Lifestyle modification
Evidence of strength
Reasonable to recommend?
Sleep with head elevated
Equivocal
Not generally
Avoid fatty meals
Equivocal
Not generally
Avoid carbonated beverages
Moderate
Yes
Select decaffeinated beverages
Equivocal
Not generally
Avoid citrus
Weak
Not generally
Eat smaller meals
Weak
Yes
Lose weight
Equivocal
Yesa
Avoid alcoholic beverages
Weak
Not generally
Stop smoking
Weak
Yes (in symptomatic persons)
Avoid excessive exercise
Weak
Yesa
Sleep on left side
Unequivocal
Yes
Encouraging patients to go to bed on an empty stomach is the most logical suggestion. Proximal acid migration is greatest during sleep and sleep also delays esophageal acid clearance. As the majority of reflux is in the first 4 h of sleep, eating within 1–2 h of sleep is much more likely to cause nocturnal reflux [1].
Elevation of the head of the bed 6–8 inches is worth considering. This is based on studies using prolonged pH monitoring that have shown an acceleration of esophageal clearance when the head of the bed is elevated compared to sleeping flat [2–4]. In addition, reflux frequency as well as total time that esophageal pH was <4 is decreased in the left side down position, compared to right side down, prone, and supine [5–9]. Sleep medications increase night time reflux and should be used with care in GERD [10].
Acidic liquids (colas and teas) and citrus products are direct esophageal irritants and may exacerbate symptoms [11–16]. A high-fat meal is known to increase reflux frequency [17, 18]. Fat delays gastric emptying, so may increase the risk of reflux through this mechanism. Chocolate also decreases LESP [19], increases esophageal acid exposure [20], and is on the list of foods to potentially avoid.
Symptomatic GERD and body weight are clearly related. Weight gain is associated with an increased risk of having symptoms of GERD and weight loss associated with a decrease in incidence [21, 22]. Increase in BMI is a risk for the development of adenocarcinoma as well in patients with Barrett’s esophagus [23] and a BMI of >30 may be a risk for failure of antireflux surgery [24] further suggesting that there is some link between obesity and GERD. Overall waist circumference is emerging as a bigger issue rather than BMI itself.
Overall, lifestyle changes are still reasonable adjuncts to treatment, even if they have a minimal impact [25]. Educating patients about the potential values of going to bed on an empty stomach and the overall potential of lifestyle modifications to reduce symptoms takes little time and ultimately might help. It is, however, difficult to push these interventions on patients who choose not to implement them as “hard data” are lacking.
Pharmacologic Therapy
Proton pump inhibitors (PPIs) are the agents of choice for antisecretory therapy in GERD. Today’s clinician needs, however, to be familiar with the still widely used antacids, H2 receptor antagonists, sucralfate, and prokinetic agents to understand their synergistic potential in GERD management.
Antacids
Antacids are effective only for symptom relief. It is rare that they are sufficient to adequately help a patient with other than occasional heartburn. Efficacy of antacids should be evaluated between equivalent doses, whether tablet or liquid. Alginic acid combined with antacid has a slightly different mechanism of action but is likely similar to other antacids in efficacy. Side effects of antacids are minimal when they are used intermittently. Chronic use of magnesium-containing antacids may cause diarrhea, and should be avoided in the patient with heart failure, renal insufficiency, and in late trimester pregnancy. Aluminum-containing antacids may cause constipation [26–28]. Popular over-the-counter antacids, such as Maalox® and Mylanta®, contain both magnesium and aluminum. Gaviscon® also has alginic acid and is often described as more effective for nocturnal reflux.
Barrier Agent
Sucralfate binds to inflamed tissue and may inhibit the erosive action of pepsin and bile [29]. Healing of erosive esophagitis compared to H2RAs is similar [31, 32]. Constipation is seen in 2 % of patients with this sucraflate. Little systemic absorption of the agent has been demonstrated making it quite safe. Because of the need to give the drug four times a day, there is little value in GERD except perhaps in pregnant women [30]. Otherwise, this compound has little to no place in modern medical therapy for GERD.
Prokinetics
A promotility, or “motility altering” agent, theoretically may represent the ideal agent to treat GERD. Improving the strength and competence of the LES, augmenting esophageal clearance to shorten the time the esophageal mucosa is exposed to a pH < 4 and to improve gastric emptying with its potential for “overflow reflux,” might constitute the ideal therapy. Unfortunately, the remaining agent available in the United States—metoclopramide—is limited in efficacy and has an unfavorable side effect profile. Usefulness is thus limited in GERD patients.
Metoclopramide is a dopamine antagonist that likely sensitizes tissues to the action of acetylcholine, increases the amplitude of gastric and esophageal contractions, transiently increases LES pressure (LESP), and predominantly accelerates gastric emptying. It produces clinically important central nervous system side effects such as drowsiness and confusion [33]. Equivalent efficacy of metoclopramide compared to Histamine receptor antagonists (H2RA) in relieving heartburn and other GERD symptoms has been documented. When compared to placebo, 10 mg of metoclopramide three times daily showed little symptom improvement. When the dose was increased to 10 mg four times daily, it is more effective than placebo in improving symptoms [34–38]. Because of its centrally acting effects; antidopaminergic side effects are observed in 20–30 % of patients. Anxiety, agitation, confusion, motor restlessness, hallucinations, and drowsiness are common side effects; depression and potentially irreversible tardive dyskinesia are the most serious complications of the drug. Side effects are likely dose related and may be higher in children and the elderly. There is currently a black box warning for side effects and informed, written consent is recommended if prescribed for long-term use. In a patient with clear evidence of gastroparesis and GERD symptoms refractory to antisecretory therapy, metoclopramide may be of additional benefit. Unfortunately, it is not effective in treating patients with esophageal motility abnormalities.
Domperidone is a peripheral dopamine antagonist that stimulates esophageal peristalsis, increases LESP, and accelerates gastric emptying. It is not FDA approved in the United States [39]. It does not have the central dopaminergic side effects of metoclopramide. There are few GERD studies with this drug, and nothing to suggest it is superior to an H2RA. It should not be administered with antisecretory agents or antacids, as reduced gastric acidity impairs its absorption [40, 41]. Hyperprolactinemia, nipple tenderness, galactorrhea, and amenorrhea are the most common side effects. This is not a GERD drug.
Bethanechol is a cholinergic drug that has been used to treat reflux and bladder spasm since the 1970s [42]. It has been demonstrated to increase the resting tone of the clasp and sling fibers of the gastroesophageal junction which are typically defective in patients with GERD [43]. Side effects relate to the relative increase in parasympathetic tone including abdominal cramps, diarrhea, bradycardia, sweating, salivation, and flushing. Its use is mostly related to pharmacologic theory and there exists no definitive clinical data to support its use over other standard therapies.
Baclofen can be helpful for patients with mild reflux, particularly with meals. Baclofen is an agonist of GABA, the major inhibitory neurotransmitter in the central nervous system. GABA receptors are also found in the enteric nervous system where it has been shown to decrease reflux through inhibition of transient LES relaxations and elevation of LES resting pressure. In a study of 20 volunteers, a single dose of baclofen reduced acid reflux events and TLESRs by about 40 % but interestingly has no effect on overall acid exposure during the 3 h study period [44]. Baclofen is associated with only mild side effects including somnolence, dizziness, and nausea and has no adverse effects on other aspects of esophageal function [45]. Baclofen is therefore considered a fairly safe option for most patients with very mild symptoms.
Antisecretory Agents
Acid control remains the medical approach of choice to treat patient with GERD. Two classes of drugs are available, H2RAs and PPIs. Both inhibit gastric secretion and raise intragastric pH though to varying degrees. Intragastric pH control is an indirect measure of efficacy of symptom relief, correlates with healing of erosive esophagitis, and is important in understanding the overall efficacy data of these agents. If gastric pH is <4, pepsinogen is activated to pepsin, which exacerbates the esophageal mucosal damage caused by contact with gastric acid during reflux events. There is a relationship between the duration of time (calculated over 24 h) that the intragastric pH is >4 and healing [46, 47].
H2RAs have been available as over-the-counter agents since 1995. There are four H2 receptor antagonists currently available—cimetidine, ranitidine, famotidine, and nizatidine. The mechanism of action for H2RAs is via competitive inhibition of the acid stimulating histamine receptors on the gastric parietal cells. As a class, H2RAs are relatively weak inhibitors of meal-stimulated acid secretion, reducing acid secretion by 60–70 % [48]. Antisecretory effects of H2RAs are best at night, with duration of acid inhibition longer when the drug is taken in the evening or before bedtime. Equally potent doses of the various H2RAs equally inhibit acid secretion.
Maintenance of symptom relief and healing with H2RAs is variable. An illustrative study [55] examined symptom relapse over four weeks in 423 patients with GERD symptoms, randomized to either a placebo or 150 mg ranitidine twice or four times daily. At the end of 24 weeks, 52 % with baseline nonerosive disease and 67 % with erosive disease experienced symptomatic relapse [31]. In an another study [56] comparing cisapride, ranitidine, and omeprazole, ranitidine 150 mg tid maintained remission in only 49 % at 1 year. Objective healing rates are somewhat better than symptom control with H2 blockers, Twelve-week healing rates as high as 70 % are seen with ranitidine at 150 mg up to four times daily [51–53] eight-week healing rates of up to 77 % at 800 mg of cimetidine twice daily [52], and famotidine 40 mg twice daily. High healing rates are unusual in clinical practice, especially with higher grades of erosive esophagitis [53, 54]. Because these results are sufficiently lower for H2RAs than for PPIs, H2RAs are rarely used as a primary prescribed GERD treatment [49, 50].
H2RAs are extremely safe. Minor GI side effects include nausea, abdominal pain, and bloating. There have been concerns about drug interactions with these agents, particularly interactions with agents affecting the cytochrome P450 system and, in particular, with cimetidine. Serum concentrations of phenytoin, procainamide, theophylline, and warfarin have been altered after administration of cimetidine, and to a lesser degree ranitidine; these effects are not seen with famotidine and/or nizatidine [57, 58]. H2RAs may not inhibit the effect of clopidogrel. The clinical consequences of these interactions are minimal and rarely result in a clinically important interaction. Awareness of these potential complications needs to be considered if H2RAs are prescribed.
PPIs provide superior control of intragastric pH over a 24-h period compared to H2RAs and effect greater symptom relief and healing (Fig. 4.1). They do so by inhibiting the hydrogen potassium ATPase in the parietal cell, the final common pathway of acid secretion [59]. Currently, there are seven PPIs available for use. Traditional delayed release PPIs are omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. Two newer formulations of PPIs have recently been added—omeprazole immediate release-sodium bicarbonate (a combination of non-enteric-coated omeprazole granules with sodium bicarbonate (OME-IR) [60] and dexlansoprazole, the R-enantiomer of lansoprazole). The latter differs from traditional delayed release PPIs by utilizing a dual delayed release technology, with two types of enteric-coated granules soluble at different pHs. It is designed such that part will dissolve in the duodenum, like the traditional delayed release PPI, and part in the distal small intestine [61].
Fig. 4.1
Relative ability of the different classes of antisecretory medications to heal esophagitis
PPIs are all weak bases that concentrate in the secretory canaliculi at pH <4. PPIs bind covalently and irreversibly to proton pumps; therefore, the degree of inhibition is related to AUC, not plasma concentration. PPIs block 70–80 % of active pumps; therefore, for acid secretion to resume, new hydrogen potassium ATPase molecules must be synthesized, a process that takes 36–96 h. Although the agents have different binding capacities, delayed release PPIs provide maximal efficacy in control of intragastric pH when taken immediately or a short time before a meal, as the drugs bind to actively secreting pumps.
Approach to the Patient
Administering PPIs before the first meal of the day, or when a second dose is needed, before the evening meal, optimizes acid control and therefore symptom relief Acid inhibition is not “complete” because of continued synthesis of new pumps [62]. When delayed release PPIs are administered twice daily, more active pumps are exposed to the drug, the steady-state inhibition of gastric acid is more rapidly achieved and more complete. Two exceptions to before meal dosing should be considered. The sodium bicarbonate in OME-IR protects the PPI granules from acid degradation and may in and of itself stimulate proton pumps. This may allow OME-IR to be effective when given at bedtime or perhaps when administered in the fasting state during the day. Dexlansoprazole uses a dual delayed release technology that results in a first peak in absorption at about 90 min after ingestion and a second 4–5 h after ingestion. The FDA label allows this drug to be given without regard to food so precise meal timing may not be required for optimal efficacy. In the vast majority of circumstances taking a PPI before the first meal of the day (usually breakfast) is still the preferred dosing regimen. Compliance seems better without a general compromise in efficacy [63].
A once daily dose should result in healing of erosive esophagitis in the vast majority (85–95 %) with minimal differences between PPIs and between studies. About 65 % will achieve “complete symptom resolution” defined as seven days without heartburn. There are patients who require an increase in dosage due to incomplete symptom relief, the presence of extra-esophageal symptoms (e.g., asthma, cough, laryngitis, and chest pain), and perhaps Barrett’s esophagus. The second dose is given before the evening meal as this provides superior intragastric pH control, particularly at night, when compared to a double dose given once daily. No data are available assessing intragastric pH control on dexlansoprazole given twice daily.
Switching PPIs when they cease to work, infrequently but occasionally, offers dramatic change in symptom relief. Observations from intragastric pH studies find wide inter-subject variability in intragastric pH control despite similar dosing regimens, which may account [64] for the occasional patient who responds to a switch from one PPI to another after one seemingly fails. Switching PPIs more than once is rarely indicated in actual practice.
Nocturnal GERD
Reflux that occurs while the patient is asleep (nocturnal reflux) whether or not it produces symptoms has the potential to be more damaging to the esophageal mucosa, as esophageal clearance is delayed during sleep.
If patients have reflux symptoms during the sleeping period on a standard once daily morning dose PPI there are several options. The single dose can be given before the dinner (evening) meal, consideration can be given to using OME-IR at bedtime, adding an H2RA at bedtime, increasing the PPI to twice daily (before breakfast and dinner or OME-IR before breakfast and bedtime), or in some cases twice daily PPI plus H2RA at bedtime. The use of OME-IR at bedtime is based on a study comparing overnight intragastric pH control in GERD patients with nocturnal symptoms treated with OME-IR 40 mg at bedtime, compared with esomeprazole 40 mg and lansoprazole 30 mg given at a similar time [65]. The former showed more rapid onset of pH control and improved overnight pH control in the vulnerable period (first 4 h of sleep) compared to the other PPIs. It is important to be aware, however, that 24-h pH control with this dosing regimen of OME-IR was not as effective as esomeprazole 40 mg given at bedtime [65].
Another potential means of controlling nocturnal reflux is to add an H2RA at bedtime to a PPI given once or twice daily to control overnight gastric pH. Once popular, this practice has diminished primarily based on studies [66, 67] that evaluated longer-term use of nocturnal H2RAs on control of intragastric pH. A clinically important number of patients will lose the initial overnight pH control (tachyphylaxis) suggesting a limit to long-term efficacy of H2RAs at bedtime. The findings of tachyphylaxis and the availability of OME-IR have limited the use of H2RAs at bedtime. In practice, an on demand H2RA at bedtime is reasonable in those situations in which night time reflux is likely to occur. Some patients experience good results with H2RAs long-term.
These studies underscore the importance of prolonged ambulatory reflux monitoring as a means of documenting the need for aggressive acid control regimen, and the need to individualize antisecretory therapy in difficult-to-treat patients. A hierarchy of intragastric pH control is outlined in Table 4.2.
Table 4.2
Hierarchy of intragastric pH control
PPI once a day |
PPI plus H2RA (OTC probably acceptable)a |
PPI bida (OME-IR at bedtime) |
PPI bid plus H2RAa |
Unexplained Chest Pain (Non-cardiac Chest Pain)
Many patients with unexplained chest pain will have GERD as the proximate cause of their symptoms. The key to managing patients with chest pain is to rule out cardiac disease prior to treatment with PPI.
A trial of antireflux therapy with a PPI is often recommended as initial therapy for suspected GERD in patients with chest pain. This so-called “PPI test” was studied in a randomized, double-blind, placebo-controlled crossover trial that evaluated one week of high-dose omeprazole as a diagnostic test for GERD in patients with non-cardiac chest pain [68]. All patients had chest pain at least three times a week. Endoscopy and 24-h ambulatory esophageal pH monitoring were performed in all. GERD was based on the presence of erosive esophagitis or abnormal 24-h pH monitoring.
The so-called “omeprazole test” (the PPI test) was diagnostic of GERD if chest pain scores improved after treatment. Seventy-eight percent of GERD-positive patients and 14 % of GERD-negative patients had positive test results, (sensitivity 78.3 % (95 % CI [confidence interval], 61.4–95.1) and specificity of 85.7 % (95 % CI, 67.4–100)), compared with endoscopy and ambulatory pH monitoring for the diagnosis of GERD. Economic analysis has estimated that this approach is cost effective.
A more recent systematic review found that PPI response compared to placebo could be predicted by endoscopy and pH studies. Incremental response to PPI over placebo is only seen in patients with an abnormal objective study [69]. This latter review suggests an early workup is perhaps the best way to avoid unneeded treatment for patients without GERD.
Extra-Esophageal Disease
There are many patients who present with a symptom other than heartburn or regurgitation that is felt to be caused by GERD. Clinical trials of treatment involving patients with extra-esophageal manifestations of GERD, specifically asthma, cough, and voice changes are few, small and in many instances uncontrolled. Early uncontrolled observations have led to the clinical impression that these patients require higher doses of PPIs (usually twice daily) for longer periods of time (up to 3–6 months) than patients with the typical symptoms of heartburn and regurgitation. Performing clinical trials in these patients is more difficult than patients with erosive esophagitis as the “gold standard” for diagnosis of GERD with extra-esophageal symptoms is not clear. As such, few randomized trials have been performed. The best of these trials offer several important generalizations:
A once daily PPI is more likely to be ineffective.
Response to symptoms is slower.
A poor response to PPI twice daily suggests a poor response to surgery.
The optimal treatment for patients with unexplained chest pain and other extra-esophageal manifestations of GERD is not clear. Until better diagnostic tests are developed, the most efficient approach is to begin empirical therapy with twice daily PPI before breakfast and dinner for two to three months (note again that dexlansoprazole has not been studied twice daily). If patients do not respond to a trial of antireflux therapy, an evaluation with prolonged ambulatory reflux monitoring with impedance/pH testing while continuing therapy may be the procedure of choice [70]. This allows assessment of both pH control and symptom correlation. In the event that pH control is incomplete—especially when overnight [71] esophageal acid exposure continues [72], and/or symptoms continue in association with continued reflux—adjustment in antisecretory therapy or addition of a reflux inhibitor may be indicated [71, 73]. Baclofen, a skeletal muscle relaxant [73], can be considered if non-acid reflux is present and associated with symptoms though the latter is not approved by the FDA. Patients successfully treated with acid suppression should be considered for long-term maintenance with PPI therapy, although no study has specifically addressed this issue (Fig. 4.2). Patients with incomplete control or onerous medical regimes may be better off with referral for antireflux surgery.
