Previous changes

December 2022 — Minor update. Interstitial nephritis added as an adverse effect of lansoprazole, in line with the manufacturer's updated SPC.

October to November 2022 — reviewed. A literature search was conducted in October 2022 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. No major changes to the recommendations have been made.

July 2022 — minor update. Severe cutaneous reactions have been added as a possible adverse effect of omeprazole in line with the updated Summary of Product Characteristics. 

September 2021 — minor update. Updated information regarding hypomagnesaemia as an adverse effect of PPIs.

February to April 2017 — reviewed. A literature search was conducted in February 2017 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials since the last revision of this topic. The recommendations on primary care management and referral have been updated in line with the National Institute for Health and Care Excellence (NICE) clinical guideline Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management (2014). The lower age limit has been changed from 16 to 18 years. The content has been amended to include proton pump inhibitor doses for treatment of severe oesophagitis, in line with the updated NICE guidance. The topic has also undergone minor restructuring.

December 2016 — minor update. Subacute cutaneous lupus erythematosus has been added as a very infrequent adverse effect of proton pump inhibitors, in line with a Medicines and Healthcare products Regulatory Agency (MHRA) Drug Safety Update (2015).

May 2014 — minor update. Domperidone has been removed as a treatment option following the publication of the European Medicines Agency (EMA) document Restrictions on the use of domperidone-containing medications.

September 2013 — minor update. Metoclopramide has been removed as a treatment option following the publication of a European Medicines Agency (EMA) document highlighting the risk of neurological adverse effects.

November 2012 — reviewed. A literature search was conducted in October 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. No changes to clinical recommendations have been made.

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic.

February 2012 — minor update. McNeil Products Ltd, in collaboration with the Medicines and Healthcare products Regulatory Agency (MHRA), has published new safety data regarding the association of domperidone with an increased risk of serious ventricular arrhythmias or sudden cardiac death (2011). This topic has been updated to reflect their advice on dosing, adverse effects, and drug interactions. 

January 2012 — minor update. Information from the manufacturer's Summary of Product Characteristics (SPCs) about the possible interaction between pantoprazole and warfarin has been added to drug interactions (2011). Information from the British National Formulary (BNF) about the potentially serious interaction between proton pump inhibitors and protease inhibitors (atazanavir and saquinavir) has also been added (2011). 

June 2011 — minor update. The 2010/2011 QIPP options for local implementation have been added to this topic. 

March 2011 — the topic structure has been revised to ensure consistency across CKS topics. No changes to clinical recommendations have been made.

July 2009 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice on the interaction between clopidogrel and proton pump inhibitors. Healthcare professionals are advised to avoid concomitant use of these drugs unless considered essential. 

March to June 2008 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence. There are no major changes to the recommendations.

November 2005 — minor technical update. 

July 2005 — updated to incorporate the Referral guidelines for suspected cancer published by the National Institute for Health and Clinical Excellence (NICE). 

December 2004 — reviewed and updated to incorporate the National Institute for Health and Care Excellence (NICE) guideline on Dyspepsia (August 2004). Validated in March 2005 and issued in April 2005.

March 2004 — updated with additional information for nurse prescribers. 

July 2003 — updated to incorporate information from the Scottish Intercollegiate Guidelines Network (SIGN) guideline Dyspepsia (March 2003). Validated in September 2003 and issued in October 2003.

December 2000 — reviewed and updated to incorporate Guidance on the use of proton pump inhibitors (PPIs) in the treatment of dyspepsia (Technology appraisal guidance 7), issued by the National Institute for Health and Care Excellence (July 2000), and the Department of Health referral guidelines for suspected upper gastrointestinal cancers. 

July 2000 — updated following the suspension of the cisapride licence and resultant withdrawal of cisapride from marketing in the UK. 

June 1998 — written.

New evidence

Evidence-based guidelines

No new evidence-based guidelines published since 1 October 2022.

HTAs (Health Technology Assessments)

No new HTA's since 1 October 2022.

Economic appraisals

No new economic approvals since 1 October 2022.

Systematic reviews and meta-analyses

Tasoudis et al, 2023 Transthoracic fundoplication using the Belsey Mark IV technique versus Nissen fundoplication: A systematic review and meta-analysis [Free full-text]

Primary evidence

No new primary evidence which reaches the CKS threshold for inclusion published since 1 October 2022.

New policies

No new national policies or guidelines since 1 October 2022.

New safety alert

No new safety alerts since 1 October 2022.

Changes in product availability

• Omeprazole 10 mg and 20 mg oral solution (Glenmark). This formulation is licensed for a range of indications for adult and paediatric patients, from age over 1 year of age and ≥ 10 kg. The product is single use, and requires assembly, before administration. Licence covers use in feeding tubes from 6 to 15Fr.  See more here.

How should I initially manage a person with proven GORD?

• Assess for any alarm symptoms that may suggest a complication or other serious underlying pathology, and manage appropriately. See the CKS topic on Gastrointestinal tract (upper) cancers - recognition and referral for more information.
• Offer written information and advice on the symptoms, self-care, and management options for gastro-oesophageal reflux disease (GORD), such as the NHS patient information leaflet Heartburn and gastro-oesophageal reflux disease (GORD).
• Offer advice on lifestyle measures that may improve symptoms. Encourage the person to:
  • Lose weight if they are overweight or obese. See the CKS topic on Obesity for more information.
  • Avoid any trigger foods, such as coffee, chocolate, tomatoes, and fatty or spicy foods.
  • Eat smaller meals and eat their evening meal 3–4 hours before going to bed, if possible.
  • Stop smoking, if appropriate. See the CKS topic on Smoking cessation for more information.
  • Reduce alcohol consumption to recommended limits, if appropriate. See the CKS topic on Alcohol - problem drinking for more information. 
• Sleep with the head of the bed raised (for example by placing wood or bricks under the bed head to raise it by 10–20 cm, if practical).
  • Advise people not to use additional pillows, as this may increase intra-abdominal pressure and worsen symptoms.
• Assess for stress and anxiety which may worsen symptoms, and encourage relaxation strategies if needed. See the CKS topic on Generalized anxiety disorder for more information.
• Ask about any over-the-counter medication such as antacids and/or alginates that have been tried for symptom relief.
• Review the person's medication, and consider reducing or stopping (if possible and appropriate) any drugs that may cause or exacerbate symptoms, such as:
  • Alpha-blockers, anticholinergics, benzodiazepines, beta-blockers, bisphosphonates, calcium-channel blockers, corticosteroids, nitrates, theophyllines, and tricyclic antidepressants.
• If the person has proven GORD:
  • Offer a full-dose proton pump inhibitor (PPI) for 4 weeks, to aid healing.
  • See the section on Proton pump inhibitors in Prescribing information for more information.
• If the person has proven severe oesophagitis:
  • Offer a full-dose PPI for 8 weeks, to aid healing.
  • Offer a full-dose PPI long-term as maintenance treatment.
  • See the section on Proton pump inhibitors in Prescribing information for more information.
• Do not arrange testing for Helicobacter pylori infection.
• Advise the person to arrange a follow-up appointment if there are refractory or recurrent symptoms following initial management.

How should I manage refractory or recurrent GORD symptoms?

• Assess for any new alarm symptoms that may suggest a complication or other serious underlying pathology, and manage appropriately. See the CKS topic on Gastrointestinal tract (upper) cancers - recognition and referral for more information.
• For people with persistent or recurrent gastro-oesophageal reflux disease (GORD) symptoms despite initial management:
  • Consider whether an alternative diagnosis, such as cardiac or hepatobiliary disease, may be contributing to symptoms. See the CKS topics on Chest pain, Angina, Gallstones, and Cholecystitis - acute for more information.
  • Check the person's adherence to initial management and reinforce lifestyle advice.
• For people with persistent or recurrent symptoms and confirmed oesophagitis, consider one of the following options, depending on clinical judgement:
  • Prescribe a further course of the initial full-dose proton pump inhibitor (PPI) for 1 month. See the section on Proton pump inhibitors in Prescribing information for more information.
  • Prescribe a double dose of the initial PPI for 1 month.
  • Add in a histamine (H₂)-receptor antagonist (H₂RA) at bedtime, particularly if there are nocturnal symptoms. Prescribe an H₂RA for short-term use (for example for a 2-week course intermittently). See the section on H2-receptor antagonists in Prescribing information for more information.
• For people with persistent or recurrent symptoms and endoscopy-negative reflux disease, consider switching to an H₂RA, for one month.
• For people with recurrent symptoms after initial management, consider the need for long-term treatment. Encourage the person to step down or stop treatment, if possible and appropriate (if there is no co-morbidity or co-medication that requires long-term PPI treatment):
  • Use a PPI at the lowest effective dose to control symptoms.
  • Use a PPI as needed, if possible and appropriate.
  • Consider self-treatment with antacid and/or alginate therapy, although this is not recommended for long-term or continuous use.
• If a person with severe oesophagitis has ongoing symptoms following initial management, consider one of the following options for 8 weeks, depending on clinical judgement:
  • Prescribe a high dose of the initial PPI.
  • Switch to an alternative full-dose or high-dose PPI.
  • See the section on Proton pump inhibitors in Prescribing information for more information.
• If a person with severe oesophagitis has controlled symptoms, offer a full-dose PPI long-term as maintenance treatment. If there are ongoing or recurrent symptoms on treatment, consider whether to:
  • Switch to an alternative full-dose or high-dose PPI, and/or
  • Seek specialist advice from a gastroenterologist.
• Offer people on long-term treatment an annual review of their symptoms and treatment, and encourage the person to:
  • Step down or stop treatment, if possible and appropriate, if there is no co-morbidity or co-medication that requires long-term full-dose PPI therapy, such as:
    • Complicated or severe oesophagitis (including past dilatation of oesophageal stricture).
    • Barrett's oesophagitis. For more information, see the CKS topic on Gastrointestinal tract (upper) cancers - recognition and referral.
    • Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) where a PPI is used for gastroprotection. For more information, see the CKS topic on NSAIDs - prescribing issues.
    • Previous bleeding peptic ulcer disease who remain Helicobacter pylori positive after at least two attempts at eradication. For more information, see the CKS topic on Dyspepsia - proven peptic ulcer.
• Consider arranging a referral to a gastroenterologist or upper gastrointestinal surgeon for specialist investigations and management, if a person has proven GORD symptoms:
  • That are refractory to treatment, persistent, or unexplained.
  • That are controlled on acid suppression therapy, but the person does not wish to continue treatment long-term.
  • That are responding to a PPI, but acid suppression therapy is not tolerated.
  • In association with risk factors for Barrett's oesophagus, for consideration of upper gastrointestinal endoscopy.

Choice of proton pump inhibitor

• Table 1 shows the recommended doses of proton pump inhibitors (PPIs) for the management of people with gastro-oesophageal reflux disease (GORD) and severe oesophagitis.

Table 1. PPI doses for management of GORD and severe oesophagitis symptoms.

Contraindications and cautions

• Proton pump inhibitors (PPIs) should not be prescribed to people:
  • With alarm symptoms before endoscopy, as PPIs may mask the symptoms of upper gastrointestinal malignancy. If the person is already taking a PPI and subsequently needs an endoscopy, the PPI should be stopped at least 2 weeks before the procedure.
• PPIs should be prescribed with caution to people:
  • At risk of osteoporosis — the person should maintain an adequate intake of calcium and vitamin D, and if necessary, be given additional bone-sparing therapy.
  • At risk of hypomagnesaemia — if possible, magnesium levels should be checked before starting PPI therapy and intermittently during long-term treatment, for example if the person is prescribed drugs that can cause hypomagnesaemia, such as digoxin and diuretics.

[MHRA, 2012a; BNF, 2022]

Adverse effects

Adverse effects of proton pump inhibitors (PPIs) are usually mild and reversible.

• Adverse effects include headache, diarrhoea, nausea, vomiting, abdominal pain, constipation, and dizziness.
• Less common adverse effects include dry mouth, peripheral oedema, sleep disturbance, fatigue, paraesthesia, arthralgia, myalgia, pruritus, and rash.
• Rare or very rare adverse effects include:
  • Subacute cutaneous lupus erythematosus (SCLE), which can occur weeks, months, or years after exposure to a PPI. If suspected discontinue the PPI and seek specialist advice if needed [MHRA, 2015].
  • Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported very rarely and rarely with omeprazole treatment.
  • Taste disturbance, hepatitis, jaundice, depression, confusion, hallucinations, hyponatraemia, interstitial nephritis, leucopenia, leucocytosis, pancytopenia, thrombocytopenia, visual disturbances, sweating, photophobia, and alopecia.
• Long-term PPI treatment may be associated with uncommon, serious adverse effects such as:
  • Hypomagnesaemia — symptoms include muscle twitching, tremors, vomiting, fatigue, and loss of appetite. Case reports after one year of PPI therapy, but may occur after 3 months. This usually improves after magnesium replacement therapy and discontinuation of the PPI [MHRA, 2012a]. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia.
  • Increased risk of fractures — especially when used at high doses for over a year in the elderly [MHRA, 2012b].
  • Clostridium difficile infection — due to the effect of decreasing gastric acidity.
  • Rebound acid hypersecretion syndrome — may occur after stopping long-term PPI therapy, although this may be more a theoretical risk than clinical phenomenon.

[NICE, 2019; BNF, 2022]

Drug interactions

Possible drug interactions with proton pump inhibitors (PPIs) include:

• Citalopram and escitalopram — co-exposure to omeprazole or esomeprazole can lead to increased levels of citalopram and escitalopram. Dose adjustment may be necessary depending on side-effects.
• Digoxin — PPIs may cause a small rise in serum digoxin levels (although not considered clinically significant). The manufacturer of lansoprazole suggests that digoxin levels should be monitored if lansoprazole is started or stopped.
• Warfarin — PPIs can occasionally enhance the effects of warfarin. The international normalized ratio (INR) should be monitored in people taking warfarin if omeprazole, pantoprazole, or esomeprazole is started or stopped.
• Methotrexate — PPIs possibly reduce excretion of methotrexate, leading to an increased risk of methotrexate toxicity.
• Phenytoin — omeprazole and esomeprazole can occasionally enhance the effects of phenytoin. The manufacturers recommend that people taking phenytoin are carefully monitored if omeprazole or esomeprazole is started or stopped.
• Azole antifungals — the absorption of ketoconazole or itraconazole may be reduced during PPI treatment. Dose adjustment of the antifungal drug may be required during long-term PPI treatment.
• Clopidogrel — omeprazole and esomeprazole reduce the antiplatelet effect of clopidogrel, and concomitant use should be avoided. The other PPIs may also reduce the efficacy of clopidogrel, and this risk should be weighed against the potential benefit of the PPI [MHRA, (2010)].
• Protease inhibitors — PPIs can significantly affect plasma levels of some protease inhibitor drugs, including:
  • Atazanavir — concurrent use of PPIs and atazanavir is not recommended as the absorption of atazanavir may be affected by a PPI (due to changes in gastric acidity). This may lead to a reduced plasma concentration of atazanavir which may affect its efficacy. If concurrent use is necessary, seek specialist advice.
  • Saquinavir — plasma concentration of saquinavir may be increased by PPI treatment, leading to increased risk of adverse effects.
  • Tipranavir — concurrent use with omeprazole or esomeprazole is not recommended, as tipranavir may reduce the plasma concentration of the PPI. If concurrent use is necessary, seek specialist advice.

 [ABPI, 2021; BNF, 2022; Preston, 2023]

Choice of H2-receptor antagonist

• Table 1 shows the recommended doses of ranitidine, famotidine, and nizatidine histamine (H₂)-receptor antagonists (H₂RAs) for the management of people with gastro-oesophageal reflux disease (GORD).

Table 1. Recommended doses of H₂RAs for the management of people with GORD.

Contraindications and cautions

• Histamine (H₂)-receptor antagonists (H₂RAs) should not be prescribed to people:
  • With alarm symptoms before endoscopy, as H₂RAs may mask the symptoms of upper gastrointestinal malignancy. If the person is already taking an H₂RA and subsequently needs an endoscopy, the H₂RA should be stopped at least 2 weeks before the procedure.
• H₂RAs should be prescribed with caution in people with renal impairment:
  • For ranitidine, if the estimated glomerular filtration rate (eGFR) is less than 50 mL/minute/1.73m², prescribe half the normal daily dose.
  • For famotidine, if the eGFR is less than 50 mL/minute/1.73m², prescribe the normal dose once every 36–48 hours, or half the normal daily dose.
  • For nizatidine, if the eGFR is 20–50 mL/minute/1.73 m², prescribe half the normal daily dose; if the eGFR is less than 20 mL/minute/1.73 m², prescribe one-quarter of the normal daily dose.
• Nizatidine should be prescribed with caution for people with hepatic impairment.

[NICE, 2019; BNF, 2022]

Adverse effects

• Adverse effects of histamine (H₂)-receptor antagonists (H₂RAs) are uncommon and include diarrhoea, headache, dizziness, rash, and tiredness.
• Rare or very rare adverse effects include hepatitis, cholestatic jaundice, bradycardia, depression, confusion, hallucinations, leucopenia, thrombocytopenia, and pancytopenia, arthralgia, and myalgia.

[BNF, 2022]

Drug interactions

• Possible drug interactions with histamine (H₂)-receptor antagonists (H₂RAs) include:
  • Azole antifungals — because of decreased gastric acidity, the absorption of ketoconazole or itraconazole may be reduced if taken with an H₂RA.
  • Protease inhibitors — atazanavir plasma levels are reduced by H₂RAs. The manufacturer of atazanavir advises adjustment of the doses of both drugs when given with an H₂RA. Seek specialist advice as needed.

[BNF, 2022]