Review article: over-the-counter drugs and the gastrointestinal tract.

An increasing number of drugs are becoming available over-the-counter, empowering patients to treat them- selves. Although drugs presently available over-the-counter are generally safe, there are issues of safety and possible delays in diagnosis of serious conditions. Therefore it is vital that patients are made aware of the indications and limitations of over-the-counter drugs through improved communication and education. Pharmacists and drug companies will have an increasingly important role in giving information and advice to patients. This review looks at the present and future of over-the-counter medication, highlighting the safety aspects.

Provision of ERCP services and training in the United Kingdom.

BACKGROUND AND STUDY AIMS: A rising demand for hands-on training in endoscopic retrograde cholangiopancreatography (ERCP) has coincided with a need for increased scrutiny of outcomes (clinical governance) and the development of less invasive methods of pancreaticobiliary imaging. We surveyed the current provision of ERCP facilities and training throughout the United Kingdom. METHODS: Questionnaires were sent to senior endoscopists in 252 acute hospitals and to 500 trainees in gastroenterology. RESULTS: Completed forms were returned from 180 hospitals (a 71% response rate) and from 233 trainees (a 47% response rate). A median of 210 ERCPs per year are carried out at each centre (range 40-1000), under the supervision of 345 senior endoscopists. ERCP training had been started by 163 trainees (70%), of whom 42 (26%) had been given one or fewer procedures to start per week. Trainees rated their training as excellent (25%), good (28%), adequate (24%) or inadequate (22%); 193 (83%) perceived that they needed training in ERCP to ensure that future career opportunities were not denied to them. CONCLUSIONS: Some centres have insufficient capacity for training in ERCP. Some form of preselection for both trainers and trainees may be required to ensure that quality is maintained. Gastroenterology training programmes should move away from encouraging all trainees to learn ERCP, and should promote the acquisition of alternative skills.

Peptic ulcer bleeding: accessory risk factors and interactions with non-steroidal anti-inflammatory drugs.

AIMS: To determine risk factors for peptic ulcer bleeding other than non-steroidal anti-inflammatory drugs (NSAIDs). Methods-Data on possible antecedent risk factors obtained in a large case control study of 1121 patients admitted to hospitals in Glasgow, Newcastle, Nottingham, Oxford, and Portsmouth with bleeding peptic ulcers were compared with the same information obtained in 989 population controls. Data were analysed by logistic regression with the calculation of odds ratios (OR) and 95% confidence intervals (CI). RESULTS: From a logistic regression model, oral anticoagulants (OR 7. 8; 95% CI 2.8-21.5), previous peptic ulcer (3.8; 2.6-4.9), treatment for heart failure (5.9; 2.3-13.1), oral corticosteroid use (2.7; 1. 3-4.5), treatment for diabetes (3.1; 1.2-4.3), and current smoking (1.6; 1.2-2.0) were all independent risk factors. No association was found with use of calcium channel antagonists. Odds ratios for concomitant NSAID usage were multiplicative with the exception of current smoking. CONCLUSIONS: Some 45% of admissions for peptic ulcer bleeding in England and Wales in those aged 60 or more are calculated to be attributable to, or associated with, these accessory risk factors, which, together with those associated with aspirin or other NSAID use will account for over 80% of predisposing factors to ulcer bleeding.

Guidelines for the management of dyspepsia.

Dyspepsia is a common problem necessitating strategies for investigation and management because of the scarcity of available resources for investigation, i.e. endoscopy, and the need to focus on those at risk of serious disease. It is agreed that those in the older age group, with the presence of alarm symptoms or non-steroidal anti-inflammatory drug use require prompt endoscopy, but there remains a significant proportion of patients in whom the underlying diagnosis is unclear, presenting a management problem. Unfortunately, no universally applicable approach to investigation and management is available. Each major community needs to modify its guidelines for the management of dyspepsia based upon such factors as the local incidence of organic disease, prevalence of Helicobacter pylori infection and lifestyle. Endoscopy off acid suppressive therapy remains the only way of making a certain diagnosis. A diagnosis of gastrooesophageal reflux disease can now be made confidently by endoscopy, with selective use of 24 h pH study of the lower oesophagus. The same cannot be said for other groups with dyspepsia where symptoms alone are a poor guide to diagnosis. Evidence is beginning to emerge, however, that further stratification of dyspeptics on the basis of symptoms and other risk factors, e.g. H. pylori status, may help in management. In addition, there is a clinical need for accurate, inexpensive tests of foregut motility. Integrating clinical data with specific investigation in dyspepsia is required in order for the practising clinician to better define the dyspeptic so that patients can be managed effectively and simply.

Postmarketing surveillance of the safety of cimetidine: 15-year mortality report.

The pattern of mortality after 15 years of observation is reported among almost 10,000 patients who were taking cimetidine when they were first recruited between 1977 and 1980. Many took the drug for a number of years, some switching to other antisecretory agents as the study progressed. The findings are reassuring and provide no evidence of any long-term adverse effects of cimetidine which might be detected by monitoring mortality rates. The data have also been used to examine the possible positive relationships between aluminium ingestion and Alzheimer's disease and H. pylori infection and ischaemic heart disease. No significant evidence was obtained in support of the existence of these relationships.

Helicobacter pylori and non-steroidal anti-inflammatory drugs: lone agents or partners in crime?

A variety of mechanisms are responsible for the gastric and duodenal mucosal injury known to result from the consumption of non-steroidal anti-inflammatory drugs (NSAIDs). Many of these mechanisms may be influenced by coexistent infection with Helicobacter pylori. However, evidence of increased risk from NSAIDs in patients with this bacterium is contradictory. While some authors have reported that symptoms, severity and prevalence of mucosal damage are higher in H. pylori-positive individuals taking NSAIDs than in those who are H. pylori negative, others have noted no significant difference. Reasons for this conflict may include the age of the subjects studied, duration of treatment, toxicity of the NSAID employed and pathogenicity factors related to different strains of H. pylori.

Dyspepsia update.

BACKGROUND: Non-Ulcer Dyspepsia (NUD) is a very common problem which has many causes. Trying to group dyspeptic patients according to symptoms has been proposed in order to improve our understanding of the problem and to aid both clinical trials and indeed practice by studying and treating homogeneous groups. REVIEW: The literature has been reviewed to see if sub-groups of dyspepsia are standing up to scrutiny and clinically relevant. RESULTS: Reflux-like dyspepsia may now be identified accurately in a high proportion by a combination of careful history and the use of intra-oesophageal 24-h pH monitoring. Acid suppressing therapy is often useful in this group. Dysmotility-like dyspepsia is currently an area of active investigation with growing evidence that there is abnormal gastric emptying. Response to pro-kinetic drugs looks encouraging. Ulcer-like dyspepsia: Appears to be the largest dyspeptic group. Acid secretion is normal. Helicobacter pylori does not correlate with any group of dyspepsia. CONCLUSION: Separating NUD into groups is becoming useful in both investigation and treatment, but more specific simple tests are needed to take this further.

The role and limitations of H2-receptor antagonists in the treatment of gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease (GERD) occurs in up to 44% of adults in the USA. Most individuals do not seek medical help, self-medicating with antacids. Manifestations of GERD range from symptoms without oesophagitis, which constitute the bulk of patients who self-medicate, to active oesophagitis and then to complications such as stricture and ulceration. It is the more severe cases who tend to come to the gastroenterologist, but it must be remembered that reflux symptoms are probably around 5-10 times more common than actual oesophagitis. Since acid in the refluxate is responsible for the bulk of the symptoms and mucosal damage, antacids are often used for quick relief--which of course may not be sustained. More prolonged suppression of acid secretion, such as by a histamine H2-receptor antagonist (H2RA) or a proton pump inhibitor (PPI), is required to give long-lasting symptomatic relief and heal any inflammatory change. H2-receptor antagonists inhibit acid secretion with an effect that lasts for 4-8 h with a single dose, decreasing stimulated acid secretion by around 70%. When treating oesophagitis, the H2RAs suffer from the disadvantage of their relatively short duration of action (compared with PPIs), development of tolerance, and incomplete inhibition of acid secretion in response to a meal. Therefore, it is not easy for the H2RAs to achieve optimum conditions for healing the more severe forms of oesophagitis--even very high doses may fail. In mild GERD the H2RAs have been shown to be effective in relieving symptoms.(ABSTRACT TRUNCATED AT 250 WORDS)

Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs.

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of peptic ulcer complications, but it is not clear whether some drugs are more likely than others to cause such complications. We compared previous use of NSAIDs in 1144 patients aged 60 and older admitted to hospitals in five large cities with peptic ulcer bleeding and in 1126 hospital controls and 989 community controls matched for age and sex. Peptic ulcer bleeding was strongly associated with use of non-aspirin NSAIDs of any type during the 3 months before admission (411 cases, 351 controls; odds ratio 4.5 [95% CI 3.6 to 5.6]). The odds ratios for peptic ulcer bleeding were lowest for ibuprofen (2.0 [1.4-2.8]) and diclofenac (4.2 [2.6-6.8]), and intermediate for indomethacin, naproxen, and piroxicam (11.3 [6.3-20.3], 9.1 [5.5-15.1], and 13.7 [7.1-26.3]). Azapropazone and ketoprofen carried the highest risks (31.5 [10.3-96.9] and 23.7 [7.6-74.2]). Risks also increased with drug dose (low dose 2.5 [1.7-3.8], intermediate 4.5 [3.3-6.0], and high 8.6 [5.8-12.6]) for all drugs combined. Appropriate clinical strategies could prevent many episodes of peptic ulcer bleeding: NSAIDs should be used only in patients who do not respond to other analgesics; the lowest possible doses should be used; and the least toxic NSAIDs should be selected.

Esophageal motor dysfunction and acid exposure in reflux esophagitis are more severe if Barrett's metaplasia is present.

OBJECTIVES: To compare esophageal motor function in patients with reflux esophagitis with controls, and identify patient characteristics that may have a bearing on the severity of esophageal motor dysfunction and acid exposure. METHODS: Esophageal motor function was assessed in 60 patients with reflux esophagitis. All patients had manometry, 50 had an esophageal transit test, and 23 had an acid clearance test. Forty-eight had dual site [5 and 10 cm above lower esophageal sphincter (LES)] esophageal pH monitoring, four had only distal pH monitoring, and one patient had only proximal pH monitoring. Thirty-four controls underwent the same tests. The association between the indices of esophageal function plus the degree of esophageal acid exposure and eight patient characteristics (age, sex, obesity, smoking, alcohol intake, hiatus hernia, grade of esophagitis, and Barrett's metaplasia) was examined in unifactorial and multifactorial analysis of variance. RESULTS: The patients had significantly lower LES pressure, lower distal and middle esophageal amplitudes, longer duration of contraction, and slower velocity of propagation. They had longer esophageal transit and acid clearance times. Barrett's metaplasia was the only factor that had an association with the magnitude of esophageal motor dysfunction and acid exposure, except age, which had a weak positive association with acid exposure (p = 0.03). Compared to the rest of the patients with esophagitis, patients with Barrett's had lower LES pressure (median = 10.5 vs. 17.5 mm Hg, p = 0.013), longer supine transit time (median = 180 vs. 13.5 s, p = 0.0001), and higher % of total time pH < 4 (median = 48.2 vs. 8.7 and 23.2 vs. 5.2; p < 0.0001 for distal and proximal esophageal acid exposure, respectively). Ten of the 12 patients with Barrett's had abnormal manometry, compared with 20 of the 48 without (chi 2 = 6.67; p < 0.01). There was a strong correlation between the degree of acid exposure in the proximal esophagus and the length of Barrett's segment (r = 0.846, 0.81, 0.725; and p < 0.001, 0.005, 0.018, for the % of times pH < 4 for total, supine, and upright periods, respectively). CONCLUSIONS: The development of Barrett's metaplasia may be determined by the degree of esophageal exposure to the refluxate which, in turn, may be a function of the severity of esophageal motor dysfunction. The length of Barrett's segment may be dependent on the extent of orad transport of the refluxate.

Simultaneous two level oesophageal pH monitoring in healthy controls and patients with oesophagitis: comparison between two positions.

For oesophageal pH monitoring, the pH probe is usually positioned 5 cm above the lower oesophageal sphincter (LOS). This is by convention, and has not been compared with other positions in its ability to discriminate between physiological and abnormal acid reflux. Using simultaneous two level 24 hour pH monitoring (5 and 10 cm above manometrically determined LOS) in 31 controls and 51 patients with reflux oesophagitis, the significance of the precise position of the probe in the oesophagus was examined. Secondly, this study compared the discrimination between the two groups achieved at the two levels. Patients had greater acid exposure than controls at both levels. In controls, acid exposure was greater at distal than at the proximal level except the supine acid exposure, which was similar at both levels. In patients, acid exposure was greater at the distal level for all variables (median % of total time pH < 4 = 11.7 v 7.6; p = 0.001). There was excellent correlation between the two levels for all variables in controls (r = 0.883, 0.935, 0.813, and p < 0.001 for percentage of time pH < 4 for total, supine, and upright times) as well as in patients (r = 0.848, 0.848, 0.779, and p < 0.001). On discriminant and receiver operating characteristic analysis, pH threshold 4 seemed as good as or better than other pH thresholds in discriminating between controls and patients. The percentage of total time pH below 4 seemed to discriminate as well or better than other variables at both levels. The distal level (5 cm above LOS) provided slightly better discrimination than proximal level (10 cm) (percentage of subjects correctly classified=81.7 v 75.6). The critical factor for the reliability of the test is not the precise position of the pH probe relative to the LOS, but that the same position is consistently used in patients and controls.

Prolonged remission of oesophagitis does not alter the magnitude of oesophageal acid exposure.

In a previous study we reported lack of improvement in oesophageal motor function after complete healing of oesophagitis achieved by treatment with omeprazole for a median duration of 12 weeks. This study investigates the effect on oesophageal acid exposure of a longer period of complete remission. It was decided to approach all patients who had 24-h pH monitoring as part of the earlier project and whose second endoscopy showing complete healing of oesophagitis as done at least 24 weeks previously. Of 38 such patients, 24 underwent endoscopy, which showed relapse of oesophagitis in 5 of them. In 18 patients who were eligible and agreed to take part, omeprazole/ranitidine was withdrawn for at least 7 days, after which pH monitoring was repeated. The median duration of remission was 39.5 weeks (range, 26-81 weeks). The median percentage of total time with pH below 4 was 11.5% before and 11.0% after (NS). The corresponding figures for the upright and supine reflux, the number of reflux episodes longer than 5 min, and the duration of the longest reflux episode were 10.7% versus 7.7%, 11.4% versus 12.1%, 7.5 versus 7.5, and 35.5 versus 30.5 min, respectively (NS for all variables). These results suggest that maintenance of remission of oesophagitis for prolonged periods does not alter the degree of acid reflux on discontinuation of medication. This has important implications for the understanding of the natural history of gastro-oesophageal reflux disease.

Safety of lansoprazole.

The care with which patients are monitored during clinical trials provides an excellent database to assess the tolerability and safety of drugs. Additional information can be obtained from knowledge of the compound itself, its metabolism and its pharmacological action. Other compounds from the same class can highlight areas that need particular study. All these factors have been used to assess the safety of lansoprazole. Lansoprazole has been administered to 4749 subjects and has been well tolerated. Only 1.2% of patients have been withdrawn from trials because of suspected drug-related events but there was no pattern and no relationship to drug dosage. Diarrhoea (3.2%) and headache (4.7%) were the most commonly reported adverse events.

Oesophageal motor function before and after healing of oesophagitis.

Forty three patients with reflux oesophagitis were studied to investigate the effect of healing on oesophageal function. All patients underwent oesophageal manometry and transit studies before and after complete healing of oesophagitis. Oesophagitis was treated with omeprazole 40 mg/day for a median duration of 12 weeks. Twenty three patients also had an acid clearance test before and after healing. Thirty eight of the 43 patients had 24 hour oesophageal pH monitoring before treatment and this was repeated after healing (while on omeprazole) in 31 of them. Thirty four volunteers served as controls. All volunteers underwent manometry, 33 had oesophageal transit studies, and 23 had acid clearance test. Patients had significantly reduced lower oesophageal sphincter pressures and distal and middle oesophageal amplitudes, longer durations of contraction, and slower velocity of propagation than the controls (16.5 v 22.5 mm Hg; 52 v 92 mm Hg; 46 v 79 mm Hg; 3.1 v 2.7 seconds; and 3.3 v 4.1 cm/second respectively with the corresponding p values = 0.017; 0.0001; 0.0001; 0.017; and 0.006). Patients had significantly longer transit times (9 v 7 and 17 v 11 seconds: p = 0.027 and 0.002 for erect and supine postures respectively). They also had longer acid clearance times (350 v 288 and 536 v 405 seconds: p = 0.044 and 0.016 for sitting and supine postures respectively). There was no significant change in any of the indices of oesophageal function after healing of oesophagitis (lower oesophageal sphincter pressure = 16.5 v 20; distal amplitude = 52 v 60; middle amplitude = 46 v 49; duration of contraction = 3.1 v 3.1; velocity = 3.3 v 3.3; erect transit time = 9 v 9; supine transit time = 17 v 24; acid clearance test (sitting) = 350 v 371; acid clearance test (supine) = 536 v 645). These results indicate that oesophageal motor dysfunction in reflux oesophagitis is a primary phenomenon.