Gastroesophageal%20reflux%20disease Treatment

Treatment Goals

• Relief of symptoms
• Healing of esophagitis
• Prevention of recurrence and complications
• Improvement of quality of life

Empiric Therapy 

• Current consensus is that for patients with uncomplicated reflux symptoms, empiric therapy is the appropriate initial management 
• Patients presenting with typical symptoms of gastroesophageal reflux disease (GERD) in the absence of long-standing, frequently recurring, progressive alarm symptoms or complicated disease may be started on empiric treatment without further investigation
• Acid suppressive therapy is currently the mainstay of treatment for symptom relief in GERD in both acute and long-term treatment
  • Proton pump inhibitor is the drug of choice and recommended as initial therapy because of its superior safety
  • Patients with chest pain or GERD-related non-cardiac chest pain should have a thorough initial cardiac evaluation prior to starting empiric therapy
• Short course therapy is effective in GERD patients treated empirically and duration varies from 2-8 weeks
  • Should be tried for 2 weeks for patients with typical GERD symptoms
  • Patients who present with atypical or extraesophageal manifestations take a longer time to respond to empiric therapy and often require twice-daily dosing for at least 12 weeks

Proton Pump Inhibitors (PPIs)

• Eg Dexlansoprazole, Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole
• Most potent type of acid suppressants
  • Provide most rapid symptom relief and heal esophagitis in the highest proportion of patients
    • Rabeprazole's high pKa gives it a slightly faster onset of action and since it is metabolized to a lesser extent via CYP2C19, gene polymorphism does not influence its gastric acid suppression
  • Cornerstone of therapy for erosive esophagitis when given at standard dose once daily for 8 weeks
• Recommended for both moderate and severe GERD and its complications (eg Barrett's esophagus, ulcerations, bleeding, strictures, malignancy)
  • No clear advantage has been shown with the use of one PPI over another in GERD therapy
• PPIs are substituted benzimidazoles that irreversibly bind the H+/K+ ATPase, the final step in gastric acid secretion
• Should be given 30-60 minutes prior to meals to give PPIs time to interact with an activated pump
  • Dexlansoprazole can be taken with or without food
• On-demand therapy with PPI is used where symptom control is the primary objective (eg patients with esophageal GERD syndrome without esophagitis or mild erosive GERD)
• Continuous therapy with PPI is recommended to maintain a healed mucosa, preventing recurrence of symptoms (eg in patients with erosive esophagitis)
• Generally well tolerated; side effects reported were minor such as diarrhea, abdominal pain, headache which resolve as treatment is discontinued
• Superiority in the treatment of reflux esophagitis is supported by several reviews and trials
• Recommended empirical therapy for patients with non-cardiac chest pain given twice daily for 4 weeks
• Initial management for patients with suspected extraesophageal reflux syndrome
  • Once- or twice-daily therapy for at least 12 weeks as empiric therapy
  • Patients with partial response to once-daily therapy, adjust dose timing and/or consider twice-daily dosing, especially in patient with nighttime symptoms, sleep disturbance, or variable schedules
  • A specialist referral should be considered if patient fails empiric therapy with PPI as non-GERD etiologies must be excluded
• Pregnant patients with GERD may be given a short-term PPI in the last two trimesters of pregnancy if clinically indicated
  • Other options include histamine₂-receptor antagonists (H₂RAs), eg Ranitidine, and antacids except for preparations containing sodium bicarbonate

Histamine₂-Receptor Antagonists (H₂RAs)

• Eg Cimetidine, Famotidine, Nizatidine, Ranitidine, Roxatidine
• Recommended in divided doses for symptomatic relief of milder forms of GERD
• Have a role in inhibiting nocturnal acid secretion in mild erosive esophagitis or non-erosive reflux disease (NERD)
  • When given either after an evening meal or at bedtime, H₂RAs often provide effective nighttime relief
  • When given as a supplement to PPI therapy, only a small dose of H₂RAs at bedtime is recommended and given at a well-separated time from PPI evening dose
  • Can be used on a short-term basis as tachyphylaxis can occur with long-term therapy
• Decrease gastric acid production, particularly in the postprandial state, without affecting esophagogastric barrier dysfunction
• Associated with a low incidence of adverse effects (4%)
• May be given intermittently to patients intolerant of PPIs
• Numerous, randomized, controlled trials have shown that standard dose of H₂RAs is more effective than placebo in the treatment of reflux symptoms and healing of esophagitis

Potassium-Competitive Acid Blocker (PCAB)

• Eg Vonoprazan
• Reversibly inhibits the activity of H⁺/K⁺ ATPase by competing for potassium on the luminal side of the parietal cell
• Indicated for reflux (erosive) esophagitis  
• A promising treatment option for patients with PPI-resistant GERD, including NERD and PPI-resistant NERD, but further studies are recommended
• Has faster onset of action compared to PPI and absorption is not affected by food

Maintenance Therapy

• Goal is to have a symptom-free patient without esophagitis
• Use the lowest dose and least potent medication that can obtain a complete and sustained symptomatic response
• The need for maintenance therapy is determined by the impact of the residual symptoms on the patient’s quality of life
• Type of maintenance therapy based on duration of treatment:
  • Continuous maintenance therapy refers to daily administration of treatment for months or even years to prevent relapse of GERD symptoms
    • Given mainly for those with frequent symptoms, strictures, or moderate to severe erosive reflux disease
  • Discontinuous therapy is either intermittent or on-demand
    • Intermittent therapy is patient-initiated short courses of therapy with a fixed duration taken even after symptoms have resolved
    • On-demand therapy is when patient starts treatment when symptoms occur and continues until these are gone
    • Both intermittent and on-demand therapy are recommended for long-term maintenance of acid suppression and in patients with mild symptoms and with PPI-responsive NERD

Options for Chronic Acid Suppression:

• Step-up therapy involves starting treatment with the less potent agents and moving up for treatment response
  • If patient does not respond to an H₂RA within 2 weeks, switch to PPI
  • If patient does not respond to the standard once-daily treatment for 8 weeks, double the dose of the same PPI (30 minutes prior to breakfast and 30 minutes prior to dinner)
    • Other therapeutic options to consider in PPI-resistant GERD include switching to a different PPI or PCAB, changing medication time, or adding a prokinetic agent, an alginate or an H₂RA at night 
  • If patient still does not respond to above regimens, patient’s symptoms are likely not secondary to reflux and warrant diagnostic testing

• Step-down therapy makes use initially of a potent acid suppressant, then decreasing dose or switching to less-potent agents
  • Begins with the patient taking PPI for 8 weeks, followed by an H₂RA if GERD symptoms were adequately controlled with a PPI
  • This is followed by stepping down further to on-demand use of antacids if patient was asymptomatic while taking an H₂RA
  • Majority of patients who experienced symptom relief after being placed on more than a single daily dose of PPI can be successfully stepped down to single-dose therapy without recurrence of reflux symptoms

• Maintenance treatment for GERD is recommended at the lowest effective dose
  • Step-down therapy should be attempted

• Chronic PPI therapy for adequate symptom control
  • Even with adequate symptom control and PPI tolerability, the likelihood of long-term spontaneous remission of the disease is low
  • Though PPIs are generally safe with long-term use, careful consideration is required in patients at risk for complications, eg iron deficiency, vitamin B12 deficiency, increased susceptibility to enteric infections, microscopic colitis, fractures and pneumonia

• For patients with suspected extraesophageal GERD syndrome with a concomitant esophageal GERD syndrome, maintenance therapy with once- or twice-daily PPIs

Adjunctive Pharmacotherapy

Antacids and Alginates

• Effective in short-term or intermittent symptom relief; antacid-alginate combination is recommended for episodic and postprandial reflux symptoms
• Usually taken after each meal and at bedtime
• Alginate reacts with gastric acid creating a viscous gel or raft above the gastric contents that acts as a mechanical barrier to reduce reflux into the esophagus
  • Mode of action is physical and does not depend on systemic absorption

Propulsives/Prokinetic Agents

• Eg Domperidone, Metoclopramide, Itopride, Mosapride
• Effective in patients with mild symptoms
• Domperidone has the advantage of having less pyramidal effects
• Oral Metoclopramide may be given to patients unresponsive to conventional therapy
• Combination of Mosapride with a PPI may have additional benefit when PPI monotherapy does not have satisfactory results, particularly in PPI resistance 
  • Studies show that Mosapride does not have any significant cardiovascular effects even with concomitant administration of Ketoconazole and Erythromycin; Mosapride does not block D₂ receptor hence does not cause extrapyramidal effects   
• Long-term use is not recommended because of risk of neurological, cardiac and other adverse effects
  • Treatment should be at the lowest effective dose and kept as short as possible

Refractory GERD

• It is the persistence of troublesome GERD symptoms in compliant patients despite standard treatment or twice-daily dosing of PPI for at least 8 weeks  
  • Troublesome symptoms impair patient's quality of life and may cause sleep disturbance and affect work 
• Patients with NERD commonly have PPI-resistant GERD symptoms
• Causes included inadequate acid suppression, weakly acidic/non-acidic reflux, reflux sensitivity or other non-reflux causes such as functional heartburn, dysmotility, eosinophilic esophagitis or overlap syndrome with IBS and visceral hypersensitivity  
• Impaired PPI treatment response may also be related to increased body weight and P450 system genotypes which affect PPI metabolism
• Further evaluation may be considered in PPI therapy non-responders and may include an upper GI endoscopy with or without enhanced imaging and function testing (ambulatory pH monitoring and 24-hour combined impedance-pH studies/esophageal manometry)       
  • Patients with suspected extraesophageal symptoms and have failed PPI therapy should be evaluated for non-GERD causes prior to starting GI evaluation with endoscopy or function testing   
• Therapeutic options to consider include increasing the PPI dose, switching to a different PPI or PCAB, changing medication time, or adding a prokinetic agent, an alginate or an H₂RA at night