 During the first 3 days of treatment, patients treated with lansoprazole 30 mg or esomeprazole 40 mg were heartburn free on most days, 53% and 51%, respectively (P ⫽ not significant). These percentages increased slightly during the first 7 days of treatment and during the first 2 weeks of treatment (Figure 4). Using the rigorous criteria of heartburn-free days and nights, Howden et al41 noted that 35% of patients treated with lansoprazole 30 mg and 27% of those treated with esomeprazole 40 mg were completely free of heartburn symptoms. Dohmen et al42 found that all of the 62 (100%) patients treated with lansoprazole 30 mg and 48 (80%) of the 60 patients given esomeprazole 40 mg were free of heartburn pain after a single dose, a difference that the investigators attributed to the disparity in first dose bioavailability of the 2 agents. Nighttime heartburn also is associated with significant impairment in patients’ quality of life, with recent evidence suggesting that it may play a critical role in the development of severe GERD-related complications.43,44 Chey et al40 noted that the percentages of nights without heartburn in patients with uninvestigated dyspepsia treated with either lansoprazole 30 mg or esomeprazole 40 mg were similar to the percentages of days without heartburn. The comparable efficacy of lansoprazole 30 mg and esomeprazole 40 mg in producing first day (48% and 42% of patients without heartburn, respectively) and first week (62% and 59% of nights without heartburn, respectively) relief of nighttime heartburn also was confirmed in the study by Howden et al.41
HEALING OF ESOPHAGITIS: COMPARISONS AMONG PROTON PUMP INHIBITORS Among patients with persistent heartburn, a substantial percentage will have esophageal erosions or ulcerations on endoscopy.45 Of those with esophagitis, 50% will have severe esophagitis and may develop stricture secondary to the inflammatory changes. The PPIs are the cornerstone of erosive esophagitis healing and maintenance, with numerous clinical studies and meta-analyses documenting their greater efficacy compared with H2-receptor antagonists.46,47 In a large meta-analysis, Huang and Hunt48 found significantly higher healing rates at week 2, weeks 3 to 4, weeks 6 to 8, and week 12 with PPI therapy compared with H2-receptor antagonists (Figure 5). Of note was the observation that 2 weeks of PPI therapy produced a higher percentage of patients with healing than did 12 weeks of H2-receptor antagonist treatment. The superiority of any PPI over another in healing erosive esophagitis rarely has been demonstrated to a clinically relevant extent, with studies confirming healing in ⬎75% of patients after 4 weeks and approximately 90% of patients after 8 weeks of treatment with either lanso18S September 6, 2004
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prazole 30 mg or esomeprazole 40 mg.39,40 As with symptom response, there is a paucity of head-to-head PPI clinical trials that assess the relative efficacy of these agents in healing erosive esophagitis. A recent systematic review of 32 direct comparative trials that evaluated the efficacy of PPIs in healing erosive esophagitis found healing rates among standard doses of omeprazole (i.e., 20 mg) to be similar to those of pantoprazole 40 mg and rabeprazole 20 mg.49 Lansoprazole 30 mg was found to be similar to omeprazole 20 mg and 40 mg and to pantoprazole 40 mg.49 Comparisons with esomeprazole 40 mg found it to be more efficacious compared with omeprazole 20 mg and, in another study, lansoprazole 30 mg. The therapeutic gain of esomeprazole was ⬍10% and primarily related to higher rates of healing in the small number of patients with more severe forms of esophagitis.
TREATMENT OF PATIENTS WITH AN INCOMPLETE RESPONSE Patients who continue to have symptoms despite our prescribing of PPIs can be perplexing. Often, their incomplete response to treatment is a simple issue of noncompliance or mistiming of their dose. It is important to query patients about their complete compliance as well as remind them that PPI therapy is most effective when administered 30 minutes before breakfast (or their first substantial meal of the day). A recent survey of ⬎1,000 primary care physicians by Chey et al40 noted that ⬎33% did not advise their patients on timing of their PPI dose. More bothersome was that nearly 33% of physicians added a bedtime dose of H2-receptor antagonist in those with an incomplete symptom response. Although this may produce symptom relief initially, Guda et al50 found no significant advantage in nocturnal heartburn relief between ranitidine and placebo add-on therapy after the initial 4 days of treatment in patients with an incomplete response to once-daily PPI therapy. In those who continue to have symptoms, increasing the PPI dose to twice daily is the recommended strategy, with the second dose administered 30 minutes before dinner.31,32 Patients who continue to have symptoms on twice-daily PPI therapy should undergo intraesophageal pH monitoring (while continuing PPI treatment) to confirm or refute the presence of pathologic acid reflux. In those with acid reflux, increasing the dose of the twicedaily therapy should be considered. If no acid reflux is present, patients should be referred to a gastroenterologist for further workup of their symptoms.
ROUTES OF PROTON PUMP INHIBITOR ADMINISTRATION Oral PPI formulations in the United States are omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. Although capsules (omeprazole, lansopraVolume 117 (5A)
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Figure 4. Percentage of heartburn-free days with lansoprazole 30 mg versus esomeprazole 40 mg once daily. During each of the treatment evaluation time points, the percentages of days without heartburn was similar in patients treated with lansoprazole 30 mg or esomeprazole 40 mg, each administered once daily. (Reprinted with permission from Clin Drug Invest.40)
Figure 5. Treatment choices for gastroesophageal reflux disease: proton pump inhibitor (PPI) versus H2-receptor antagonist therapy. At each of the time points evaluated in 17 treatment arms of studies included in this large meta-analysis, treatment with a PPI produced significantly higher percentages (*P ⬍0.001) of healing in per-protocol patients with erosive esophagitis compared with H2-receptor antagonists. The rate of healing after 2 weeks of PPI therapy is greater than that attained after 12 weeks of an H2-receptor antagonist (67% vs. 62%). (Adapted from Gastroenterology.48)
zole, and esomeprazole) and tablet (pantoprazole and rabeprazole) preparations remain the most commonly prescribed dosing formulations, alternative methods and routes of PPI administration have been developed. These include emptying the enteric-coated capsule contents into soft foods or liquids before administration orally or via a nasogastric tube. More recently, alternative dosing formulations have been developed and marketed, including intravenous preparations of pantoprazole and lansoprazole, an orally disintegrating tablet formulation of lansoprazole,51 and a packet of strawberry-flavored lansoprazole granules for oral suspension (Table 2). These alternative dosing formulations extend the benefits of PPI therapy for acid-related disorders to patients who are un-
able to swallow intake capsules and tablets, such as children, the elderly, and the critically ill.
SAFETY PROFILE OF PROTON PUMP INHIBITORS The safety profile of the PPI has been confirmed to be excellent in their ⬎16 years of use worldwide in ⬎200 million individuals. Recently, the issue of gastric acid being required for dietary vitamin B12 cleavage from protein, and the possibility that acid inhibition may interfere with this process has been raised.52,53 Reduced serum vitamin B12 levels have been documented occasionally during long-term treatment with PPIs54; however, these reports have been primarily in patients with Zollinger-
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Table 2. Proton Pump Inhibitor Formulations and Administration Options
Capsule or tablet Capsule granules sprinkled on select soft foods Capsule granules mixed into select beverages Capsule granules flushed through nasogastric tube with select beverages Component of of Prevpac* triple-therapy administration pack Intravenous formulation Packet for oral suspension Oral disintegrating tablet
Lansoprazole
Esomeprazole
Rabeprazole
Pantoprazole
Omeprazole
⻫ ⻫
⻫ ⻫
⻫
⻫
⻫ ⻫
⻫ ⻫
⻫
⻫ ⻫ ⻫ ⻫
⻫
NDA ⫽ New Drug Application. * Prevpac (lansoprazole-amoxicillin-clarithromycin), TAP Pharmaceuticals Products Inc., Lake Forest, IL.
Ellison syndrome who have sustained drug-induced achlorhydria.52 Patients receiving long-term PPI therapy may require monitoring of their vitamin B12 status or, alternatively, administration of a multivitamin that contains vitamin B12.53
“CURBSIDE CONSULTATION” WITH THE EXPERT Should the timing of a patient’s acid-related symptoms influence the choice of therapy? Patients with symptoms that are primarily nocturnal may experience more complete symptom relief by administering their once-daily PPI therapy before dinner rather than before breakfast. In those who continue to have symptoms, the use of a twicedaily regimen is the recommended treatment strategy to control nocturnal heartburn. Does it ever make sense to change from one particular PPI to another? In patients who have good symptom control on a PPI, changing therapy is not justified. Those who continue to have heartburn and are being treated with an agent that has a lower relative bioavailability, such as omeprazole, may have more complete symptom control with lansoprazole or esomeprazole. How significant is tachyphylaxis with H2 receptor antagonists? All patients who take continuous H2-receptor antagonists develop tachyphylaxis, albeit with varying time to onset. Some studies have noted tachyphylaxis occurring within 48 hours of treatment with the intravenous formulations. To avoid tachyphylaxis, if patients are going to be supplemented with H2-receptor antagonists as add-on therapy to their PPI therapy, the H2-receptor antagonists should not be given ⬎3 to 4 times a week.
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ship to healthcare utilization and quality of life. Dig Dis Sci. 2000;45:809 –818. Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis. 1976;21:953–956. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology. 2002;122:1500 –1511. Levin TR, Schmittdiel JA, Kunz K, et al. Costs of acidrelated disorders to a health maintenance organization. Am J Med. 1997;103:520 –528. Smith JL, Opekun AR, Larkai E, Graham DY. Sensitivity of the esophageal mucosa to pH in gastroesophageal reflux disease. Gastroenterology. 1989;96:683–689. Lynn RB. Mechanisms of esophageal pain. Am J Med. 1992;92(suppl):11S–19S. Tobey NA, Carson JL, Alkiek RA, Orlando RC. Dilated intercellular spaces: a morphological feature of acid reflux— damaged human esophageal epithelium. Gastroenterology. 1996;111:1200 –1205. Weusten BL, Akkermans LM, VanBerge-Henegouwen GP, Smout AJ. Symptom perception in gastroesophageal reflux disease is dependent on spatiotemporal reflux characteristics. Gastroenterology. 1995;108:1739 –1744. Bradley LA, Richter JE, Pulliam TJ, et al. The relationship between stress and symptoms of gastroesophageal reflux: the influence of psychological factors. Am J Gastroenterol. 1993;88:11–19. Koek GH, Tack J, Sifrim D, et al. The role of acid and duodenal gastroesophageal reflux in symptomatic GERD. Am J Gastroenterol. 2001;96:2033–2040. Modlin IM, Sachs G. Gastric acid secretion. In: AcidRelated Diseases: Biology and Treatment. Konstanz, Germany: Schnetztor-Verlag GmbH D-Konstanz, 1998:61– 91. Bell NJ, Hunt RH. Progress with proton pump inhibition. Yale J Biol Med. 1992;65:649 –657. Gold BD. Gastroesophageal Reflux Disease: Could intervention in childhood reduce the risk of later complications? Am J Med. 2004;117(suppl 5A):23S–29S. Sherman PM. Appropriate strategies for testing and treating Helicobacter pylori in children: when and how? Am J Med. 2004;117(suppl 5A):30S–35S.
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A Symposium: Therapeutic Choices in Reflux Disease: Defining the Criteria for Selecting a PPI/Freston 15. Kromer W. Relative efficacies of gastric proton-pump inhibitors on a milligram basis: desired and undesired SH reactions. Impact of chirality. Scand J Gastroenterol. 2001; 36(suppl 234):3–9. 16. Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related disease. J Am Pharm Assoc (Wash). 2000;40: 52–62. 17. Welage LS. Pharmacologic properties of proton pump inhibitors. Pharmacotherapy. 2003;23:74S–80S. 18. Delhotal-Landes B, Flouvat B, Duchier J, et al. Pharmacokinetics of lansoprazole in patient with renal or liver disease of varying severity. Eur J Clin Pharmacol. 1993;45:367–371. 19. Bell NJV, Hunt RH. Time to maximum effect of lansoprazole on gastric pH in normal, male volunteers. Aliment Pharmacol Ther. 1996;10:897–904. 20. Howden C. Clinical pharmacology of omeprazole. Clin Pharmacokinetics. 1991;20:38 –49. 21. Andersson T, Andren K, Cederberg C, et al. Pharmacokinetics and bioavailability of omeprazole after single and repeated oral administration in healthy subjects. Br J Clin Pharmacol. 1990;29:557–563. 22. Andersson T, Rohss K, Bredberg E, Hassan-Alin M. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther. 2001;15:1563–1569. 23. Hassan-Alin M, Andersson T, Bredberg E, Rohss K. Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects. Eur J Clin Pharmacol. 2000;56:665–670. 24. Ching MS, Mihaly GW, Angus PW, et al. Oral bioavailability of omeprazole before and after chronic therapy in patients with duodenal ulcer. Br J Clin Pharmacol. 1991;31:166 – 170. 25. Junghard O, Hassan-Alin M, Hasselgren G. The effect of the area under the plasma concentration time vs time curve and the maximum plasma concentration of esomeprazole on intragastric pH. Eur J Clin Pharmacol. 2002;58:453–458. 26. Furata T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther. 1999;65:552–561. 27. Wolfe MM, Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology. 2000;118:S9 –S31. 28. Prichard PJ, Yeomans ND, Mihaly GW, et al. Omeprazole: a study of its inhibition of gastric pH and oral pharmacokinetics after morning or evening dosage. Gastroenterology. 1985;88:64 –69. 29. Tolman K, Taubel J, Warrington S, Lukasik N, Chiu Y. Lansoprazole achieves faster control of intragastric acidity than rabeprazole within the first 5 hours of administration. Am J Gastroenterol. 2000;95:2468. Abstract 196. 30. Huang J-Q, Goldwater DR, Thomson ABR, et al. Acid suppression in healthy subjects following lansoprazole or pantoprazole. Aliment Pharmacol Ther. 2002;16:425–433. 31. Frazzoni M, DeMicheli E, Grisendi A, Savarino V. Lansoprazole vs. omeprazole for gastro-oesophageal reflux disease: a pH-metric comparison. Aliment Pharmacol Ther. 2002;16: 35–39. 32. Frazzoni M, DeMicheli E, Grisendi A, Savarino V. Effective intra-oesophageal acid suppression in patients with gastrooesophageal reflux disease: lansoprazole vs. pantoprazole. Aliment Pharmacol Ther. 2003;17:235–241.
33. Lind T, Rydberg L, Kyleback A, et al. Esomeprazole provides improved acid control vs. omeprazole in patients with symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2000;14:861–867. 34. Rohss K, Hasselgren G, Hedenstrom H. Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour intragastric pH in patients with symptoms of gastroesophageal reflux disease. Dig Dis Sci. 2002;47:954 –958. 35. Huang JQ, Sridhar S, Hunt RH. Are there any differences in symptom relief and healing esophagitis between proton pump inhibitors: a meta-analysis of comparative trials [abstract]. Gut. 1999;45:P513. 36. Orebaugh HC, Christiason BS, Go MF. Is a PPI a PPI: does patient PPI preference reflect improved pH control? Gastroenterology. 2003;124:A-233. Abstract S1617. 37. Katz PO, Miner P, Wilder-Smith SH, Chen Y, Sostek MB. Rational for switching proton pump inhibitor (PPI) therapy: an intraindividual analysis of gastric acid suppression following treatment with different PPIs. Gastroenterology. 2003;124:A-226. Abstract S1583. 38. Richter JE, Kahrilas PJ, Sontag SJ, et al. Comparing lansoprazole and omeprazole in onset of heartburn relief: results of a randomized, controlled trial in erosive esophagitis patients. Am J Gastroenterol. 2001;96:3089 –3098. 39. Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol. 2002;97:575–583. 40. Chey WD, Huang B, Jackson RL, et al. Lansoprazole and esomeprazole in symptomatic GERD. Clin Drug Invest. 2003;23:69 –84. 41. Howden CW, Ballard ED II, Robieson W, et al. Evidence for therapeutic equivalence of lansoprazole 30 mg and esomeprazole 40 mg in the treatment of erosive esophagitis. Clin Drug Invest. 2002;22:99 –109. 42. Dohmen W, Fuchs W, Seelis REA. Onset and duration of pain relief in gastro-esophageal reflux disease (GERD): a clinical comparison of lansoprazole, omeprazole MUPS and esomeprazole [abstract]. Gastroenterology. 2002; 122(suppl 1):A201. 43. Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern Med. 2001;161:45–52. 44. Gallup Organization. A Gallup Organization National Survey: Understanding Heartburn in America. Princeton, NJ: The Gallup Organization, May, 2000. 45. Katelaris P, Hollowary R, Talley N, et al. Gastro-oesophageal reflux disease in adults: guidelines for clinicians. J Gastroenterol Hepatol. 2002;17:825–833. 46. Hatlebakk JG, Katz PO, Castell DO, et al. Medical therapy: management of the refractory patient. Gastroenterol Clin North Am. 1999;28:847–858. 47. Richter JE. Peptic strictures of the esophagus. Gastroenterol Clin North Am. 1999;28:875–891. 48. Huang J-Q, Hunt RH. Meta-analysis of comparative trials for healing erosive esophagitis with proton pump inhibitors and H2-receptor antagonists. Gastroenterology. 1998;114: A154. Abstract G0633. 49. Vakil N, Fennerty MB. Systematic review: direct comparative trials of the efficacy of proton pump inhibitors in the management of gastro-oesophageal reflux disease and peptic ulcer disease. Aliment Pharmacol Ther. 2003;18: 559 –568. 50. Guda N, Mueller R, Vakil N. The effect of over the counter
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ment with proton pump inhibitors. J Clin Gastroenterol. 2000;30:29 –33. 53. Force RW, Meeker AD, Cady PS, et al. Ambulatory care increased vitamin B12 requirement associated with chronic acid suppression therapy. Ann Pharmacother. 2003;37: 490 –493. 54. Khatib MA, Rahim O, Kania R, Molloy P. Iron deficiency anemia: induced by long-term ingestion of omeprazole. Dig Dis Sci. 2002;47:2596 –2597.
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Gastroesophageal reflux disease (GERD) is among the most common disorders of the gastrointestinal tract, with symptoms affecting a substantial proportion of the US population on a daily basis. Heartburn and related symptoms arise from a number of pathophysiologic mechanisms, including dilated intercellular spaces, increased duration of acid reflux, greater proximal extent of reflux, and esophageal sensitivity. Chronic reflux may result in serious complications, such as esophageal erosions or ulceration, stricture, and Barrett esophagus. The goals of GERD therapy are to relieve patients’ symptoms and prevent complications. Proton pump inhibitors (PPIs) represent the most effective treatment option for GERD, relieving symptoms, healing erosions, and maintaining a healed mucosa. Differences in the pharmacokinetics and pharmacodynamics among the PPIs may result in differences in intragastric pH holding time as well as the onset of symptom relief. Lansoprazole and esomeprazole produce similar degrees and onset of symptom relief, with both providing greater symptom relief as compared with omeprazole. Although manufactured as capsules containing enteric-coated granules, lansoprazole, omeprazole, and esomeprazole maintain their high level of pharmacologic efficacy when the capsule contents are emptied into soft foods or various liquids. Lansoprazole and pantoprazole also are manufactured as intravenous formulations, and lansoprazole is available as strawberry-flavored granules for oral suspension and as an orally disintegrating tablet. These alternative routes of administration are particularly beneficial in the management of acid-related disorders in infants, children, the elderly, and patients of all ages who have difficulty swallowing or are unable to swallow intact capsules or tablets and those in the critical care setting. Am J Med. 2004;117(5A):14S–22S. © 2004 by Elsevier Inc.
From the University of Connecticut Health Center, Farmington, Connecticut, USA. Requests for reprints should be addressed to James W. Freston, MD, PhD, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-1111. 14S
© 2004 by Elsevier Inc. All rights reserved.
G
astroesophageal reflux disease (GERD) symptoms are extremely common in the United States, affecting ⬎18 million people, with nearly 10% of individuals having heartburn and regurgitation daily.1,2 In addition to having significant impact on patients’ quality of life, GERD represents a significant burden to the healthcare labor force as well as to financial resources of the healthcare system. Between 2% and 4% of all visits to a primary care provider are because of symptoms of GERD. Of a total estimated disease cost of $9.3 billion, $5.8 billion is spent on acid-neutralizing or antisecretory medications.3 Even among a managed care population in a large city in the United States, the costs of acid-related disorders approached $59 million.4 Left untreated, chronic reflux may result in serious complications, such as esophageal erosion or ulceration, stricture, and Barrett esophagus. In adults and children with reflux disease, the goals of treatment are the same— prompt and sustained symptom relief, healing of the injured esophageal mucosa, and prevention of refluxrelated serious complications, including esophageal adenocarcinoma. An understanding of the pathogenesis of gastroesophageal reflux (GER), specifically, acid exposure that results in heartburn, explains why proton pump inhibitors (PPIs) are considered the cornerstone of GERD management.
PATHOGENESIS OF GASTROESOPHAGEAL REFLUX DISEASE SYMPTOMS The symptoms of GERD and, specifically, heartburn result from mucosal acid exposure5 as well as from the increased stimulation of acid-sensitive sensory nerve endings that exist deep in the mucosal lining of the esophagus.6 It has been documented that patients with GERD symptoms have dilated intercellular spaces.7 These dilated spaces allow acid to have increased access to mucosal nerve endings, thereby eliciting symptoms of heartburn and pain. In addition, there may be other modulating factors that influence the perception of heartburn during an acid reflux event, such as duration of the acid reflux event, proximal extent of the reflux (e.g., reflux episodes of longer duration and greater proximal extent are more likely to elicit symptoms), composition of the refluxate, psychological factors (e.g., stress), and esophageal sensitivity.8 –10 1548-2766/04/$22.00 doi:10.1016/j.amjmed.2004.07.020
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Table 1. Bioavailability of Selected Oral Proton Pump Inhibitors
Lansoprazole 30 mg Esomeprazole 40 mg Omeprazole 20 mg
Day 1 (%)
Day 5 (%)
Relative Change (%)
83 64 40
85 89 65
⫹4 ⫹39 ⫹62
PROTON PUMP INHIBITORS: PHARMACOKINETIC AND PHARMACODYNAMIC CONSIDERATIONS The PPIs provide more effective acid suppression than the H2-receptor antagonists, are more effective at reaching target pH values ⬎4 for ⱖ18 hours per day,11,12 and therefore are considered the drugs of choice for patients with symptomatic GER. Most research supporting PPIs as the mainstay of reflux disease management and as an integral component of Helicobacter pylori eradication regimens pertains to the adult population. However, equally supportive clinical results are emerging in studies involving children, as reviewed by Gold13 and Sherman14 in this supplement. Each of the 5 currently available PPIs has unique pharmacokinetic and pharmacodynamic effects that may have clinical implications with respect to the rate of esophagitis healing, the onset of symptom relief, or the duration of symptom relief. All PPIs are prodrugs that require acid to become protonated and thereby converted to the active form.15 The oral capsule formulations of omeprazole, lansoprazole, and esomeprazole contain enteric-coated delayed-release granules, whereas pantoprazole and rabeprazole use solid tablet formulations to protect the prodrug components from premature activation and degradation in the gastric lumen.16 Once these medications reach the duodenum (pH ⱖ5.6), the enteric coatings and tablets are dissolved, and the unprotonated prodrug is rapidly and extensively absorbed. The prodrug is delivered by the circulatory system to the parietal cell, which it enters; the prodrug then diffuses into the acidic secretory canaliculus where it becomes protonated, trapped, and then covalently binds with H⫹, K⫹-adenosine triphosphatase. This binding irreversibly inhibits the adenosine triphosphatase from exchanging H⫹ for K⫹, the final step in acid secretion.17 Although all PPIs undergo first-pass metabolism to inactive products, differences exist among the agents in bioavailability. Data from pharmacokinetic studies indicate that lansoprazole has the highest day 1 bioavailability (⬎80%) that remains relatively constant (an approximate 4% increase) during 5 days of continuous administration (Table 1).18,19 In contrast, the bioavailability patterns of omeprazole and esomeprazole, 2 closely related molecules, are different from that of lansoprazole. The
bioavailability of omeprazole and esomeprazole is substantially lower after the first dose relative to bioavailability after 5 days of continuous administration (Table 1).18 –23 The bioavailability of omeprazole increases from 40% to 65%, and the bioavailability of esomeprazole increases from 64% to 89%. It has been theorized that this increase in bioavailability is the result of these 2 agents’ emerging effect on gastric pH—as gastric pH increases during the 5 days of administration, a decrease in acid degradation of these agents in the gastric lumen occurs together with an inhibition of the drugs’ metabolism.21,23,24 The differences in bioavailability as well as other pharmacokinetic parameters (e.g., speed of activation, potency, and relative degree of receptor binding) may result in variation in intragastric acidity control among the agents. PPIs are able to inhibit only active proton pumps. Therefore, the degree of acid inhibition is not only related to area under the curve but also to timing of the dose. Specifically, the longer the plasma concentration remains above the threshold concentration necessary to inhibit the proton pumps, the greater the number of pumps that will be inhibited.11,25 For a given PPI, the higher the area under the curve the greater the degree of acid inhibition.11,26 PPIs with a high bioavailability after the first dose are able to inhibit a greater number of active proton pumps. Therefore, they would attain a pharmacodynamic steady-state level more quickly, reflected as the increase in percentage of the day during which gastric pH ⬎4.11 Timing of the dose is critical to achieving maximal acid suppression and therapeutic benefit. Because a greater number of proton pumps are activated with a meal that follows a prolonged fast, PPI therapy should be administered 30 to 60 minutes before breakfast (or the first substantial meal of the day). This timing allows not only increased absorption of the drug but also enables higher levels of drug to reach the parietal cells just at the time that the greatest number of pumps are likely to be activated.27,28 Studies comparing PPIs have determined that differences do exist in the relative degrees of proton pump inhibition as measured by effects on intragastric pH. Tolman et al29 compared the intragastric pH effects on day 1 and day 5 in a crossover trial involving healthy volunteers given lansoprazole 30 mg and rabeprazole 20 mg. Whereas the effects on intragastric pH were similar during the 24-hour evaluation periods, lansoprazole exhibited a significantly (P ⬍0.001) greater effect on intragastric pH during the first 5 hours after administration on day 1 and on day 5 compared with rabeprazole (Figure 1). Studies comparing pH holding times of lansoprazole and pantoprazole have noted similar results. Huang et al30 performed 2 crossover trials of lansoprazole 30 mg and pantoprazole 40 mg and found that the percentages of time 24-hour intragastric pH exceeded 3 and 4 were sig-
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Figure 1. Comparison of lansoprazole and rabeprazole on intragastric acidity in healthy volunteers. In a crossover trial of healthy volunteers (n ⫽ 65), lansoprazole 30 mg produced significantly (*P ⬍0.001) greater percentages of time intragastric pH ⬎4 during the first 5 hours of administration on both day 1 and day 5 as compared with rabeprazole 20 mg. Overall 24-hour percentages of time pH ⬎4 were similar between the treatment groups on both day 1 and day 5. (Adapted from Am J Gastroenterol.29)
Figure 2. Percentage of time 24-hour intragastric pH ⬎3 and 4 on days 1 and 5. In 2 crossover studies of healthy subjects, treatment with lansoprazole 30 mg versus pantoprazole 40 mg produced significantly higher percentages of time that 24-hour intragastric pH was ⬎3 and ⬎4 on day 1. By day 5, the differences in 24-hour intragastric pH narrowed between the 2 proton pump inhibitors. However, lansoprazole produced numerically higher percentages of time that achieved statistical significance for pH ⬎4 in 1 of the 2 studies. *P ⬍0.001 and †P ⬍0.02, lansoprazole 30 mg vs. pantoprazole 40 mg. (Adapted from Aliment Pharmacol Ther.30)
nificantly (P ⬍0.01) greater with lansoprazole as compared with pantoprazole on day 1 in both studies. By day 5, the differences between the 2 PPIs narrowed. However, lansoprazole still produced higher percentages of time that intragastric pH exceeded these thresholds, with significance observed in percentage of time pH ⬎4 in 1 of the 2 studies (Figure 2). In 2 separate studies involving patients with complicated or atypical GERD, Frazzoni et al31,32 noted that normalization of esophageal pH is accomplished more readily with lansoprazole compared with omeprazole31 or pantoprazole.32 Of 36 patients treated with lansopra16S September 6, 2004
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zole 30 mg, significantly fewer had persistently abnormal reflux compared with those treated with omeprazole 20 mg (10 of 36 [28%] vs. 23 of 34 [68%], P ⬍0.001).31 Similar results were observed in the later study of pantoprazole32: esophageal acid exposure was normalized in 100% (26 of 26) of patients treated with lansoprazole 30 mg or 60 mg/day (35% treated with double dose) compared with 75% (18 of 24) of those treated with pantoprazole at a dose of 40 mg or 80 mg/day (P ⫽ 0.008). The stereoselective metabolism of PPIs also may affect intragastric pH. As an example, esomeprazole consists of Volume 117 (5A)
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Figure 3. Speed of heartburn relief with lansoprazole versus omeprazole. A total of 3,530 patients with endoscopically diagnosed erosive gastroesophageal reflux disease were treated with lansoprazole 30 mg or omeprazole 20 mg once daily for 8 weeks. At the end of day 1, a significantly greater percentage of lansoprazole-treated patients reported complete heartburn relief. This significant benefit with lansoprazole persisted throughout the treatment period. *P ⬍0.0001 and †P ⬍0.001, lansoprazole vs. omeprazole. (Reprinted with permission from Am J Gastroenterol.10,38)
only the (S)-enantiomer of the racemic (S)- and (R)-enantiomers of omeprazole. The (S)-enantiomer has a slower clearance compared with the racemic mixture and, therefore, would be expected to attain higher serum levels and thus, greater effects on proton pump inhibition and intragastric pH. In 2 studies comparing the intragastric pH effects of esomeprazole with omeprazole, small but statistically significant differences between the 2 agents were found.33,34 In a double-blind, crossover study of 36 patients with GERD, esomeprazole 20 mg maintained intragastric pH ⬎4 for a mean of 12.7 hours and produced a median intragastric pH of 4.1 compared with pH ⬎4 of 10.7 hours and a median intragastric pH of 3.6 with omeprazole 20 mg (P ⬍0.01 for each comparison).33 In an open-label, crossover study of 130 patients with GERD, the investigators doubled the doses of esomeprazole and omeprazole and found similar numerically small, yet statistically significant differences between the 2 agents.34 On day 1, the mean percentage of the 24-hour period with intragastric pH ⬎4 was 48.6% with esomeprazole 40 mg compared with 40.6% with omeprazole 40 mg, percentages that increased to 68.4% and 62.0%, respectively, on day 5 (P ⬍0.001 for each comparison).
HEARTBURN RELIEF COMPARISONS AMONG PROTON PUMP INHIBITORS The pharmacokinetic and pharmacodynamic differences among the PPIs may impact the main clinical end points: onset and degree of heartburn relief. The speed of symptom relief has been linked to how quickly a pH ⬎4 is achieved in the intragastric compartment,12,35 with several studies finding disparity between omeprazole and lansoprazole and similarity between esomeprazole and lansoprazole. It is important to note that the ability to discern consistent and meaningful clinically differences is limited by the low number of head-to-head PPI clinical
trials that have been performed, as well as by the variability in study design, clinical end point assessments and definitions, and doses used. Clinically, symptom relief may be linked to a patient’s preference of a particular PPI over another.36,37 Huang et al35 performed a meta-analysis of randomized, controlled clinical trials and found a significantly (P ⬍0.001) greater effect on symptom relief after 1 to 2 weeks in patients treated with lansoprazole 30 mg compared with those treated with omeprazole 20 mg. In an 8-week study of ⬎3,500 patients with endoscopically diagnosed erosive GERD, Richter et al38 found a significant difference in favor of lansoprazole 30 mg over omeprazole 20 mg at week 1. In addition, a significantly (P ⬍0.001) higher percentage of patients treated with lansoprazole 30 mg had heartburn relief on day 1 compared with those treated with omeprazole 20 mg (Figure 3). Head-to-head trials comparing symptom relief with lansoprazole 30 mg and esomeprazole 40 mg have found that these 2 PPIs are largely equivalent in controlling heartburn in patients with either erosive esophagitis diagnosed by endoscopy or in patients who present to the primary care physician with uninvestigated heartburn. In a trial involving ⬎5,200 patients with erosive esophagitis treated with lansoprazole 30 mg or esomeprazole 40 mg, Castell et al39 measured symptom relief as complete heartburn resolution at 4 weeks (60% vs. 63%), heartburn-free days (71% vs. 73%), time to first resolution of daytime heartburn (2 days each treatment), and time to first resolution of nighttime heartburn (1 day each treatment). With the exception of complete heartburn resolution after 4 weeks of treatment (P ⬍0.05), there were no statistically significant differences between lansoprazole and esomeprazole. Similar findings were reported in another large (⬎3,000 patients) trial comparing lansoprazole 30 mg and esomeprazole 40 mg performed by Chey
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et al.40 During the first 3 days of treatment, patients treated with lansoprazole 30 mg or esomeprazole 40 mg were heartburn free on most days, 53% and 51%, respectively (P ⫽ not significant). These percentages increased slightly during the first 7 days of treatment and during the first 2 weeks of treatment (Figure 4). Using the rigorous criteria of heartburn-free days and nights, Howden et al41 noted that 35% of patients treated with lansoprazole 30 mg and 27% of those treated with esomeprazole 40 mg were completely free of heartburn symptoms. Dohmen et al42 found that all of the 62 (100%) patients treated with lansoprazole 30 mg and 48 (80%) of the 60 patients given esomeprazole 40 mg were free of heartburn pain after a single dose, a difference that the investigators attributed to the disparity in first dose bioavailability of the 2 agents. Nighttime heartburn also is associated with significant impairment in patients’ quality of life, with recent evidence suggesting that it may play a critical role in the development of severe GERD-related complications.43,44 Chey et al40 noted that the percentages of nights without heartburn in patients with uninvestigated dyspepsia treated with either lansoprazole 30 mg or esomeprazole 40 mg were similar to the percentages of days without heartburn. The comparable efficacy of lansoprazole 30 mg and esomeprazole 40 mg in producing first day (48% and 42% of patients without heartburn, respectively) and first week (62% and 59% of nights without heartburn, respectively) relief of nighttime heartburn also was confirmed in the study by Howden et al.41
HEALING OF ESOPHAGITIS: COMPARISONS AMONG PROTON PUMP INHIBITORS Among patients with persistent heartburn, a substantial percentage will have esophageal erosions or ulcerations on endoscopy.45 Of those with esophagitis, 50% will have severe esophagitis and may develop stricture secondary to the inflammatory changes. The PPIs are the cornerstone of erosive esophagitis healing and maintenance, with numerous clinical studies and meta-analyses documenting their greater efficacy compared with H2-receptor antagonists.46,47 In a large meta-analysis, Huang and Hunt48 found significantly higher healing rates at week 2, weeks 3 to 4, weeks 6 to 8, and week 12 with PPI therapy compared with H2-receptor antagonists (Figure 5). Of note was the observation that 2 weeks of PPI therapy produced a higher percentage of patients with healing than did 12 weeks of H2-receptor antagonist treatment. The superiority of any PPI over another in healing erosive esophagitis rarely has been demonstrated to a clinically relevant extent, with studies confirming healing in ⬎75% of patients after 4 weeks and approximately 90% of patients after 8 weeks of treatment with either lanso18S September 6, 2004
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prazole 30 mg or esomeprazole 40 mg.39,40 As with symptom response, there is a paucity of head-to-head PPI clinical trials that assess the relative efficacy of these agents in healing erosive esophagitis. A recent systematic review of 32 direct comparative trials that evaluated the efficacy of PPIs in healing erosive esophagitis found healing rates among standard doses of omeprazole (i.e., 20 mg) to be similar to those of pantoprazole 40 mg and rabeprazole 20 mg.49 Lansoprazole 30 mg was found to be similar to omeprazole 20 mg and 40 mg and to pantoprazole 40 mg.49 Comparisons with esomeprazole 40 mg found it to be more efficacious compared with omeprazole 20 mg and, in another study, lansoprazole 30 mg. The therapeutic gain of esomeprazole was ⬍10% and primarily related to higher rates of healing in the small number of patients with more severe forms of esophagitis.
TREATMENT OF PATIENTS WITH AN INCOMPLETE RESPONSE Patients who continue to have symptoms despite our prescribing of PPIs can be perplexing. Often, their incomplete response to treatment is a simple issue of noncompliance or mistiming of their dose. It is important to query patients about their complete compliance as well as remind them that PPI therapy is most effective when administered 30 minutes before breakfast (or their first substantial meal of the day). A recent survey of ⬎1,000 primary care physicians by Chey et al40 noted that ⬎33% did not advise their patients on timing of their PPI dose. More bothersome was that nearly 33% of physicians added a bedtime dose of H2-receptor antagonist in those with an incomplete symptom response. Although this may produce symptom relief initially, Guda et al50 found no significant advantage in nocturnal heartburn relief between ranitidine and placebo add-on therapy after the initial 4 days of treatment in patients with an incomplete response to once-daily PPI therapy. In those who continue to have symptoms, increasing the PPI dose to twice daily is the recommended strategy, with the second dose administered 30 minutes before dinner.31,32 Patients who continue to have symptoms on twice-daily PPI therapy should undergo intraesophageal pH monitoring (while continuing PPI treatment) to confirm or refute the presence of pathologic acid reflux. In those with acid reflux, increasing the dose of the twicedaily therapy should be considered. If no acid reflux is present, patients should be referred to a gastroenterologist for further workup of their symptoms.
ROUTES OF PROTON PUMP INHIBITOR ADMINISTRATION Oral PPI formulations in the United States are omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole. Although capsules (omeprazole, lansopraVolume 117 (5A)
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Figure 4. Percentage of heartburn-free days with lansoprazole 30 mg versus esomeprazole 40 mg once daily. During each of the treatment evaluation time points, the percentages of days without heartburn was similar in patients treated with lansoprazole 30 mg or esomeprazole 40 mg, each administered once daily. (Reprinted with permission from Clin Drug Invest.40)
Figure 5. Treatment choices for gastroesophageal reflux disease: proton pump inhibitor (PPI) versus H2-receptor antagonist therapy. At each of the time points evaluated in 17 treatment arms of studies included in this large meta-analysis, treatment with a PPI produced significantly higher percentages (*P ⬍0.001) of healing in per-protocol patients with erosive esophagitis compared with H2-receptor antagonists. The rate of healing after 2 weeks of PPI therapy is greater than that attained after 12 weeks of an H2-receptor antagonist (67% vs. 62%). (Adapted from Gastroenterology.48)
zole, and esomeprazole) and tablet (pantoprazole and rabeprazole) preparations remain the most commonly prescribed dosing formulations, alternative methods and routes of PPI administration have been developed. These include emptying the enteric-coated capsule contents into soft foods or liquids before administration orally or via a nasogastric tube. More recently, alternative dosing formulations have been developed and marketed, including intravenous preparations of pantoprazole and lansoprazole, an orally disintegrating tablet formulation of lansoprazole,51 and a packet of strawberry-flavored lansoprazole granules for oral suspension (Table 2). These alternative dosing formulations extend the benefits of PPI therapy for acid-related disorders to patients who are un-
able to swallow intake capsules and tablets, such as children, the elderly, and the critically ill.
SAFETY PROFILE OF PROTON PUMP INHIBITORS The safety profile of the PPI has been confirmed to be excellent in their ⬎16 years of use worldwide in ⬎200 million individuals. Recently, the issue of gastric acid being required for dietary vitamin B12 cleavage from protein, and the possibility that acid inhibition may interfere with this process has been raised.52,53 Reduced serum vitamin B12 levels have been documented occasionally during long-term treatment with PPIs54; however, these reports have been primarily in patients with Zollinger-
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Table 2. Proton Pump Inhibitor Formulations and Administration Options
Capsule or tablet Capsule granules sprinkled on select soft foods Capsule granules mixed into select beverages Capsule granules flushed through nasogastric tube with select beverages Component of of Prevpac* triple-therapy administration pack Intravenous formulation Packet for oral suspension Oral disintegrating tablet
Lansoprazole
Esomeprazole
Rabeprazole
Pantoprazole
Omeprazole
⻫ ⻫
⻫ ⻫
⻫
⻫
⻫ ⻫
⻫ ⻫
⻫
⻫ ⻫ ⻫ ⻫
⻫
NDA ⫽ New Drug Application. * Prevpac (lansoprazole-amoxicillin-clarithromycin), TAP Pharmaceuticals Products Inc., Lake Forest, IL.
Ellison syndrome who have sustained drug-induced achlorhydria.52 Patients receiving long-term PPI therapy may require monitoring of their vitamin B12 status or, alternatively, administration of a multivitamin that contains vitamin B12.53
“CURBSIDE CONSULTATION” WITH THE EXPERT Should the timing of a patient’s acid-related symptoms influence the choice of therapy? Patients with symptoms that are primarily nocturnal may experience more complete symptom relief by administering their once-daily PPI therapy before dinner rather than before breakfast. In those who continue to have symptoms, the use of a twicedaily regimen is the recommended treatment strategy to control nocturnal heartburn. Does it ever make sense to change from one particular PPI to another? In patients who have good symptom control on a PPI, changing therapy is not justified. Those who continue to have heartburn and are being treated with an agent that has a lower relative bioavailability, such as omeprazole, may have more complete symptom control with lansoprazole or esomeprazole. How significant is tachyphylaxis with H2 receptor antagonists? All patients who take continuous H2-receptor antagonists develop tachyphylaxis, albeit with varying time to onset. Some studies have noted tachyphylaxis occurring within 48 hours of treatment with the intravenous formulations. To avoid tachyphylaxis, if patients are going to be supplemented with H2-receptor antagonists as add-on therapy to their PPI therapy, the H2-receptor antagonists should not be given ⬎3 to 4 times a week.
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A Symposium: Therapeutic Choices in Reflux Disease: Defining the Criteria for Selecting a PPI/Freston 15. Kromer W. Relative efficacies of gastric proton-pump inhibitors on a milligram basis: desired and undesired SH reactions. Impact of chirality. Scand J Gastroenterol. 2001; 36(suppl 234):3–9. 16. Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related disease. J Am Pharm Assoc (Wash). 2000;40: 52–62. 17. Welage LS. Pharmacologic properties of proton pump inhibitors. Pharmacotherapy. 2003;23:74S–80S. 18. Delhotal-Landes B, Flouvat B, Duchier J, et al. Pharmacokinetics of lansoprazole in patient with renal or liver disease of varying severity. Eur J Clin Pharmacol. 1993;45:367–371. 19. Bell NJV, Hunt RH. Time to maximum effect of lansoprazole on gastric pH in normal, male volunteers. Aliment Pharmacol Ther. 1996;10:897–904. 20. Howden C. Clinical pharmacology of omeprazole. Clin Pharmacokinetics. 1991;20:38 –49. 21. Andersson T, Andren K, Cederberg C, et al. Pharmacokinetics and bioavailability of omeprazole after single and repeated oral administration in healthy subjects. Br J Clin Pharmacol. 1990;29:557–563. 22. Andersson T, Rohss K, Bredberg E, Hassan-Alin M. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther. 2001;15:1563–1569. 23. Hassan-Alin M, Andersson T, Bredberg E, Rohss K. Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects. Eur J Clin Pharmacol. 2000;56:665–670. 24. Ching MS, Mihaly GW, Angus PW, et al. Oral bioavailability of omeprazole before and after chronic therapy in patients with duodenal ulcer. Br J Clin Pharmacol. 1991;31:166 – 170. 25. Junghard O, Hassan-Alin M, Hasselgren G. The effect of the area under the plasma concentration time vs time curve and the maximum plasma concentration of esomeprazole on intragastric pH. Eur J Clin Pharmacol. 2002;58:453–458. 26. Furata T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther. 1999;65:552–561. 27. Wolfe MM, Sachs G. Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome. Gastroenterology. 2000;118:S9 –S31. 28. Prichard PJ, Yeomans ND, Mihaly GW, et al. Omeprazole: a study of its inhibition of gastric pH and oral pharmacokinetics after morning or evening dosage. Gastroenterology. 1985;88:64 –69. 29. Tolman K, Taubel J, Warrington S, Lukasik N, Chiu Y. Lansoprazole achieves faster control of intragastric acidity than rabeprazole within the first 5 hours of administration. Am J Gastroenterol. 2000;95:2468. Abstract 196. 30. Huang J-Q, Goldwater DR, Thomson ABR, et al. Acid suppression in healthy subjects following lansoprazole or pantoprazole. Aliment Pharmacol Ther. 2002;16:425–433. 31. Frazzoni M, DeMicheli E, Grisendi A, Savarino V. Lansoprazole vs. omeprazole for gastro-oesophageal reflux disease: a pH-metric comparison. Aliment Pharmacol Ther. 2002;16: 35–39. 32. Frazzoni M, DeMicheli E, Grisendi A, Savarino V. Effective intra-oesophageal acid suppression in patients with gastrooesophageal reflux disease: lansoprazole vs. pantoprazole. Aliment Pharmacol Ther. 2003;17:235–241.
33. Lind T, Rydberg L, Kyleback A, et al. Esomeprazole provides improved acid control vs. omeprazole in patients with symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2000;14:861–867. 34. Rohss K, Hasselgren G, Hedenstrom H. Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour intragastric pH in patients with symptoms of gastroesophageal reflux disease. Dig Dis Sci. 2002;47:954 –958. 35. Huang JQ, Sridhar S, Hunt RH. Are there any differences in symptom relief and healing esophagitis between proton pump inhibitors: a meta-analysis of comparative trials [abstract]. Gut. 1999;45:P513. 36. Orebaugh HC, Christiason BS, Go MF. Is a PPI a PPI: does patient PPI preference reflect improved pH control? Gastroenterology. 2003;124:A-233. Abstract S1617. 37. Katz PO, Miner P, Wilder-Smith SH, Chen Y, Sostek MB. Rational for switching proton pump inhibitor (PPI) therapy: an intraindividual analysis of gastric acid suppression following treatment with different PPIs. Gastroenterology. 2003;124:A-226. Abstract S1583. 38. Richter JE, Kahrilas PJ, Sontag SJ, et al. Comparing lansoprazole and omeprazole in onset of heartburn relief: results of a randomized, controlled trial in erosive esophagitis patients. Am J Gastroenterol. 2001;96:3089 –3098. 39. Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol. 2002;97:575–583. 40. Chey WD, Huang B, Jackson RL, et al. Lansoprazole and esomeprazole in symptomatic GERD. Clin Drug Invest. 2003;23:69 –84. 41. Howden CW, Ballard ED II, Robieson W, et al. Evidence for therapeutic equivalence of lansoprazole 30 mg and esomeprazole 40 mg in the treatment of erosive esophagitis. Clin Drug Invest. 2002;22:99 –109. 42. Dohmen W, Fuchs W, Seelis REA. Onset and duration of pain relief in gastro-esophageal reflux disease (GERD): a clinical comparison of lansoprazole, omeprazole MUPS and esomeprazole [abstract]. Gastroenterology. 2002; 122(suppl 1):A201. 43. Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern Med. 2001;161:45–52. 44. Gallup Organization. A Gallup Organization National Survey: Understanding Heartburn in America. Princeton, NJ: The Gallup Organization, May, 2000. 45. Katelaris P, Hollowary R, Talley N, et al. Gastro-oesophageal reflux disease in adults: guidelines for clinicians. J Gastroenterol Hepatol. 2002;17:825–833. 46. Hatlebakk JG, Katz PO, Castell DO, et al. Medical therapy: management of the refractory patient. Gastroenterol Clin North Am. 1999;28:847–858. 47. Richter JE. Peptic strictures of the esophagus. Gastroenterol Clin North Am. 1999;28:875–891. 48. Huang J-Q, Hunt RH. Meta-analysis of comparative trials for healing erosive esophagitis with proton pump inhibitors and H2-receptor antagonists. Gastroenterology. 1998;114: A154. Abstract G0633. 49. Vakil N, Fennerty MB. Systematic review: direct comparative trials of the efficacy of proton pump inhibitors in the management of gastro-oesophageal reflux disease and peptic ulcer disease. Aliment Pharmacol Ther. 2003;18: 559 –568. 50. Guda N, Mueller R, Vakil N. The effect of over the counter
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ment with proton pump inhibitors. J Clin Gastroenterol. 2000;30:29 –33. 53. Force RW, Meeker AD, Cady PS, et al. Ambulatory care increased vitamin B12 requirement associated with chronic acid suppression therapy. Ann Pharmacother. 2003;37: 490 –493. 54. Khatib MA, Rahim O, Kania R, Molloy P. Iron deficiency anemia: induced by long-term ingestion of omeprazole. Dig Dis Sci. 2002;47:2596 –2597.
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