Management of Gastroesophageal Reflux Disease
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Management of Gastroesophageal Reflux
Disease
RADU TUTUIAN, MD; DONALD O. CASTELL, MD
ABSTRACT: Gastroesophageal reflux disease (GERD) is effect profile outweighs their benefits. Antireflux surgery
a chronic condition requiring long-term treatment. Sim- in carefully selected patients (ie, young, typical GERD
ple lifestyle modifications are the first methods em- symptoms, abnormal pH study, and good response to
ployed by patients and, because of their low cost and PPI) is as effective as PPI therapy and should be offered
simplicity, should be continued even when more potent to these patients as an alternative to medication. Still,
therapies are initiated. Potent acid-suppressive therapy patients should be informed about the risks of antireflux
is currently the most important and successful medical surgery (ie, risk of postoperative dysphagia; decreased
therapy. Whereas healing of the esophageal mucosa is ability to belch, possibly leading to bloating; increased
achieved with a single dose of any proton pump inhib- flatulence). Endoscopic antireflux procedures are rec-
itor (PPI) in more than 80% of cases, symptoms are more ommended only in selected patients and given the rel-
difficult to control. Patients with persistent symptoms on ative short experience with these techniques, patients
therapy should be tested (preferably with combined treated with endoscopic procedures should be enrolled
multichannel intraluminal impedance and pH) for asso- in a rigorous follow-up program. KEY INDEXING
ciation of symptoms with acid, nonacid, or no GER. TERMS: Gastroesophageal reflux disease (GERD); Proton
Long-term follow-up studies indicate that PPIs are effi- pump inhibitors; Antireflux surgery. [Am J Med Sci
cacious, tolerable, and safe medication. So far, promo- 2003;326(5):309–318.]
tility agents have shown limited efficacy, and their side-
and has few side effects, specialists (gastroenterolo-
A pproximately 40% of the US population has
symptoms of gastroesophageal reflux disease
(GERD),1 making it the fourth most prevalent gas-
gists and gastrointestinal surgeons) are likely to see
only the “tip of the iceberg” represented by patients
trointestinal disease in the United States.2 GERD is with severe or persistent symptoms not responsive
a chronic disease requiring long-term therapy. As a to standard treatment.4 When evaluated by gastro-
general rule, the management of GERD should fol- enterologists, treatment targets reduction of esoph-
low a step-wise approach, starting with simple ther- ageal acid exposure. Supported by a good correlation
apeutic modalities and gradually advancing to more between control of intragastric pH and healing of
potent and more aggressive modalities based on 2 erosive esophagitis,5 medical strategies employ
goals: healing of lesions and alleviation of pharmacological suppression of gastric acid produc-
symptoms. tion, whereas surgical and endoscopic strategies em-
The pattern of presentation and therapy is well- ploy augmentation of the gastroesophageal junction.
expressed by the “heartburn iceberg” shown in Fig- The above concepts have primarily been studied in
ure 1. The vast majority of patients have only occa- patients with so-called “typical” symptoms of GERD
sional symptoms and will empirically treat (heartburn, regurgitation) but apply equally to those
heartburn with over-the-counter (OTC) medications with atypical (chest pain, asthma/cough, hoarse-
and not seek medical attention.3 Patients with fre- ness, sore throat) symptoms or complications (ulcer-
quent symptoms will seek medical attention and are ation, strictures, metaplasia) of the disease.
often evaluated by primary care physicians and
given prescriptions for acid-suppressive therapy. Simple Therapeutic Modalities (Lifestyle
Because acid-suppressive therapy is very effective Modifications)
In the current days of very potent acid-suppres-
From the Division of Gastroenterology/Hepatology, Medical sive therapy, simple, alternative, patient-driven,
University of South Carolina, Charleston, South Carolina. and less expensive GERD treatments tend to be
Correspondence: Radu Tutuian, M.D., Division of Gastroenter-
ology/Hepatology, Medical University of South Carolina, 96 forgotten. Most of these methods were the main
Jonathan Lucas Street, 210 CSB, Charleston, SC 29425 (E-mail: therapeutic modalities before the late 1970s and
tutuianr@musc.edu). include elevation of head of the bed, wearing loose-
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES 309Management of Gastroesophageal Reflux Disease
Table 1. Lifestyle Modifications That Can Help Improve GERD
Symptoms
Sleep with the head of the bed elevated
Sleep on the left side
Avoid late meals/avoid recumbent position 3 hours after meals
Avoid high-fat meals
Use smaller meals
Use saliva-stimulating agents (ie, hard candies, chewing gum)
Wear loose-fitting clothing
Restrict smoking, alcohol, coffee, chocolate
Lose weight
smoking and alcohol are based on studies indicating
decreases in LES pressures and/or increased num-
ber of gastroesophageal reflux episodes. Ingestion of
high-fat meals decreases LES pressure,13 increases
frequency of transient lower esophageal relax-
ations,14 and increases esophageal acid exposure for
Figure 1. Pattern of presentation and therapy of GERD patients
up to 3 hours after meals.15 Increased esophageal
expressed by the “heartburn iceberg.” Endo, endoscopic antireflux acid exposure has been documented after ingestion
procedure. of chocolate16 and alcohol17 and after smoking.18,19
The use of antacids in treatment of GERD relies
on the neutralizing capabilities of these compounds
fitting clothing, avoidance of meals before bedtime, on acid gastric secretions. The superiority of antac-
weight loss, and restriction of smoking, alcohol, cof- ids over placebo was proven in double-blind studies
fee, and fat.6 Today, these lifestyle modifications in patients with reflux esophagitis.20,21 Other place-
often also include use of antacids, alginate, and bo-controlled studies have shown the superiority of
over-the-counter (OTC) doses of histamine-2 recep- an alginic acid-antacid combination in controlling
tor antagonists (H2RA). reflux symptoms.22 The observation of the floating
Elevation of the head of the bed helps improve- nature of alginic acid within the stomach suggested
ment of esophageal acid clearance and decreases the that it might work well in patients with symptoms
total recumbent acid exposure.7 These hypotheses during the upright position,23 a hypothesis sup-
are supported by studies indicating significant re- ported in subsequent studies.24
duction in nocturnal acid clearance time and total After several years of proven efficacy and safety of
nocturnal acid exposure using 6-inch blocks to ele- standard-dose H2RAs, the class of medication be-
vate the head of the bed.8 A more patient-friendly came available as low-dose over-the-counter (OTC)
alternative is to sleep predominantly on the left preparations for “conservative” treatment of GERD.
side.9 Avoidance of meals for 3 hours before bedtime There is only limited information available showing
is based on studies indicating that postprandial re- symptomatic improvement with OTC doses of
cumbency leads to a significant increase in the num- H2Ras,25 although several studies have documented
ber and duration of reflux events10 the ability of these preparations to decrease intra-
Wearing loose-fitting clothing as a measure to gastric acidity.26,27 In 2002, the American Gastroen-
reduce gastroesophageal reflux is based on the hy- terology Association (AGA) issued a consensus state-
pothesis that tight clothing increases intragastric ment declaring OTC H2RA and antacid the first line
pressure and therefore the gastroesophageal pres- of treatment for patients with mild GERD symp-
sure gradient across the lower esophageal sphincter toms. The combination H2RA/antacid was consid-
(LES),11 the so-called “tight pants syndrome.” Even ered better at symptom relief than its constituent
though there are no good studies supporting this components alone.
hypothesis, this relatively simple and intuitive mea- Table 1 summarizes the life-style modification ap-
sure should not be ignored. proach to GERD. Even though recently developed
Based on studies showing a correlation of morbid acid-suppressive agents are highly effective in treat-
obesity with reflux and lower LES pressures,12 ment of GERD, these simple measures should be
weight reduction in the attempt to improve GERD is discussed with patients. Their simplicity and low
a rational approach. Even though not formally stud- cost justify them as phase 1 therapy to be continued
ied, it is commonly believed that typical GERD in all patients suffering from this disorder. OTC
symptoms improve in patients during weight antacids or even H2RAs should be recommended for
reduction. occasional “breakthrough” symptoms while patients
Recommendations to avoid certain foods and limit are receiving more potent therapies.
310 November 2003 Volume 326 Number 5Tutuian and Castell
Pharmacologic Management of GERD heal erosive esophagitis not healed at 12 weeks.32
H2RAs relieve GERD symptoms in about half of
The objectives of pharmacological treatment of patients after 6 to 12 weeks.33
GERD are relief of symptoms, avoidance of compli- Even in this era of potent acid-suppressive PPIs,
cations, and healing of esophageal mucosa. The H2RAs provide the advantage of prompt relief of
principal classes of pharmacological agents are: acid heartburn,34 and when administered at bedtime,
suppressive drugs [H2RAs, proton pump inhibitors they improve nocturnal gastric acid control in GERD
(PPIs)], promotility agents (bethanechol, metoclo- patients taking PPIs.35
pramide, cisapride, domperidone, erythromycin, te- Proton Pump Inhibitors. PPIs are superior to
gaserod), mucosal protective agents (sucralfate), and
H2RAs in treating erosive esophagitis36 and its com-
agents to reduce transient lower esophageal sphinc-
plications,37 relieving symptoms from erosive and
ter relaxation (TLESR) (baclofen).
nonerosive GERD,38,39 and preventing recurrence of
Acid-Suppressive Drugs GERD-associated symptoms.40 Studies by Zeitoun,41
Histamine-2 Receptor Antagonists. H2RAs Lundell et al,42 Vantrappen et al,43 and Klinken-
were the antisecretory therapy of choice from the berg-Knol et al36 indicate superiority of the PPI
mid-1970s until the introduction of PPIs into clinical versus H2RA. Thus, they have surpassed H2RAs as
practice in the late 1980s.28 Currently in the United the antisecretory agents of choice (Figure 2). PPIs
States, 4 H2RAs are available for clinical use: rani- are substituted benzimidazoles that irreversibly
tidine (Zantac), famotidine (Pepcid), cimetidine bind the H⫹,K⫹-ATPase, the final common step in
(Tagamet), and nizatidine (Axid). Even though the acid secretion.44
more recently developed PPIs have been shown to Currently, 5 PPIs are commercially available in
be superior, the H2RAs still remain useful in the United States: omeprazole, lansoprazole, rabe-
treatment of milder forms of the disease and for prazole, pantoprazole, and esomeprazole. FDA-ap-
on-demand therapy, particularly for nocturnal proved doses (20- and 40-mg omeprazole, 15- and
GERD symptoms. 30-mg lansoprazole, 20-mg rabeprazole, 40-mg pan-
Prescription dosages of H2RAs can be grouped toprazole, and 40-mg esomeprazole) are for use once
into standard dose (150 mg of ranitidine, 20 mg of daily, which provides sufficient acid suppression to
famotidine, 400 mg of cimetidine, and 150 mg of effectively treat most patients. Symptom relief can
nizatidine, each twice daily) and high dose (obtained be expected in about 78% of cases (range, 62–94%)
by doubling the standard doses). The healing rates and esophagitis healing in 83% (range, 71–96%).45
with H2RAs range between 50 and 70% at 8 weeks Whether one PPI is superior to the others is con-
and 60 to 80% at 12 weeks.29 Most studies have troversial. For every study showing that one PPI is
shown superiority of H2RAs to placebo but no sig- superior to another, there is another study showing
nificant differences among high and standard doses the opposite. Overall, based on similar esophageal
(possible type II error, because most studies were healing rates of over 80% at 8 weeks46 and similar
powered to show differences from placebo). It was intragastric pH profiles after 7 days of dosing,47 all
soon recognized that esophageal healing rates cor- first-generation PPIs (omeprazole, lansoprazole, ra-
related with decrease of esophageal acid exposure, beprazole, pantoprazole) can be considered to have
duration of acid suppressive therapy, and degree of equivalent effectiveness (Figure 3). Minor differ-
esophagitis.30 Studies have shown that esophageal ences in pharmacodynamics and price exist.48 How-
healing rates at 12 weeks were higher than healing ever, individual variability in patient response to
rates at 8 weeks,31 but 24 weeks of H2RA could not PPI can vary widely. Therefore, we recommend
Figure 2. Comparison of omeprazole versus raniti-
dine in healing reflux esophagitis after 8 weeks of
treatment. Studies by Zeitoun,41 Lundell et al,42
Vantrappen et al,43 and Klinkenberg-Knol et al36
indicate superiority of the PPI versus H2RA. Num-
bers indicate dose of omeprazole used in the study.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES 311Management of Gastroesophageal Reflux Disease
Figure 3. Comparison of first-generation PPIs for short-term Figure 5 . Proportion of patients with nocturnal acid break-
treatment healing rates. Bars indicate percentage healing after 8 through (defined as intragastric pH ⬍ 4 for at least 60 continuous
weeks of treatment. Numbers indicate patients in respective minutes) on PPI bid ⫹ H2RA at bedtime versus PPI twice per day
studies. alone.35
switching to another PPI as the first step in patients Despite the efficacy of single-dose proton pump
not responding to one PPI. inhibitor in controlling intragastric acidity, improv-
The most recent “second-generation” PPI, esome- ing symptoms, and healing of erosive esophagitis,
prazole, the active S-isomer in the racemic mixture some patients do not heal as well and may require
of omeprazole,49 has been reported to have slightly increased dosing. In addition, patients with extrae-
better effect on GERD.50 Results from a large, dou- sophageal presentations (asthma, cough, or laryngi-
ble-blind study suggest that the advantages of es- tis) may require higher doses for effective symptom
omeprazole become more important in patients with control.53–55 Rather than doubling the single dose
more severe disease (Figure 4).51 amount, it is preferable to give the PPI twice daily.
The timing of administering the PPI in relation This recommendation is based on studies in healthy
with meals is important. The ideal window to take subjects indicating that 20 mg of omeprazole before
the PPI is 15 to 30 minutes before meals. This allows breakfast and before dinner was superior in control-
the medication to be absorbed to be available to the ling intragastric pH compared with 40 mg of ome-
proton pumps when they are activated by the meal. prazole before breakfast or before dinner.56
PPIs taken before meals provide better intragastric A more recent discovery has been that PPIs may
pH control compared with being taken after the not achieve adequate control of intragastric pH57;
meal.52 Inadequate timing is frequently seen clini- even with twice-daily dosing, they are not always
cally, especially when patients are prescribed PPI able to control nocturnal acid breakthrough.58 A
twice daily without further instructions; patients single dose of H2RAs added at bedtime to the PPI
frequently take the medication in the morning and can reduce nocturnal acid breakthrough (Figure
before bedtime (without a meal). 5).59 Concerns that combination of PPI and H2RAs
Figure 4. Comparison of esomeprazole versus lan-
soprazole in 8-week healing rates of erosive esoph-
agitis by baseline grade of esophagitis. The benefits
of esomeprazole are higher in more severe cases of
esophagitis.
312 November 2003 Volume 326 Number 5Tutuian and Castell Table 2. Suggested Approach to Acid Suppressive Therapy Step Medical regimen 1 Single-dose PPI (AM before meals) 2 Switch to another PPI 3 PPI AM plus evening (or bedtime) H2RA 4 PPI twice daily before meals 5 PPI twice daily before meals plus H2RA at bedtime might decrease the efficacy of PPIs were cleared by studies indicating similar intragastric acid control on daily PPI after placebo or H2RAs the night be- fore.60 Therefore H2RAs are still potentially effec- tive drugs for on-demand therapy of both daytime Figure 6. Suggested diagnostic GERD algorithm. and nocturnal GERD symptoms. Based on existing data we propose the step-up therapeutic approach to acid suppression guided as As mentioned before, GERD is a chronic disease illustrated in Table 2. Symptom response to a trial of requiring long-standing therapy. Although daily PPI therapy is currently a popular recommended maintenance therapy on standard-dose PPI sustains diagnostic approach to GERD (“PPI-trial”).61 Pa- relapse rates well under 20% for 12 months,68,69 tients failing PPI trials or not responding to PPI change to H2RAs or placebo will increase the relapse therapy should undergo reflux testing to evaluate to more than 50 to 70% and 70 to 90%, respective- the amount of reflux and its relation to symptoms. ly.70,71 Long-term safety and efficacy of standard For more than 20 years, esophageal pH testing has PPI doses are supported by European studies with been the accepted standard for diagnosing patient follow-up over a decade.72 GERD.62,63 For optimal study interpretation pa- tients should be off PPI therapy for at least 7 days Promotility Agents (PMAs) before undergoing esophageal pH testing. Patients The rationale for using PMAs in treatment of with GERD who failed to respond to standard PPI GERD is based on the hypothesis that normalizing treatment because of insufficient dosing might ex- underlying dysmotility or augmenting existing mo- perience symptom exacerbation during this period tility would decrease esophageal acid contact time. that may help clarify the diagnosis. An overall comment regarding PMAs in GERD is An important alternative diagnosis in patients that as a group, they have limited effectiveness or with persistent symptoms on therapy is the possi- undesirable side effects. bility of symptomatic nonacid reflux, which will be Bethanechol is a cholinergic agonist that will in- missed by conventional pH testing because of the crease esophageal peristalsis and LES pressure but limitations of this technique in identifying nonacid also stimulate gastric secretion. Compared with pla- reflux.64,65 Currently, combined multichannel in- cebo, it will improve GERD symptoms but has no traluminal impedance and pH (MII-pH) is evolving advantages in healing esophagitis.73,74 At the recom- as dual modality reflux testing. Because MII-pH mended dose for treatment of GERD (25 mg 4 times detects reflux by changes in intraluminal electric per day), it may have cholinergic side effects, includ- conductivity, both acid and nonacid reflux events ing diarrhea, abdominal cramping, fatigue, and can be identified.66,67 Preliminary data from a mul- blurred vision. ticenter collaborative study suggest that only 20% of Metoclopramide is a smooth-muscle stimulant patients with persistent symptoms on acid-suppres- that inhibits dopamine receptors. It enhances gas- sive therapy have their symptoms related to acid tric emptying and LES pressure but has no effect on reflux. The other 80% usually present a diagnostic esophageal peristalsis. Even though it may improve dilemma as to whether their symptoms are associ- GERD symptoms, it does not show healing rates to ated with nonacid reflux or not associated with any justify its side-effect profile: galactorrhea, men- type of GER. Combined MII-pH will further clarify- strual dysfunction, lethargy, and extrapyramidal ing this possible association, including recognition motor defects. The most concerning side effect is that 40% of patients with persistent symptoms on tardive dyskinesia, which can occur in up to 20% of therapy have no temporal correlation between patients and can be permanent.75 symptoms and any type of reflux. Therefore, we Cisapride stimulates acetylcholine release, in- believe that combined MII-pH should be considered creasing LES pressure, aiding esophageal peristal- the next step in diagnostic management of patients sis, and accelerating gastric emptying. Placebo-con- not responding to PPI therapy (Figure 6). trolled trials have shown significant improvements THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES 313
Management of Gastroesophageal Reflux Disease
in GERD symptoms76; because of its cardiovascular antireflux procedures were done to increase LES
side effects, however, it is no longer available. pressure.90 At present, given that TLESR is consid-
Tegaserod, a selective 5-HT4 receptor partial ago- ered the main mechanism by which GERD occurs,
nist, is a potent promotility agent throughout the surgery is done to lengthen the intraabdominal por-
gastrointestinal tract that is also considered to de- tion of the LES, to reduce the volume of the gastric
crease visceral sensitivity77 and promote gastric fundus and prevent effacing of the LES during gas-
emptying.78 In 1 study in GERD patients, it was tric distention in the postprandial period.91
shown to decrease postprandial esophageal acid ex- Preoperative evaluation of patients undergoing
posure79 suggesting a potential role in treatment of antireflux surgery includes: esophageal manometry,
GERD. upper gastrointestinal endoscopy, 24-hour esopha-
Domperidone and erythromycin are the other pro- geal pH monitoring, barium esophagogram, and gas-
motility agents currently being investigated for tric emptying studies.92 This is necessary to select
treatment of GERD. Both agents enhance gastric the ideal candidates for the procedure, who should
emptying but do not have significant effects on be young (because they will require long-term GERD
esophageal peristalsis. Their side effect profiles may therapy), should have typical GERD symptoms
also limit their clinical utility. (heartburn, regurgitation), should have an abnor-
mal ambulatory pH test, and should have responded
Mucosal Protective Agents to PPI therapy. Antireflux procedures should be
The role of sucralfate in treatment of GERD has used with caution in patients with atypical manifes-
not been studied as extensively as H2RAs and PPIs. tations (ie, chest pain, acid taste), in patients not
Sucralfate is believed to physically adhere to injured responding to PPI therapy, and patients with inef-
mucosa and thereby create a protective barrier fective esophageal motility. Contraindications to
against acid gastric secretions. Randomized compar- perform surgical interventions are major esophageal
isons showed superiority to placebo and healing motility abnormalities (ie, achalasia, scleroderma).
comparable with standard dose H2RAs.80 Recently, a randomized clinical trial in 310 pa-
tients comparing surgery and omeprazole showed
Agents to Reduce TLESRs similar success/failure rates over a 5-year period.93
Recently, transient lower esophageal sphincter re- Results from community hospitals report rates of
laxations (TLESRs) have been recognized to be the complications/defective fundoplication (ie, dyspha-
major mechanism of gastroesophageal reflux.81– 83 gia, 31%; bloating, 46%; flatulence, 67%; and recur-
Baclofen, an agonist of ␥-aminobutyric acid type B, rent esophagitis, 26%) during a 78-month follow-
was shown to reduce the rate of postprandial up,94 which underlined the importance of having an
TLESRs and acid reflux episodes in healthy volun- experienced surgeon in a hospital that has a high
teers84 and patients with reflux esophagitis.85 In a procedure volume.
mechanistic study using combined MII-pH in
healthy volunteers and patients with GERD, a sin- Endoscopic Management of GERD
gle dose of 40 mg of baclofen significantly reduced all
types (acid and nonacid) of postprandial reflux.86 Recent development in endoscopic techniques pro-
The side-effect profile of dizziness or nausea may posed a series of procedures to treat GERD. Radio-
restrict its clinical utility. frequency ablation of the lower esophageal sphincter
(Stretta procedure) uses a balloon-tipped 4-needle
Surgical Management of GERD catheter that delivers radiofrequency (RF) energy to
the smooth muscle of the gastroesophageal junction.
Surgical antireflux procedures are highly effective The initial proposed mechanism of action was con-
treatment modalities in appropriately selected pa- sidered to be generation of a scarring tissue that
tients. Before potent acid suppressive therapy be- would decrease the amount of reflux.95 Subse-
came available, surgery was considered superior to quently, it was proposed that RF ablation of the LES
medical therapies.87 The rationales for antireflux might in fact decrease the number of transient lower
surgery have evolved parallel to clarifications in esophageal sphincter relaxations.96 This procedure
pathophysiologic mechanisms of reflux disease. Al- is recommended in patients suffering from chronic
though hiatal hernia was considered to be of major heartburn requiring maintenance antisecretory
importance in production of GERD, antireflux sur- therapy but without a hiatal hernia ⬎2 cm, severe
gery was performed to reduce the hiatal hernia and esophagitis, or complications of gastroesophageal re-
keep the LES within the abdominal cavity.88 Re- flux disease. After the initial success, more recent
ports showing that only 9% of patients with hiatal studies indicate that the procedure improves symp-
hernia had typical reflux symptoms89 suggested that toms (ie, severity of GERD, scores on GERD-related
other factors might play a more important role. questionnaires), but results regarding improvement
When low LES pressures were considered the major of esophageal acid exposure are conflicting.97,98
factor in gastroesophageal junction incompetence, Around the same time, the FDA approved a sec-
314 November 2003 Volume 326 Number 5Tutuian and Castell
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