Biography - Avril Ryan holds an M.Pharm from Liverpool John Moore’s University (2007) and a B.A.Mod in Biochemistry, from Trinity College, Dublin (2003). Avril completed her Pre-registration training in Belfast City Hospital and currently works as Pharmacist Manager in Unicare/DocMorris Pharmacy in North Dublin.

CPD 22: GASTRO-OESOPHAGEAL REFLUX DISEASE

Gastro-oesophageal reflux disease

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60 Second Summary GORD is defined as symptoms and/or tissue damage caused by the backward flow of gastric contents into the oesophagus.

Symptoms include heartburn, dysphagia and regurgitation.

Exact causes remain uncertain, however a compromised lower oesophageal sphincter is known to play a role.

Lifestyle advice to reduce symptoms includes; weight loss, avoid large meals, avoid trigger factors (e.g. fatty foods, caffeine and smoking).

Endoscopy is the investigation of choice but is not routinely recommended for all patients.

Alarm symptoms include: chronic gastrointestinal bleeding, progressive unintentional weight loss and persistent vomiting.

Full dose PPIs for one or two months is the treatment of choice for patients without alarm symptoms.

H2RAs are not as effective as PPIs in reducing symptoms.

Antacid/alginate can be used to relieve symptoms, but little evidence for their efficacy exists.

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Gastro-oesophageal reflux disease (GORD) is a term often used interchangeably with dyspepsia (bad digestion). GORD can be defined as any symptomatic clinical condition or histopathological alteration present in the upper gastro-intestinal (GI) tract, present over a period of at least four weeks, resulting from episodes of reflux of acid, pepsin and occasionally bile into the oesephagus from the stomach1.

INCIDENCE

It is estimated that GORD occurs in 30 per cent of the population occasionally and affects 7 per cent of the population on a daily basis. It is slightly more common in women than men. Approximately 50 per cent of pregnant women suffer from symptoms of GORD. The prevalence of GORD increases with age. GORD is responsible for 10 per cent of GP visits and 50 per cent of gastroenterologists’ workloads.1

GASTRIC ACID AND THE STOMACH

Gastric acid is produced by the parietal cells in the stomach to aid digestion. The acidic pH of 1.35-3.5 is maintained by the proton pump H+/K+ ATPase. This acidic environment is necessary for proteins to denature and expose their peptide bonds, which is a vital first step in digestion. The lining of the stomach is resistant to

the irritating effects of gastric acid. The lower oesophagus also contains a natural protective mechanism, to prevent this acid from causing harm. However, when gastric acid reflux is excessive or prolonged, it can cause symptoms of GORD.

SYMPTOMS

The characteristic symptom of GORD is chronic heartburn: a burning discomfort or pain felt in the stomach passing upwards behind the breastbone. Numerous less-common symptoms exist, including dysphagia, belching, bloating, non-cardiac chest pain, waterbrash (sudden excess of saliva), chronic sore throat and cough, laryngitis, inflammation of the gums, erosion of the enamel of the teeth and bad breath.

CAUSES OF GORD

Although the underlying causes of GORD remain uncertain, the structure and function of the gastro-oesophageal junction are of key importance in this condition. A band of muscles at the junction of the stomach and oesophagus (called the lower esophageal sphincter, or LES) normally acts, in conjunction with the diaphragm, as a barrier to prevent reflux of stomach contents into the oesophagus (Diagram 1). If that barrier is relaxed at inappropriate times or is otherwise compromised, reflux occurs.

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice.

2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area.

3. PLAN - If I have identified a knowledge gap

- will this article satisfy those needs - or will more reading be required?

4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs?

5. WHAT NEXT - At this time you may like to record your learning for future use or assessment. Follow the 4 previous steps, log and record your findings.

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Gastro-oesophageal reflux, which involves the backflow of acidic or non-acidic stomach contents into the oesophagus, is a normal physiological phenomenon occurring during brief periods of gastro-oesophageal sphincter relaxation. However, when refluxed acid exceeds normal limits, this can affect quality of life and expose sufferers to risks of complications.

CPD 22: GASTRO-OESOPHAGEAL REFLUX DISEASE

Hiatus hernia is often present in patients with severe GORD. Since large volumes of gastric contents can pass unimpeded into the hiatal sac in those suffering from hiatus hernia, this can exacerbate the severity of reflux.2 Despite its well-recognised role in the pathophysiology of peptic ulcer disease, there is no evidence that Helicobacter pylori infection contributes to GORD.3

LIFESTYLE FACTORS AND GORD

Despite a lack of evidence, lifestyle factors have been implicated in GORD. Epidemiological studies show a weak link between obesity and GORD. Obese people generally tend to eat larger meals and choose rich, energy-dense foods. This can increase intra-abdominal pressure, which can contribute to GORD.

In addition to this, fatty foods can delay gastric emptying, which can also contribute to GORD. Suffers should therefore be advised to eat smaller, more frequent meals. Alcohol, caffeine, chocolate, cigarette smoking and spicy foods can also exacerbate the symptoms of GORD as they can decrease the tone of the lower oesophageal sphincter, thereby causing reflux. The symptoms of GORD can also be precipitated by pregnancy, due to increased in intra-abdominal pressure and incompetence of the lower oesophageal sphincter muscle caused by to hormonal changes.

MEDICATION AND GORD

A variety of medicines have been implicated in GORD. Certain drugs, if not swallowed with an adequate amount of water, can stick in the oesophagus and become released slowly, causing oesophagitis. Drugs that are especially notorious for this are non-steroidal anti-inflammatory drugs (NSAIDs), doxycycline and bisphosphonates. NSAIDs can also cause further problems by inhibiting the production of prostaglandins that protect the gastric and oesophageal mucosa. This affects up to 10 per cent of patients taking NSAIDs regularly.

Tricyclic antidepressants, nitrates, calcium

channel blockers, anticholinergics and theophyllines can also contribute to GORD, as they relax the tone of the lower oesophageal sphincter muscle. Soluble drug formulations can also aggravate GORD by causing excess gas production, leading to distention of the stomach, thereby further aggravating GORD.

GENETICS AND GORD

Both inherited and acquired factors contribute to the development of GORD. Genetic factors contribute to 18-31 per cent of the causes of GORD. The prevalence of reflux symptoms is higher in the parents of affected people and identical twins have a higher concordance of reflux disease compared to non-identical twins.4

COMPLICATIONS OF GORD

Symptoms of GORD are often recurrent. Repeated exposure of the oesophagus to refluxed acidic gastric contents can result in damage of the oesophageal mucosa. This can lead to oesphagitis (which can cause benign narrowing of the oesophagus due to stricture formation), oseophageal ulceration and Barrett’s oesophagus. Severe oesophagitis and oesophageal ulceration can precipitate anemia due to excessive bleeding.

Barrett’s oesophagitis, (also known as columnar-lined oesophagitis) is a pre-malignant condition where any portion of the normal squamous lining of the oesophagus has been replaced with macroscopically visible metaplastic columnar epithelium. This condition is seen in 12 per cent of patients with GORD who undergo endoscopies.5 Since the metaplastic columnar lining of the oesophagus is relatively insensitive to acid, many people suffering from this condition do not have severe symptoms.

Barrett’s oesophagus is more common in those suffering from long-standing reflux symptoms and patients over 40 years old. It does not represent the end spectrum in GORD. In fact, it is a different phenotypic response of the oesophageal mucosa to acid reflux.6

Cancer is another complication of GORD. The risk of developing cancer of the oesophagus is slightly increased in those who have long-term acid reflux compared to normal. Furthermore, the risk of oesophageal cancer increases 10 fold in patients with Barrett’s oesophagus compared to normal.

INVESTIGATIONS

The UK National Institute for Health and Clinical Excellence (NICE) guidelines on the management of dyspepsia (including reflux symptoms) state that routine endoscopy is not necessary for all patients presenting with symptoms of GORD. The reason for this is that symptoms of GORD are a poor predictor of gastrointestinal disease and over 50 per cent of patients that undergo endoscopy have no symptoms and are described as having endoscopy-negative reflux disease.1

Endoscopy, which is the investigation of choice, involves the passage of a thin, flexible telescope down the oesophagus in order to view the oesophagus, stomach and duodenum. It can also be used to take biopsies and remove polyps. Endoscopy is used to determine whether or not the patient has developed oesophagitis and also assist with differential diagnosis (e.g. gastric or duodenal ulceration).

It is recommended that patients undergoing endoscopies should discontinue proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs) for a minimum of two weeks prior to the procedure, since acid suppression therapy could mask or delay the detection of gastric and oesophageal adenocarcinoma.1

Additional tests include full blood counts to rule out anaemia, barium swallow to show hiatus hernia (although endoscopy is generally used to detect this condition), and oesophageal pH monitoring. This invasive procedure can be useful for symptomatic patients with endoscopy-negative reflux disease.

ALARM SYMPTOMS

Urgent specialist referral for endoscopic investigation (to be seen within two weeks) is indicated for patients with alarm features. Alarm features are present in 10 per cent of patients presenting with dyspepsia and GORD in primary care.1 Alarm features include patients of any age with dyspepsia when presenting with any of the following;

• Chronic gastrointestinal bleeding (e.g. vomiting blood);

• Progressive unintentional weight loss;

• Progressive difficulty swallowing;

• Persistent vomiting;

• Iron deficiency anaemia;

• Epigastric mass;

• A suspicious barium meal result.1

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Diagram 1: Gastro oesophageal Reflux and how it occurs.

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CPD 22: GASTRO-OESOPHAGEAL REFLUX DISEASE

Referral for endoscopy should also be considered for patients over 55 years of age with unexplained and persistent recent-onset dyspepsia, those who have previously had a gastric ulcer, gastric surgery, pernicious anaemia, continued need for NSAID use, a family history of gastric cancer or anxiety about cancer.1 Gastric cancer has been found to be present in approximately 4 per cent in patients referred urgently for alarm features of GORD.1

MANAGEMENT OF GORD

Management of GORD aims to heal mucosal inflammation and resolve symptoms. This can involve the removal of precipitating factors, lifestyle advice, pharmacological intervention and surgery.

LIFESTYLE ADVICE

Available trials of lifestyle advice to reduce symptoms of dyspepsia and GORD are small and inconclusive. Nevertheless, individual patients may be helped by lifestyle advice (Table 1) and there may be more general health benefits that this sort of advice can offer.

PHARMACOLOGICAL TREATMENTS

Pharmacological treatments include proton pump inhibitors (PPIs), H2 Receptor antagonists (H2RAs) and antacids.

• Proton pump inhibitors - Proton pump inhibitors (PPIs) inhibit gastric acid secretion by blocking the H+/K+ ATPase proton pump in the gastric parietal cells. Systemic reviews for the Cochrane Collaboration have found that PPIs are more effective that H2RAs at healing oesophagitis and maintaining remission from mucosal injury and symptoms.6 According to NICE guidelines, patients with reflux symptoms but no alarm symptoms should receive initial treatment with full dose PPIs for one or two months.1

The majority of patients will experience a recurrence of symptoms within one year. If symptoms do recur, patients should be given PPIs at the lowest dose required to control symptoms, with a limited number of repeat prescriptions. This ‘step down’ approach recommended by NICE contrasts with the earlier ‘step up’ approach to treatment that was commonly used by prescribers, where patients would be started on antacid/alginate preparations, stepped up to H2RAs and then to PPIs if needed.

Five PPIs are currently licensed in Ireland for the treatment of GORD: omeprazole, esomeprazole, lanzoprazole, pantoprazole and rabeprazole. The licensed doses for PPIs for the treatment and maintenance of GORD are shown in Table 2.

No significant differences have been found between ‘equivalent’ doses of PPIs. Choice should therefore be based on cost and individual patient response. Generally, PPIs are well tolerated with the most common side effects being gastro-intestinal disturbances, headache and dizziness. Food intake can interfere with some PPIs. Food can modestly reduce the bioavailability of lanzoprazole.8 Lanzoprazole should therefore be taken in the morning one hour before food. Food intake delays and decrease the absorption of esomeprazole, but this does not have any significant influence on the effect of esomeprazole on intragastric acidity.9 The absorption of omeprazole, rabeprazole and pantoprazole is not affected by the presence of food.

As shown in Table 3, different potential for drug interactions have been found with the different PPIs. By reducing the acidity of the stomach, PPIs can affect the absorption of some drugs. Lanzoprazole, pantoprazole and rabeprazole have fewer documented drug interactions than omeprazole and esomeprazole.

CONCERNS OVER PPI USE

Long-term management of PPIs over ten years has been shown to be safe and effective, although the dose requirement may need to be increased over time.6 Recently, however, there have been concerns relating to the possible adverse clinical consequences of their use. It has been suggested that PPI use may increase the risk of gastric cancer due to prolonged acid suppression, although

Table 1: Lifestyle advice to be given to patients suffering from GORD Weight loss Since obesity is associated with GORD, healthy eating and

weight reduction advice should be given to patients.

Avoid large meals Eating large meals can lead to distention of the stomach precipitating symptoms of GORD, therefore eating small, regular meals should be advised.

Avoid eating before bedtime

Food and drink should be avoided within 3–4 hours of bedtime, since eating late can worsen reflux.

Elevate head in bed Lying flat may increase reflux episodes as gravity does not prevent acid regurgitation, raising the head in bed about 10-20cm can reduce or prevent nocturnal symptoms.

Stop smoking Smoking lowers the lower oesophageal sphincter pressure allowing more gastric juices up into the oesophagus.

Avoid food and drink that provoke symptoms

Caffeine, alcohol, chocolate and spicy foods and fatty foods should be avoided.

Avoid tight clothing

Tight clothing, particularly around the abdomen can aggravate symptoms of GORD.

Avoid drugs that aggravate symptoms

Such as NSAIDS, Tricyclic antidepressants, doxycycline and soluble formulations.

Table 2: Licensed doses for PPIs for the treatment and maintenance of GORD7 Proton Pump inhibitor

GORD - Healing GORD - Maintenance

Lansoprazole 30mg daily for 4-8 weeks

15-30mg daily

Omeprazole 20-40mg daily for 4-12 weeks

20mg daily

Pantoprazole 20-40mg daily for 2-8 weeks

20mg once daily or once daily when required

Rabeprazole 20mg daily for 4-8 weeks

10-20mg daily

Esomeprazole 40mg daily for 4-8weeks

20mg daily

TABLE 1: LIFESTYLE ADVICE TO BE GIVEN TO PATIENTS SUFFERING FROM GORD

TABLE 2: LICENSED DOSES FOR PPIS FOR THE TREATMENT AND PROPHYLAXIS OF GORD

Table 2: Licensed doses for PPIs for the Treatment and Maintenance of GORD

Proton Pump inhibitor GORD - Treatment GORD - Prophylaxix

Lansoprazole7 30mg daily for 4 weeks 15-30mg daily

Omeprazole8 10-20mg daily for 4 weeks

10-40mg daily

Pantoprazole9 20-40mg daily for 2-4 weeks

Rabeprazole10 20mg daily for 4-8 weeks 10-20mg daily

Esomeprazole11 40mg daily for 4-8weeks 20mg daily

TABLE 3 – CLINICALLY SIGNIFICANT DRUG INTERACTIONS OF PPISTable 2: Licensed doses for PPIs for the Treatment and Maintenance of GORD

Proton Pump inhibitor GORD - Treatment GORD - Prophylaxix

Lansoprazole7 30mg daily for 4 weeks 15-30mg daily

Omeprazole8 10-20mg daily for 4 weeks

10-40mg daily

Pantoprazole9 20-40mg daily for 2-4 weeks

Rabeprazole10 20mg daily for 4-8 weeks 10-20mg daily

Esomeprazole11 40mg daily for 4-8weeks 20mg daily

Table 3 – Clinically Significant Drug Interactions of PPIs

PPIs Interactions caused by Drugs that interact

Lansoprazole8 Drugs with pH dependent absorption

Atazanavir, Ketoconazole, Itraconazole, Digoxin.

Drugs metabolised by Cytochrome p450 enzyme CYP34A.

Theophylline, Tacrolimus.

Omeprazole7 Drugs with pH dependent absorption

Atazanavir, Ketoconazole, Itraconazole, Digoxin

Drugs metabolised by Cytochrome p450 enzyme CYP2C19

Phenytoin, Cilostazol.

Pantoprazole9 Drugs with pH dependent absorption

Atazanavir.

Rabeprazole10 Drugs with pH dependent absorption

Ketoconazole, Itraconazole, Atazanavir.

Esomeprazole11 Drugs with pH dependent absorption

Digoxin,Ketoconazole, Itraconazole.

Drugs metabolised by Cytochrome p450 enzyme CYP2C19

Phenytoin, Diazepam, Citalopram.

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CPD 22: GASTRO-OESOPHAGEAL REFLUX DISEASE

there is no robust evidence to support this suggestion. In addition to this, since continued acid suppression can affect the sterility of the stomach, this can predispose patients to gastrointestinal infections such as Clostridium difficile toxin.

It has also been suggested that PPIs reduce the efficacy of clopidogrel by preventing its activation. Further evidence is required to confirm this. PPIs have also been linked to an increase in hip fractures due to reduced calcium absorption caused by low or no gastric acid production.1

• H2 Receptor antagonists - H2 receptor antagonists (H2RAs) reduce gastric acid production by blocking the action of histamine at H2 receptors in the parietal cells in the stomach. H2RAs are not as effective as PPIs in reducing dyspeptic symptoms in patients with GORD.1 Although the symptoms of the majority of patients with GORD are improved with PPI therapy, some patients on PPI therapy continue to have persistent symptoms and remain a challenge to treat. Some of these patients may respond to H2RA therapy. H2RAs may also be added at bedtime to extend the length of treatment in patients with nocturnal symptoms.

The most commonly used H2RAs are ranitidine and famotidine, due to their lower potential for drug interactions than cimetidine. Cimetidine is a Cytochrome p450 inhibitor and can interact with drugs such as benzodiazepines and propranolol as well as drugs with a narrow therapeutic index such as cyclosporin, phenytoin and oral anticoagulants. Side effects of H2RAs include gastrointestinal disturbances, headaches, dizziness, tiredness and altered liver function tests, although generally these drugs are well tolerated.

• Antacids and alginates - Antacids and antacid/alginate combinations are widely prescribed by GPs for GORD and are also commonly used by patients as over-the-counter medication. Despite their popularity, there is surprisingly little evidence for the efficacy of these drugs. They have been found to be more effective than placebo in relieving reflux symptoms, but there is no evidence of their ability to heal oesophagitis.1

Antacid and alginate preparations usually contain aluminum or magnesium to neutralise gastric acid and work by forming a ‘raft’ on the stomach contents, thereby protecting the oesophageal mucosa from gastric reflux. These preparations should be taken when symptoms occur unexpectedly, which are usually one hour after meals and at bedtime.

Liquid antacid/alginates provide relief from symptoms more rapidly than tablet formulations. Antacid/alginate preparations should not be taken at the same time as other drugs, as they can impair the

absorption of certain medication. Side effects of antacid/alginate preparations are usually mild and temporary. They include diarrhoea (particularly magnesium-containing preparations), constipation (particularly aluminum-containing preparations) and belching.

Since sodium bicarbonate can often be found in these preparations, preparations with a high sodium content should be avoided in patients on a sodium-restricted diet such as those with heart failure and chronic kidney disease, as well as patients on lithium therapy.

• Prokinetic agents - Prokinetic agents can be used if an inadequate response to PPI therapy is achieved. Although evidence for the use of domperidone and metoclopramide is sparse, it is thought that these agents can help to relieve the symptoms of GORD by improving the gastro-oesophageal sphincter function and accelerating gastric emptying.

• Surgery - Surgery is not recommended for the routine management of persistent GORD, although patients whose quality of life remains significantly impaired may benefit from surgery. Anti-reflux surgery, called fundoplication, augments the reflux barrier by a full or partial ‘wrap’ of the gastric fundus around the lower oesophagus. Surgery is no better than long-term medical therapy at achieving remission from symptoms. There is also a small risk (0.5 per cent-1 per cent) of post-operative mortality associated with this surgery.1

ROLE OF THE PHARMACIST

Pharmacists can play a significant role in the management of patients with GORD. They can:

• Identify alarm signs and recommend urgent GP referral;

• Identify medicines that may precipitate symptoms;

• Advise on drug formulations that may affect symptoms;

• Offer lifestyle advice;

• Advise patients to avoid any known precipitants that they attribute to their symptoms;

• Provide weight management and dietary advice and support.

• Advise and support patients through smoking-cessation programmes;

• Advise on pharmacy-only H2RAs and PPIs available where suitable;

• Advise on the range of alginates/antacids available and the most suitable formulations for individual patients;

• Identify any potential drug interactions that could occur between drugs used to treat GORD and concurrent medication.

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REFERENCES

1. National Institute of Clinical Excellence (NICE) Guidelines; Managing dyspepsia in adults in primary care, 2004.

2. Sifim D., Dupont L. et al. Weakly acidic reflux in patients with chronic unexplained cough during 24hour pressure, pH and impedance monitoring. Gut 2005;54:449-454.

3. Fass R, Ofman JJ. Gastroesophageal reflux disease-should be adopt a new conceptual framework? Am J Gastroenterol 2001;96:2569-74

4. Sifim D. Relevance of volume and proximal extent of reflux in gastro-oesophageal reflux disease. Gut 2005;54:175-8.

5. Rex DK et al. Screening of Barrett’s oesophagus in colonoscopy patients with and without heartburn. Gastroenterology 2003;125:1599-606.

6. Fox M, Forgacs, I. Clinical review; Gastro-oesophageal reflux disease BMJ 2006;332:88-93

7. Pfizer Healthcare, Zoton Capsule. Summary of Product Characteristics 2012.

8. Astra Zeneca Pharmaceuticals (Ireland) Ltd., Losec Mups. Summary of Product Characteristics 2012.

9. Takada Products Ireland Ltd., Protium tablets. Summary of Product Characteristics 2012.

10. Janssen-Cilag Ltd., Pariet tablets. Summary of Product Characteristics 2012.

11. Astra Zeneca Pharmaceuticals (Ireland) Ltd., Nexium tablets. Summary of Product Characteristics 2012.