Gastroesophageal reflux disease has a high incidence and prevalence in the general population. Clinical manifestations are heterogenous, and so is the response to medical treatment. Proton pump inhibitors are still the most common agents used to control reflux symptoms and for healing esophagitis, but they are not a one-size-fits-all solution for the disease. Patients with persistent troublesome symptoms despite medical therapy, those experiencing some adverse drug reaction, or those unwilling to take lifelong medications deserve valid alternatives.
Gastroesophageal reflux disease (GERD) is a common and increasing gastrointestinal disorder with an estimated 20% prevalence worldwide and a geographical trend towards Western countries. The last 30 years have seen an almost 80% increase in its prevalence, mainly attributed to population aging and changes in lifestyle and dietary habits linked to the obesity epidemic 
. Its chronic and recurrent course notably impacts patients’ physical and mental health. Additionally, a relevant socio-economic burden follows with both direct and indirect costs 
GERD occurs as a consequence of the failure of the normal anti-reflux barriers to protect the esophageal mucosa against a reflux of gastric content, which leads to troublesome symptoms or local complications secondary to mucosal damage, as stated in the Montreal consensus of 2006 
. The lower esophageal sphincter (LES), along with the crural diaphragm, works as a “high-pressure zone” that prevents abnormal retrograde flow of gastric content into the esophagus. In healthy individuals, the LES and the diaphragmatic hiatus open synchronously in response to swallowing or belching: in this setting, GERD represents a physiological event and can happen many times per day. When dysfunction of this “high-pressure zone” occurs, transient complete relaxations of the LES (TLESRs) not initiated by swallowing can become frequent in the postprandial period and contribute to up to 90% of reflux episodes 
. Major mechanisms involved in GERD pathophysiology also include mechanical incompetence of the LES due to a short length or a low resting pressure, impaired esophageal clearance, impaired mucosal barrier, and delayed gastric emptying. Adjunctive risk factors are the presence of hiatal hernia or an increase in intra-abdominal pressure as seen in obesity, bile acid reflux, excessive alcohol or caffeine consumption, smoking habit, and the use of certain medications such as nitrates, calcium channel blockers, antidepressants, benzodiazepines, and non-steroidal anti-inflammatory drugs 
Clinical manifestations of GERD are heterogeneous. The main presentation includes the “typical” esophageal symptoms of heartburn and regurgitation, variably accompanied by epigastric pain, dyspepsia, bloating, and dysphagia. A plethora of “atypical” manifestations are also acknowledged, defined as extraesophageal syndromes, including cardiac (e.g., non-cardiac chest pain, arrhythmias) and laryngopharyngeal or pulmonary symptoms (e.g., chronic cough, sore throat, hoarseness, globus sensation, asthma) 
The clinical history of typical symptoms combined with effective medical treatment response has traditionally been used as a cost-effective solution to formulate a presumptive diagnosis of GERD without further investigation 
. Patient self-report on symptoms is believed to be more reliable than physician assessment. Many symptom-focused self-administered questionnaires have been validated over the years as a measure of response to treatment. These questionnaires play a more important role in clinical trials than in clinical practice, and the most often employed are the Gastro-esophageal Reflux Disease Health-Related Quality of Life (GERD-HRQL) 
, GERD Questionnaire (GERD-Q) 
, Frequency Scale for the Symptoms of GERD (FSSG or F-scale) 
, and Reflux Symptom Index (RSI) for laryngopharyngeal symptoms 
Lifestyle modifications and medical treatment are widely recognized as the initial strategy for GERD treatment, as they are effective for symptomatic relief and mucosal healing in a large proportion of patients.
Weight loss and physical activity, good sleep hygiene, modifications of meal habits, and limited intake of ‘triggering’ foods are usually recommended to patients, despite controversial evidence 
Medical treatment focuses on using antisecretory drugs, including histamine receptor blockers (H2RAs), which act through the competitive inhibition of a histamine-stimulated acid secretion, and proton pump inhibitors (PPIs), which covalently bind and disable activated hydrogen potassium ATPase. A series of coadjuvant drugs are also available, including alginate-based antacid combinations, mucosal protective agents, and prokinetics.
2. Antisecretory Drugs
H2RAs played a key role until the introduction of PPIs. They can suppress both basal and stimulated gastric acid secretion by reversibly binding to the histamine H2 receptors located on gastric parietal cells; the onset of action takes about 60 min, with a range of duration from 4 to 10 h. Marketed H2RAs include cimetidine, famotidine, and nizatidine; ranitidine has been withdrawn for carcinogen contamination during manufacturing. H2RAs are generally well tolerated, with mild side effects including headache, drowsiness, fatigue, abdominal pain, constipation, or diarrhea; central nervous system side effects such as delirium or confusion have been described in elderly patients with renal or hepatic impairment.
H2RAs are approved for short-term use (intermittent, or as needed) in uncomplicated GERD, both in monotherapy and in association with antacids or PPIs at a once-daily dose at nighttime to eliminate nocturnal acid breakthrough episodes. Tachyphylaxis or tolerance, generally occurring within 7 to 14 days of continued treatment, limits their use as maintenance therapy 
. Over the past 30 years, PPIs (omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole) have progressively become the cornerstone of GERD medical treatment, proving superior to H2RAs in terms of acid suppression.
As they directly block the acid pump itself, acid secretion is inhibited for up to 36 h until replacement pumps can be synthesized; they are able to maintain intragastric pH > 4 for between 15 and 21 h daily, show superior efficacy in postprandial and nocturnal intragastric pH control, and can be used for long-term maintenance without the need for dose escalation. However, suboptimal dose timing may limit their efficacy because of a short serum half-life and the need for meal-induced ATPase activation; this leads to the necessity of preprandial dosing (about 30 to 60 min before a meal) and multiday treatment 
A 4- to 8-week course of PPIs at standard dose is highly effective in heartburn remission and mucosal healing in erosive esophagitis, with a success rate above 80%. Nevertheless, the maintenance of endoscopic remission lowers to about 65% at 12 months.
Mixed results are seen when focusing on symptoms. For patients with a full response to a first PPI course, tapering to the lowest dosage effective for symptom control is advisable for the long term. Additionally, a subset of patients can do well with intermittent or on-demand treatment, disproving the adage “once on a PPI, always on a PPI”. That being said, about one third of patients will still experience inadequate symptom control at some point, especially those with NERD or atypical symptoms 
Partial or complete failure with daily PPI therapy is referred to as refractory GERD. Many factors can contribute to a lack of response to PPIs, including an inadequate dosage or incorrect prescription, non-adherence to therapy, rapid drug metabolism, residual acid reflux due to inadequate acid suppression, nocturnal acid escape, or non-acid reflux. Nevertheless, the possibility of misdiagnosis should not be underestimated, considering FH in the first place 
. Concurrently, in the last decade, a growing number of publications have warned about the potential adverse effects of long-term PPI therapies, such as the risk of small intestinal bacterial overgrowth (SIBO) and micronutrient malabsorption, intestinal infections including Clostridium difficile, osteoporosis-related fractures, kidney disease, dementia, cardiovascular events, and gastric cancer 
. Even though no certain causality has been established, clinicians and patients have felt increasingly encouraged to investigate alternative non-drug therapeutic approaches.
3. Antacids, Alginate, and Mucosal Protective Agents
Antacids are compounds containing sodium bicarbonate, aluminum hydroxide, magnesium hydroxide, magnesium carbonate, or calcium carbonate, which buffer excess gastric hydrochloric acid and inhibit pepsin activity; they offer rapid but temporary symptomatic relief. For a protracted effect, combinations of alginate and low-dose antacids are used; alginate is a natural polysaccharide polymer that acts as a mechanical barrier, forming a gel raft that displaces and neutralizes the post-prandial “acid pocket” in the proximal stomach. The latest developed formulations contain hyaluronic acid and chondroitin-sulphate on a bioadhesive carrier, which form a protective layer to favor mucosal hydration, healing, and regeneration 
Patients reporting mild to moderate intermittent reflux symptoms can consider alginate-based antacid combinations and mucosal protective agents as initial therapy because of their efficacy on demand, safety profile, and over-the-counter availability. These drugs are useful for relieving both heartburn and laryngopharyngeal symptoms; they can also have a role as an add-on to H2RAs or PPIs in patients with an incomplete response. Central to their efficacy is the ability to target reflux mechanisms not strictly related to the acid content, such as pepsin’s proteolytic activity, an impaired mucosal barrier, or visceral hypersensitivity 
Regarding prokinetics, such as metoclopramide, domperidone, or levosulpiride, there is no high-quality evidence to recommend their routine use in GERD. However, a benefit from their usage exists for patients with associated delayed gastric emptying or gastroparesis 
4. Potassium-Competitive Acid Blockers (PCABs)
The latest innovation in the medical management of GERD is represented by potassium-competitive acid blockers (PCABs), with the first-in-class named Vonoprazen. Their mechanism of action consists of preventing potassium ions from binding to gastric ATPase, providing reversible acid suppression. Vonoprazen has been approved in Japan since 2015 for treating GERD, peptic ulcer disease, and Helicobacter pylori infection. More recently, its safety and efficacy have been proved in PPI refractory GERD. Food and Drug Administration (FDA) approval came in 2022, but the drug is not marketed in Europe yet