As a drug class, H₂RAs are well tolerated, have few side effects, and are generally safe to use. The most common side effects are gastrointestinal, including nausea, vomiting, abdominal pain or bloating, diarrhea, and constipation. Other side effects include headaches, dizziness, and rashes. H₂RAs are metabolized through the liver cytochrome P450 pathway. This raises the possibility of drug–drug interactions, especially with other agents that are also metabolized through the same pathway. This is particularly the case with cimetidine, the first H₂RA. Serum concentrations of several drugs are altered following administration of cimetidine including warfarin, theophylline, phenytoin, lidocaine, procainamide, tramadol, and beta-blockers. Cimetidine is also a competitive antagonist of the dihydrotestosterone (DHT) receptor. This was shown to lead to galactorrhea in women and gynecomastia in men. The more recently developed H₂RAs are not as potent inhibitors of the cytochrome P450 pathway and appear less likely to significantly alter the metabolism of other agents. It does not appear that H₂RAs affect the serum concentration of clopidogrel.

PPIs demonstrate superior pH control over H₂RAs over a 24-h period. While omeprazole, OME-IR, rabeprazole, pantoprazole, and lansoprazole all provide a similar degree of intragastric pH control (11–13 h with pH > 4), esomeprazole at 40 mg daily dosing does provide a slightly longer duration of control (Fig. 5.2) [20, 21]. The newest PPI, dual-release dexlansoprazole, has been shown to maintain pH > 4 for up to 17 h with once-daily administration [16].

While PPIs may not lead to complete symptom relief in all patients, they are superior to H₂RAs in their capacity to improve symptoms [22] . In addition, compared with H₂RAs, PPIs have shown superior healing rates in patients with erosive esophagitis [23]. A large meta-analysis of 43 articles in 1997 showed superior healing of all grades of erosive esophagitis and heartburn relief when using PPIs, as compared with H₂RAs, sucralfate, or placebo [22]. The mean overall healing percentage irrespective of drug dose or treatment duration ( ≤ 12 weeks) was the highest with PPIs (83.6± 11.4 %) versus H₂RAs (51.9 ± 17.1 %), sucralfate (39.2 ± 22.4 %), or placebo (28.2 ± 15.6 %). The mean heartburn-free proportion of patients was highest with PPIs (77.4 ± 10.4 %) versus H₂RAs (47.6 ± 15.5 %), and PPIs showed a significantly faster healing rate (11.7 %/week) versus H₂RAs (5.9 %/week) and placebo (2.9 %/week).

While all PPIs have similar healing rates of erosive esophagitis after 8 weeks of treatment, esomeprazole 40 mg has shown a small advantage when compared with omeprazole 20 mg, pantoprazole 40 mg, and lansoprazole 30 mg [24–26]. Esomeprazole’s advantage is mostly seen with LA grades C and D esophagitis. Another large meta-analysis in 2006 compared rates of esophagitis healing and symptom relief with esomeprazole versus alternative PPIs (except OME-IR and dexlansoprazole) [27]. The analysis included 10 studies and 15,136 patients. At 8 weeks, there was a 5 % (relative risk, RR, 1.05; 95 % CI 1.02–1.08) relative increase in the probability of erosive esophagitis healing with esomeprazole, which led to an absolute risk reduction of 4 % and a number needed to treat (NNT) of 25. The calculated NNTs by LA grades A through D were 50, 33, 14, and 8, respectively. Esomeprazole also led to an 8 % (RR, 1.08; 95 % CI 1.05–1.11) relative increase in the probability of GERD symptom relief at 4 weeks .

In a comparative trial of dexlansoprazole 60 or 90 mg daily with lansoprazole 30 mg daily for 8 weeks, dexlansoprazole achieved non-inferiority to lansoprazole [28]. Dexlansoprazole achieved healing rates of 92–95 % of patients in individual studies versus 86–92 % for lansoprazole, but the difference was not statistically significant (p > 0.025). However, in an integrated analysis of healing in patients with moderate-to-severe erosive esophagitis (LA grades C and D), dexlansoprazole was superior to lansoprazole at healing severe disease. Figure 5.3 shows a summary of healing rates at 8 weeks among various PPIs [21, 24–26, 28, 29].

Many GERD patients suffer from nocturnal symptoms, which is likely an underappreciated problem. While sleeping, the body’s natural defense mechanisms against GERD, such as saliva production and peristalsis, are significantly reduced. Nocturnal reflux can significantly impact quality of life and lead to sleep disturbances. Critical to symptom control is maintaining a gastric pH > 4. However, intragastric pH monitoring studies show that despite being on twice-daily PPI therapy, overnight pH can drop to less than 4 for over an hour [33]. This is called nocturnal acid breakthrough (NAB).

Patients with NAB have several treatment options: (1) single-dose PPI can be administered before the evening meal, (2) patients can be placed on a PPI before breakfast and OME-IR or an H₂RA at bedtime, or (3) patients can be placed on twice-daily PPI plus an H₂RA at bedtime. One study of 49 patients found that bedtime administration of OME-IR had superior overnight intragastric pH control compared with lansoprazole and esomeprazole [34]. H₂RAs are used most commonly to optimize overnight pH control when given at bedtime as an adjunct to PPI therapy. One small study of 12 volunteers found that omeprazole 20 mg twice daily plus ranitidine (150 mg or 300 mg) at bedtime provided superior overnight pH control compared with omeprazole 20 mg twice daily plus an additional omeprazole dose at bedtime [35]. Another study of 105 GERD patients on PPI twice daily (60 patients) or PPI twice daily plus an H₂RA at bedtime (45 patients) showed that the median percentage time that gastric pH remained > 4 was 51 % in the twice-daily PPI group compared with 96 % in the twice-daily PPI plus bedtime H₂RA group [36]. This contrasts with another study of 22 patients (13 with GERD and 9 controls) which evaluated pH control after each of four treatment regimens: (1) omeprazole 20 mg twice daily for 2 weeks, (2) omeprazole 20 mg twice daily plus ranitidine 300 mg at bedtime for 4 weeks, (3) omeprazole 20 mg before breakfast and at bedtime for 2 weeks, and (4) omeprazole 20 mg every 8 h for 2 weeks [37]. Results showed that the treatment regimens resulted in NAB elimination in 9–41 % of patients. However, no single treatment regimen resulted in more significant NAB control than the others and there were not any differences in percentage time that pH was < 4 for any treatment regimen .

There is concern over H₂RA tolerance, that is, the potential that H₂RAs may lose their effect following prolonged use. One study of 20 GERD patients and 23 healthy volunteers obtained baseline pH testing and then administered 2 weeks of omeprazole 20 mg twice daily before meals [38]. pH testing was then repeated. Subjects next received 4 weeks of PPI plus ranitidine 300 mg at bedtime, and pH testing was obtained on days 1, 7, and 28. Results showed that combination PPI and H₂RA therapy reduced NAB only with the introduction of therapy. No difference in acid suppression between the twice-daily PPI and twice-daily PPI plus H₂RA groups was seen following 1 week of combination therapy. In the majority of patients following 1 month of H₂RA therapy, gastric acidity returned to pre-H₂RA levels.

While many patients may develop tolerance to H₂RAs, clinical experience has shown that some patients have a sustained response. The most recent American College of Gastroenterology (ACG) guidelines state that a bedtime H₂RA can be added to daytime PPI therapy in patients with evidence of nighttime reflux [31]. To reduce the chance of drug tolerance, as-needed use of an H₂RA at night might be more practical if the patient eats late or has an unusually large evening meal .

The majority of GERD patients have a normal endoscopy and, therefore, NERD. Among patients who experience symptoms of heartburn with NERD, PPI therapy has been shown to be superior to H₂RAs and prokinetics . In a large Cochrane systematic review of 32 trials, the RR for heartburn remission in placebo-controlled trials for PPIs was 0.37 (two trials, 95 % CI 0.32–0.44), for H₂RAs was 0.77 (two trials, 95 % CI 0.6–0.99), and for prokinetics was 0.86 (one trial, 95 % CI 0.73–1.01) [39]. In a direct comparison of PPIs and H₂RAs, PPIs were more effective at achieving heartburn remission (seven trials, RR 0.66, 95 % CI 0.6–0.73). In the treatment of endoscopy-negative reflux disease, the RR for heartburn remission for PPI versus placebo was 0.71 (ten trials, 95 % CI 0.65–0.78) and for H₂RA versus placebo was 0.84 (two trials, 95 % CI 0.74–0.95). The RR for PPI versus H₂RA was 0.78 (three trials, 95 % CI 0.62–0.97). The authors’ conclusion was that PPIs are more effective than H₂RAs in relieving heartburn in patients with endoscopy-negative reflux disease, although the magnitude of benefit was greater for those treated empirically [39].

Interestingly, however, early studies have also shown that patients with NERD may not respond as well to PPIs as patients with erosive disease . One study compared omeprazole 10 or 20 mg once daily with placebo in patients with heartburn , but without endoscopic signs of esophagitis [40]. Following 4 weeks of treatment, only 46 and 31 % of patients in the 20 and 10 mg groups, respectively, reported complete absence of heartburn, while 13 % in the placebo arm reported absence of heartburn. While superior to placebo, the rate of symptomatic relief was lower than reported in most erosive esophagitis trials. A second study of 209 patients comparing omeprazole 20 mg daily to placebo found similar results [41]. Following 4 weeks of treatment, only 43 % of patients were completely asymptomatic from heartburn and regurgitation , again a lower rate than most erosive esophagitis trials. Another study compared a 4-week trial of omeprazole 20 mg and 10 mg once daily in 277 patients with erosive esophagitis and 261 patients without erosive esophagitis [42]. Only 29 % of patients with nonerosive disease reported complete symptom relief on omeprazole 20 mg at 4 weeks, while 48 % of patients with erosive esophagitis reported relief.