Gastroesophageal reflux disease (GERD), a common disorder with troublesome symptoms caused by reflux of gastric contents into the esophagus, has adverse impact on quality of life. A variety of medications have been used in GERD treatment, and acid suppression therapy is the mainstay of treatment for GERD. Although proton pump inhibitor is the most potent acid suppressant and provides good efficacy in esophagitis healing and symptom relief, about one-third of patients with GERD still have persistent symptoms with poor response to standard dose PPI. Antacids, alginate, histamine type-2 receptor antagonists, and prokinetic agents are usually used as add-on therapy to PPI in clinical practice. Development of novel therapeutic agents has focused on the underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxation, motility disorder, mucosal protection, and esophageal hypersensitivity. Newer formulations of PPI with faster and longer duration of action and potassium-competitive acid blocker, a newer acid suppressant, have also been investigated in clinical trials. In this review, we summarize the current and developing therapeutic agents for GERD treatment.
Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder in the general population, and its prevalence is increasing worldwide [
There are many factors contributing to GERD, including transient lower esophageal sphincter relaxation (TLESR), reduced LES pressure, impaired esophageal mucosal defense, poor esophageal clearance, visceral hypersensitivity, hiatal hernia, and delayed gastric emptying, and TLESRs is the predominant mechanism of reflux formation [
Acid suppression is the mainstay of therapy for GERD and proton pump inhibitors (PPIs) are the most potent drug in this regard. Although the use of PPIs is the treatment of choice for GERD, still approximately one-third of patients with GERD fail to response symptomatically to a standard dose PPI, either partially or completely [ Antacids Alginate Sucralfate Acid suppressants Histamine type-2 receptor antagonist Proton pump inhibitor Potassium-competitive acid blocker TLESR reducers mGluR5 antagonist Prokinetic agents Metoclopramide Domperidone Tegaserod Mosapride Itopride Rikkunshito Pain modulators Tricyclic antidepressants Trazodone Selective serotonin reuptake inhibitors Serotonin-norepinephrine reuptake inhibitor Theophylline.
Before H2RA development, antacids were widely used as initial treatment for patient with reflux symptoms. Antacids are compounds containing different combinations, such as calcium carbonate, sodium bicarbonate, aluminum, and magnesium hydroxide. They provide rapid but short-term symptom relief by buffering gastric acid. Antacids are a convenient over-the-counter treatment for GERD, but only one-quarter of patients have symptom relief after antacid use. Nevertheless, these drugs have no efficacy in healing erosive esophagitis [
Alginate is anionic polysaccharide occurring naturally in brown algae and has a unique property different from traditional antacids. Alginate and bicarbonate, usually contained in alginate-based formulations, interact with gastric acid to form a foamy gel, and this foamy gel, like a raft floating on the surface of gastric contents, creates a relative pH-neutral barrier [
Sucralfate, a complex salt of sucrose sulfate and aluminum hydroxide, contributes to mucosal protection by several different actions. It provides a physical barrier to block diffusion of acid, pepsin, and bile acids across esophageal mucosa and attenuate the erosive injury of acid and alkali. The potential benefits of sucralfate include mucosa repair and ulcer healing [
Before development of PPIs, H2RAs were the first acid-suppressive agents and have better efficacy than antacids in healing of erosive esophagitis and alleviating reflux symptoms. H2RA reduces gastric acid output as well as gastric acid volume by competitive inhibition of histamine at H2 receptors and reducing pepsin secretion. However, patients with severe erosive esophagitis have poorer therapeutic response to H2RA, and most patients with GERD have only improved, but not eliminated, reflux symptoms after H2RA use. H2RAs also have their limitations in treating erosive esophagitis, such as their relatively short duration of action (compared with PPIs), development of tolerance, and incomplete inhibition of acid secretion in response to a meal [
Although H2RAs are not as effective as PPI in acid suppression, the potential effect of H2RAs on the nighttime histamine-driven surge in gastric acid secretion makes H2RAs an add-on therapy for patients with nighttime symptoms on PPI treatment such as nocturnal acid breakthrough (NAB). NAB is defined as a gastric pH < 4 for a period greater than 1 hour overnight in patients on twice-daily PPI therapy and occurs in more than 70% of patients on PPI therapy [
PPI blocks the gastric
Although PPI is the most successful acid suppressant in the treatment of GERD, unsatisfactory results still exist during PPI therapy. Fifty-nine percent of GERD patients with long-term PPI therapy still have persistent reflux symptoms [ Non-reflux-related causes Esophageal motility disorder, like achalasia, scleroderma Other esophagitis, like eosinophilic, pill, infection Functional heartburn or functional chest pain Reflux-related causes Compliance Rapid PPI metabolism (CYP2C19 polymorphisms) Nocturnal acid breakthrough Gastric acid hypersecretory states, like Zollinger-Ellison syndrome Anatomic abnormality, like large hiatal hernia Delayed gastric emptying Weakly acidic reflux Duodenogastroesophageal (bile) reflux Impairment of esophageal mucosal integrity Esophageal hypersensitivity Psychological comorbidity, like depression, anxiety, life stress Concomitant functional bowel disorder.
Traditional PPIs (omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole) have relatively slow onset of action and provide insufficient 24-hour suppression of gastric acid under a once-daily dosage regime. Novel PPIs have been designed to improve the PPI efficacy with the advantage of rapid onset of action, extended-released profile, and longer half-life.
Tenatoprazole is a novel PPI characterized by an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors. Tenatoprazole has longer plasma half-life in comparison with other PPIs, providing a prolonged duration of acid inhibition and a shorter nocturnal acid breakthrough [
Traditional PPIs are DR PPI because they are acid-labile and need enteric coating to prevent degradation in the stomach, resulting in relatively slow onset of pharmacological action. Traditional PPIs require several doses to achieve adequate acid suppression but fail to achieve adequate 24-hour acid suppression, allowing nocturnal acid breakthrough. Unlike DR PPI, immediate-release (IR) omeprazole is a formulation of nonenteric-coated omeprazole combined with sodium bicarbonate, which protects omeprazole from degradation by gastric acid, and is characterized by more rapid onset of antisecretory action compared with DR PPIs. Based on administration time, IR omeprazole provides profound control of postprandial and nocturnal intragastric acidity. The faster action of IR omeprazole is not influenced by concomitant antacid or food, which attenuates the efficacy of traditional DR PPI on acid suppression [
Extended-release (ER) rabeprazole is designed to provide initial acid suppression similar to DR PPI and maintain the plasma exposure of PPI over a longer period, achieving sufficient duration of acid suppression over a 24-hour period. Each ER rabeprazole formulation contains a single rabeprazole enteric-coated DR tablet and multiple rabeprazole pulsatile-release tablets, with prolonged pharmacodynamics effect performed by releasing rabeprazole in the intestine and colon separately. A study conducted in healthy volunteers showed that once-daily ER rabeprazole demonstrated a significantly longer gastric acid suppression (mean percentage of time with gastric pH > 4) over a 24-hour period compared with esomeprazole 40 mg and standard DR rabeprazole 20 mg, and formulations containing 50 mg ER rabeprazole showed the best pharmacodynamics profile compared with other dosages [
VECAM is a combination of a PPI and succinic acid (an acid pump activator that has the same acid-stimulating activity as pentagastrin) and has a meal-independent antisecretory effect. Coadministration of succinic acid with PPI resulted in augmented PPI effects in animal models. A recent study that evaluated efficacy of once-daily VECAM and omeprazole in healthy volunteers showed that VECAM was significantly better in maintaining intragastric pH > 4 during the nighttime than omeprazole 20 mg, which may provide a therapeutic gain in nocturnal symptom control [
Long-term use of PPI as maintenance treatment raises the concern of long-term safety of PPI use. Several studies suggest that PPI use may be associated with osteoporotic fractures, enteric infections, community-acquired pneumonia, benign fundic gland polyps, malabsorption of calcium, magnesium, vitamin B12, and iron and decreasing efficacy of clopidogrel. However, most of these results came from observation in epidemiologic case-control studies, and many confounders may contribute to these associations. To date, the evidence of serious side effects from long-term PPI use is poor, and absolute risk of complications attributed to PPIs is low [
Potassium-competitive acid blockers (P-CABs) are another class of acid suppressants developed in the last few years and inhibit proton pumps via a different mechanism than PPIs. By competing with binding of the potassium-binding site of proton pump, P-CABs reversibly inhibit gastric
TAK-438 is a new type of P-CAB developed recently and has a slower dissociation rate from proton pumps than other P-CABs by higher pKa. In animal studies, TAK-438 showed a more potent and longer-lasting antisecretory effect than lansoprazole and other P-CABs [
TLESRs are defined as periods of spontaneous, simultaneous relaxation of the lower esophageal sphincter and crural diaphragm. Reflux of gastric content during TLESRs causes reflux symptoms, and TLESRs are the main mechanism of all types of gastroesophageal reflux, including acid and nonacid reflux episodes [
GABAB receptors are located at many sites within the central and peripheral nervous systems. GABA, as a major inhibitory neurotransmitter within the central nervous system, controls TLESRS by GABAB receptors expressed in LES-projecting neurons of the vagal nerve and the subnucleus centralis of the nucleus tractus solitarius. Other than effect from central nuclei, peripheral GABAB receptors also have inhibitory effect on gastric vagal mechanoreceptors and gastric distention-related TLESRs [
Baclofen, usually used in the management of spasticity, is a prototypical GABAB agonist and has effects in the control of TLESRs, initially noted in animal and healthy human studies [
Arbaclofen placarbil is an actively transported prodrug of the active R-isomer of baclofen and is efficiently absorbed throughout the intestine and colon, which allows it to be developed in a sustained release formulation. Arbaclofen placarbil has lower dosing frequency and more stable plasma concentration compared with baclofen to improve the safety profile [
Lesogaberan, a GABAB agonist that does not cross the blood-brain barrier and mainly acts on peripheral GABAB receptors, is designed to overcome the side effects of baclofen. In healthy volunteers, lesogaberan significantly reduces the number of TLESRs by 36% and acid reflux episodes by approximately 44% and increases LES pressure by 39% compared with placebo [
Glutamate is the primary neurotransmitter involved in signalling from visceral and somatic primary afferents to the central nervous system. Peripherally located mGluR5 receptors have been associated with control of TLESRs, noted by animal studies initially, and mGluR5 antagonists are considered as potential therapy for patient with GERD [
ADX10059 is a potent selective negative allosteric modulator of the mGluR5 and is the most extensively studied agent of mGluR5 antagonists. In the first proof-of-concept study, two groups of 12 patients with GERD demonstrated ADX10059 250 mg three times daily significantly reduced esophageal acid exposure and symptomatic reflux episodes and were welltolerated [
AZD2066 is a novel elective, noncompetitive antagonist of mGluR5 and has been studied in healthy volunteers. In a randomized crossover study, AZD2066 significantly reduced TLESRs and reflux episodes in healthy volunteers and had acceptable safety and tolerability profile [
Function of gastroesophageal motility is an important factor influencing the pathophysiology of GERD, and disordered gastroesophageal motility includes reduced LES pressure, ineffective esophageal motility, and delayed gastric emptying [
Mosapride, a prokinetic with selective 5-HT4 receptor agonist and weak 5-HT3 receptor antagonist actions, is effective in reducing acid reflux in the esophagus by improving esophageal motility and gastric emptying. Furthermore, mosapride is well tolerated and no serious adverse events are reported [
Itopride, a D2 antagonist with anticholinesterase activity, accelerates gastric emptying through both antidopaminergic and antiacetylcholinesterase actions. It is usually used in the treatment of patients with functional dyspepsia and has good efficacy in postprandial fullness and early satiety. A pilot study conducted in 26 patients with GERD symptoms showed that itopride 100 mg three times a day improved GERD symptoms and decreased esophageal acid exposure, and no serious adverse events were noted [
Rikkunshito, a traditional Japanese medicine, is composed of eight crude herbs and is widely used in Japan for patients with various gastrointestinal symptoms such as anorexia, nausea, and vomiting. Rikkunshito ameliorates the effects of nitric oxide-mediated gastric function to improve gastric emptying; besides, it also increases ghrelin levels, a potent stimulant for gastric emptying and gastrointestinal motility [
Visceral hypersensitivity has been suggested to be an important mechanism of refractory GERD in patients with NERD and functional heartburn. The pathophysiology of esophageal hypersensitivity is complex, and visceral hypersensitivity resulting from upregulation of nociceptive pathways by peripheral and central sensitization and psycho neuroimmune interactions is proposed. Heightened perception threshold and response function for stimulus within physiology range, like weakly acidic, nonacidic, or bile reflux, cause chest pain, heartburn, or reflux symptoms in these patients [
Transient receptor potential vanilloid 1 (TRPV1) is a polymodal receptor, sensitive to noxious heat, change in pH (acidosis and alkalosis), endovanilloids, and numerous pungent plant products such as capsaicin, piperine, and eugenol, and it can be both upregulated and sensitized during inflammation and injury via peripheral and central nervous pathways. Studies have demonstrated that TRPV1 is a critical channel for mediating thermal hyperalgesia from noxious heat stimulation in mice, and these results have generated great interest in developing TRPV1 antagonists as pain modulators [
The mechanisms of refractory GERD are complicated, and clarification of the possible causes of PPI failure is important to deal with these patients. Compliance to therapy should be checked first by physician, and the presence of functional gastrointestinal disorders, psychological distress, functional heartburn, or other esophagitis not related to reflux should also be carefully evaluated in these patients.
With some proven benefits, switching to another PPI or doubling the PPI dose has become the most common therapeutic strategy for patients who failed PPI once-daily treatment in clinical practice. When prescribing high-dose PPI, the dose is given twice daily before breakfast and dinner to have better control of intragastric pH [
To date, PPIs are still the most effective therapeutic tool and should be suggested as mainstay of treatment in patients with GERD. If symptoms continue despite adequate PPI use, the poor compliance or inadequate dosing time should be excluded before diagnosing refractory GERD in patients with poor response to PPI. The causes of refractory GERD are complex, and symptoms from weakly acidic or nonacid reflux suggest that acid suppression cannot be the only solution for all patients with GERD. New PPI formulations and new acid suppressants, P-CABs, have not shown clinical superiority to current PPIs. Nevertheless, newer PPI formulations with longer duration of action provide additional benefit in patients with poor compliance or nocturnal symptoms. In addition to PPI, TLESR reducers have been considered as the most promising strategies in the management of GERD. However, the therapeutic gain of TLESR reducers observed in patients with GERD was relatively small. Prokinetics have potential role as add-on therapy to PPIs and may provide additional benefit in special groups. Pain modulators that attenuate esophageal hypersensitivity are in the early phase of development, and the efficacy as well as tolerability needs further investigation. Overall, the target population for these new therapeutic agents remains to be defined by future studies. Despite the well-established benefits of current PPIs in the management of GERD, unmet needs are still present and require further pharmacologic development to provide viable options for better GERD treatment.
The authors are thankful for the supports from Excellence for Cancer Research Center Grant, DOH102-TD-C-111-002, Department of Health, Executive Yuan, Taiwan, and Kaohsiung Medical University Hospital (KMUH101-1R02 and KMUH101-1R01).