In studies where all patients in the general population presenting with dyspepsia were referred for endoscopy, the prevalence of pathology was:

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1 There is so much we don t know in medicine that could make a difference, and often we focus on the big things, and the little things get fgotten. To highlight some smaller but imptant issues, we ve put together a series of pearls that the Red Whale found at the bottom of the ocean of knowledge! Dyspepsia Doc, you ve got to do something about my guts every time I go out with my mates I m doubled up afterwards I ve tried taking ibuprofen befe the beers, but it just doesn t help! This common condition costs the NHS 1 billion annually affected individuals have a nmal life expectancy but an impaired quality of life. It was recently reviewed in the BMJ (BMJ 2013;347:f5059). Definitions and aetiology Dyspepsia affects 20 40% of the wld s population! Dyspepsia = epigastric pain discomft f 3m me in the absence of predominant heartburn regurgitation. Gastro-oesophageal reflux disease (GORD) = discomft f 3m where heartburn regurgitation are dominant. Dyspepsia is associated with: NSAID use H. pyli infection Anxiety Overlaps with IBS and GORD. The majity of patients presenting with dyspepsia in primary care can be safely managed with lifestyle advice and if necessary empirical treatment with acid suppression. However, our first job is to decide which patients need further investigation. Who needs H. pyli testing? NICE guidelines (NICE 2005, CG17) offer GPs a choice of treat then test test then treat and suggest they are equally effective. However, the Health Protection Agency remind us that the prevalence of H. pyli is falling in developed countries and is less than 15% in most areas of the UK they recommend we should treat empirically with acid suppression first in most cases and test the following groups: Patients with dyspepsia that is unresponsive to lifestyle change and 1m of PPI. Patients with a past histy of peptic duodenal ulcer who have never been tested. Patients starting long-term NSAIDs. Unexplained iron deficiency anaemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency. Which H. pyli test should be used? The urea breath test and stool antigen tests are the most accurate because they detect current infection. The following caveats exist: Do not perfm the urea breath test stool antigen test within 2w of taking a PPI within 4w of taking antibiotics they may lead to false negative results. Blood serology is good at ruling out H. pyli infection, but cannot differentiate between current and past infection. It is most useful in the context of acute GI bleed where you may not want to stop the PPI f the test. Who needs referral f endoscopy? In studies where all patients in the general population presenting with dyspepsia were referred f endoscopy, the prevalence of pathology was: Erosive oesophagitis 13% Peptic ulcer disease 8% Gastro-oesophageal cancer 0.3% No clinically significant finding (functional dyspepsia) 70 80%. In the UK, we should refer patients presenting with dyspepsia and any of the following red flag features f urgent endoscopy: Age 55y with new onset dyspepsia. Chronic gastrointestinal bleeding. Dysphagia. Progressive unintentional weight loss. Persistent vomiting. Iron deficiency anaemia. Epigastric mass. In reality, we often end up referring patients f endoscopy when first and second line treatments have failed - this is sometimes necessary to reassure both patient and doct and allow us to move on to consider alternative strategies!

2 Treatment options Having decided which patients need further investigations, you can get on and try treatment in the rest! 1. Offer empirical acid suppression therapy f 4w then try to stop: Often we reach straight f the PPIs but the Diamond trial challenged this (Lancet 2009;373:215). It was a primary care based study that randomised 650 patients presenting with dyspepsia to: Step up therapy (antacid then H2RA then PPI) Step down therapy (PPI then H2RA then antacid). Each step lasted 4w and patients progressed between steps accding to symptom control. Both treatment regimens were equally effective but costs were significantly lower with the step up approach let s offer patients a choice! 2. If acid suppression is inadequate to manage symptoms, test and treat f H. pyli: Patients with a positive H. pyli test should be offered eradication treatment as the NNTs f treatment are impressive: NNT = 2 to prevent a relapse of duodenal ulcer. NNT = 3 to prevent relapse of gastric ulcer. NNT = 14 to improve symptoms in functional dyspepsia. The following regimens are recommended by the HPA based on current UK sensitivities (but follow local guidance if it exists because some areas in the UK have high clarithromycin resistance). When choosing antibiotics, take into account previous antibiotic prescriptions in the past 12m because a script f clarithromycin metronidazole f any other reason in the past year makes resistance me likely this is not the case f amoxicillin. First-line 7 day triple therapy regimens PPI twice daily (Omeprazole 20mg twice daily Lansoprazole 30mg twice daily) PLUS Amoxicillin 1g twice daily and Clarithromycin 500mg twice daily Metronidazole 400mg twice daily and Clarithromycin 250mg twice daily Amoxicillin 1g twice daily and metronidazole 400mg twice daily Second line 14 day quadruple therapy regimen PPI twice daily (Omeprazole 20mg twice daily Lansoprazole 30mg twice daily) PLUS tripotassium dicitratobismuthate 240mg twice daily PLUS

3 2 antibiotics (pick those not previously used) Tetracycline 500mg four times daily Metronidazole 400mg twice daily Clarithromycin 500mg twice daily Amoxicillin 1g twice daily The majity of patients do not need a test of cure. If severe symptoms persist, wait 4 8w after completion of eradication treatment and use the breath test stool antigen test (serology can remain positive f up to a year). 3. Prokinetic drugs These may be helpful in functional dyspepsia especially if patients rept symptoms of delayed gastric emptying. A Cochrane review looked at 24 placebo-controlled trials of prokinetics and found an NNT = 6. However, the majity of these trials used cisapride which has now been withdrawn because of concerns about cardiac safety. There was only one trial including domperidone and no RCTs f metoclopramide. In addition the MHRA has recently raised concerns about the safety profile of domperidone and metoclopramide see drug dilemma below! 4. Antidepressants F functional dyspepsia, low dose tricyclics (amitriptyline and imipramine) have been shown to be modestly effective compared with placebo SSRIs have not. What about sequential H. pyli eradication regimens? We have previously taught about the potential benefits of higher H. pyli eradication rates using a sequential eradication regimen comprising: Amoxicillin 1g twice daily + PPI twice daily f 5d then Clarithromycin 500mg twice daily + Metronidazole 400mg twice daily +PPI twice daily f a further 5d. A recent BMJ meta-analysis looked at this issue incpating 46 RCTs, none of which were perfmed in the UK and most of which were perfmed in countries with higher clarithromycin and metronidazole resistance that we see in the UK (BMJ 2013;347:f4587). They found that: Sequential therapy had superi eradication rates to standard 7d triple therapy (86.5% vs. 71%). Sequential therapy had similar eradication rates to 10d, 14d and bismuth-containing treatment regimens. Should this change our practice? No. In 2012, the leading gastroenterologists of the wld met and produced guidelines on H. pyli testing and treatment Maastricht IV (Gut 2012;61:646). They concluded on the basis of current evidence that, in countries with low clarithromycin resistance (<20%), standard triple therapy should be first line and bismuth-containing quadruple therapy should be second line because of simpler regimes, lower likelihood of promoting resistance and better concdance. Clarithromycin resistance rates in the UK are currently between 4 and 11% highest in London (HPA). This is why the regimens in the box above are recommended. However, this may change!

4 Drug Dilemma: Prokinetics Prokinetics are commonly used as add-on treatments in functional dyspepsia. The majity of the trials which showed benefit used cisapride which was withdrawn from the market some years ago because of concerns about cardiac safety. It was replaced clinically with domperidone and metoclopramide. However in the last 12 months the MHRA have raised concerned and suggested new restrictions be placed on both of these drugs: Metoclopramide (MHRA Drug Safety Update August 2013) This warning followed a French review of all the literature and safety data regarding the potential neurological side effects of metoclopramide which have been known f a long time sht term extra-pyramidal disders and tardive dyskinesias. It concluded that the harms outweighed the benefits in long term high dose use. The risks were higher in children than adults. They made the following recommendations: Indication: Adults: f the symptomatic management of nausea and vomiting including that occurring post-operatively, associated with chemotherapy with migraine. Children: as a second line agent only f the management of chemotherapy surgical nausea and vomiting. Contraindicated in under 1 year olds. They do not mention any license indication f use in dyspepsia (and note there are no RCTs of metoclopramide used in this context). Duration and dosage Prescribe f sht term use only (maximum 5 days recommended). Maximum dose f adults is 30mg/24 hour period usually 10mg tds. Maximum dose f children 1 year older is mg kg per dose (maximum 0.5mg/kg/24 hours). Domperidone (MHRA Drug Safety Update May 2014) Concerns have been expressed about the risk of cardiac arrhythmias associated with domperidone after a review of all published and unpublished safety date. It has been found to be associated with an increased risk of QTc prolongation, tsades de pointes and ventricular tachycardia. This has been found to be particularly the case at high doses (>30mg daily) and use f prolonged durations. Harms were also me common in those aged >60 years F this reason the MHRA are specifically recommending: Domperidone should no longer be used f bloating, heartburn dyspepsia because there is no good evidence it is beneficial and the harms may outweigh the benefits in this situation. It is contraindicated in individuals where cardiac conduction is could be impaired in those with heart failure those taking other QTc prolonging drugs/ potent CYP3A4 inhibits e.g. fluconazole, itraconazole (your computer prescribing system should warn of these interactions). The benefits may outweigh the harms f nausea and vomiting and if used: It should be prescribed at the lowest dose (maximum 30mg daily when given ally 30mg twice daily when given as supposities) and f the shtest duration possible (usually <7 days). In children under 12 years, the maximum daily recommended dose is 0.75mg/kg as 3 divided doses over 24 hours. What does this mean in practice? The MHRA release suggested we should review these medications at the next routine review. It would be sensible to do a search f all patients with metoclopramide and domperidone on repeat prescription and have a plan of how and when we will review this. If the indication f use has been dyspepsia, we can consider whether it is still needed and if so consider alternatives as detailed above. F some patients this may require referral advice from gastroenterology. This means there are no prokinetics licensed in the UK f the management of GORD functional dyspepsia. Summary: Dyspepsia Dyspepsia is common and most patients can be treated on the basis of histy alone. Refer patients with red flags f endoscopy. Test f H. pyli if there is initial treatment failure, a histy of peptic ulcers an intention to start long-term NSAIDs. Use the urea breath test stool antigen test. Pick eradication regimen accding to local sensitivities and the patient s personal antibiotic histy. If despite this patients remain symptomatic with functional dyspepsia, consider amitriptyline. The MHRA have expressed safety concerns about domperidone and metoclopramide and no longer recommend their use f functional dyspepsia. Identify all repeat prescriptions f domperidone and metoclopramide what is the indication? Review with the patient at the next medication review and develop an alternative management plan.

5 Focussed Learning Activity: Dyspepsia Read the section above. Write brief notes on your key learning points don t regurgitate the section, focus on the things you did not know/want to remember. This might include: A reminder of definitions Groups f whom we should consider H pyli testing Red flags f urgent endoscopy Treatment options Local H pyli sensitivities - you might need to ask The prokinetics drug dilemma Other learning points Think about your current practice regarding investigation, referral, empirical and eradication treatment in the light of what you have learned reading this section. Write a brief reflective piece on your current management, what guidance rationale you have based this on in the past, and how you might change your practice in the future.

6 Run a search f any patients with repeat prescriptions f domperidone metoclopramide. Review the indication f which these drugs have been prescribed. Consider what action you will take f those not consistent with the MHRA recommendations. Make brief notes of your findings and any actions you have taken. Thinking back over this learning activity ( the parts you have found useful to complete), what is the key learning point? What will you do differently?

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