Emergency admissions for upper gastrointestinal disease and their relation to NSAID use.

BACKGROUND: There are considerable variations in estimates of the number of emergency upper gastrointestinal admissions per annum which are attributable to nonsteroidal anti-inflammatory drug (NSAID) use. AIM: To obtain a more accurate estimate of the number of these emergency admissions per annum in UK. METHODS: A retrospective survey of the case notes of all emergency admissions for upper gastrointestinal disease ('Cases') to two English District General Hospitals with a combined catchment population of 550,000. Records of all community deaths attributed to upper gastrointestinal diagnoses (with the same ICD codes) were also surveyed. Matched controls were identified from emergency admissions not caused by upper gastrointestinal diagnoses. The proportions of patients taking NSAIDs on admission to hospital (or at the time of death at home) and the outcome following admission to hospital were analysed. RESULTS: 620 emergency upper gastrointestinal admissions were identified and matched with 460 controls. Cases were more likely to be NSAID users than Controls (31% vs. 16%, OR 2.4, 95% CI: 1.8, 3.3: P < 0.001). Case NSAID use was higher in females and with increasing age. As severity of mode of presentation worsened, the probability of NSAID use increased (e.g. OR relative to controls for peptic pain 1.9, for perforation 5.9). Blood transfusion requirements were significantly higher (P < 0.0001) in Cases taking NSAIDs, although NSAID use did not influence mortality. Extrapolation from these data indicate that there are 65,000 emergency upper gastrointestinal admissions per annum in UK; 12,000 of these admissions (including 2230 deaths) are attributable to NSAID use. A further 330 attributable deaths occur in the community. CONCLUSIONS: There is a strong association between NSAID use and propensity for upper gastrointestinal emergency admission; NSAID use is associated with significant morbidity and mortality each year in UK.

The effect of tramadol on dento-alveolar surgical pain.

The aim of the study was to assess the analgesic effect of tramadol in the relief of pain after dentoalveolar operations that involve the removal of bone and suturing. Four-hundred and fifty-two patients over the age of 18 years who were to undergo removal of impacted teeth (n = 362), removal of root (n = 79), or alveolectomy, enucleation of cysts, or removal of soft tissue (n = 11) under local anesthesia were studied. Patients were randomly allocated to receive tramadol 100 mg or 50 mg four times daily, or 50 mg twice daily, or placebo. Median pain scores on the day of operation in the three tramadol groups were similar (2 in each group, ranges 1-5, 1-4.8, and 1-5 respectively) and were all significantly lower than that in the placebo group (2.3 range 1-4.2). The median number of Paracetamol tablets taken by patients in the three tramadol groups was 2 (ranges 0-8, 0-12 and 0-8 respectively), and were all significantly less than in the placebo group (4, range 0-12). More patients given tramadol reported complete pain relief than the placebo group. The advantages of tramadol continued over the next 2 days. There were no serious or unexpected adverse effects. It is concluded that tramadol is an effective analgesic after dentoalveolar operations.

Review article: controversies in NSAID-induced gastroduodenal damage--do they matter?

BACKGROUND: This article reviews various issues surrounding NSAID-induced gastroduodenal ulceration, about which there appear to be conflicting views and data in the literature. These issues include the size, clinical relevance and main site of the problem; when complications occur (early or late?); the relevance of non-ulcer lesions and whether adaptation is a clinically relevant phenomenon. METHOD: A comprehensive literature search was carried out to identify relevant new data published since 1987. RESULTS: NSAIDs are causally associated with more gastric than duodenal ulcers but their use may be associated with duodenal ulcers or complications. Erosive lesions may progress to more severe damage. The theories of early or late onset of complications during a course of NSAID therapy may not be mutually exclusive. CONCLUSIONS: Available data indicate that NSAID ulcers are at least as dangerous as classic peptic ulcers, and result in significant morbidity and mortality which in the patient population does not appear to be significantly reduced by processes such as adaptation.

The prevention and healing of acute non-steroidal anti-inflammatory drug-associated gastroduodenal mucosal damage by misoprostol.

This double-blind study assessed the acute development of NSAID-associated gastroduodenal (GD) damage and its prevention by misoprostol. Patients requiring chronic NSAID therapy were stratified into two groups depending on initial endoscopic appearance, Group I: normal (n = 223); Group II: non-ulcer lesions (n = 78). After 2 weeks of therapy with NSAID and either misoprostol 400-800 micrograms daily or placebo the incidence of severe mucosal damage (including ulcers) was significantly reduced by misoprostol (odds ratio; 95% CI). Group I: 4.52; 1.94, 10.51 (P = 0.018); Group II: 10.93; 1.09, 109.60 (P = 0.014); Groups I and II combined: 5.95; 3.23, 10.94 (P = 0.0003). Misoprostol exerted a significant protective effect against progression of minor to severe damage in Group II (P < 0.001). Endoscopic findings did not correlate significantly with gastrointestinal symptoms and misoprostol did not interfere with the NSAID efficacy. Significant GD damage occurs early in the course of NSAID treatment and misoprostol significantly reduces the incidence of such damage.

Misoprostol--a logical therapeutic approach to gastroduodenal mucosal injury induced by non-steroidal anti-inflammatory drugs?

Misoprostol is a synthetic analogue of naturally occurring prostaglandin E1. The basis of the damaging actions of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastrointestinal (GI) tract is believed to be a consequence of two events: a direct damaging action on mucosal integrity and depletion of endogenous mucosal prostaglandins (PGs). Due to the latter effect, and because current evidence indicates that PGs play an important role in maintaining the integrity of the GI tract, misoprostol has been developed as a logical therapy to prevent and heal gastric and duodenal damage caused by NSAIDs. The purpose of this review is to consider the need for such a therapy, to describe its pharmaceutical development, to review its pharmacology and to review its efficacy compared with other available agents.

Effect of misoprostol on concentrations of prostaglandins in synovial fluid.

The effect of misoprostol, a synthetic analogue of prostaglandin E, on prostaglandin concentrations in synovial fluids was investigated in a randomised placebo controlled, double blind study. The synovial fluid concentrations of prostaglandin E1, 6-keto-prostaglandin F1 alpha, and thromboxane B2 were measured at the beginning and end of a 24 hour period in 25 patients with effusions of the knee joint. During this period the patients were treated with diclofenac (50 mg every eight hours) and either misoprostol (400 micrograms) or placebo every 12 hours. The concentrations of prostaglandin E and 6-keto-prostaglandin F1 alpha were not significantly altered during treatment. There was an unexpected significant reduction in thromboxane B2 concentrations in the group treated with misoprostol (within group analysis). Although the mean concentration with misoprostol was about half the mean concentration with placebo, this difference was not statistically significant in the between group analysis. These results indicate that misoprostol is unlikely to exert a proinflammatory effect or to interfere with the prostaglandin mediated effects of non-steroidal anti-inflammatory drugs. The significant decrease in thromboxane B2 concentrations in the misoprostol treated group suggests that misoprostol may exert an anti-inflammatory effect.

Gastric output of pancreatic secretory trypsin inhibitor is increased by misoprostol.

Pancreatic secretory trypsin inhibitor (PSTI) is a potent protease inhibitor that also has growth promoting activity. It has recently been identified in the foveolar cells of the stomach, which secrete mucus. We examined the effects of the prostaglandin E1 analogue misoprostol on gastric PSTI output. Seven normal volunteers took part. An initial period of gastric aspiration was followed by four 40 minute periods of gastric perfusion at 5 ml/minute of: 0.14 mol/l saline, 0.17 mmol/l bicarbonate, bicarbonate with misoprostol 400 micrograms, and then bicarbonate again. All perfusates contained polyethylene glycol 4000 as a marker. Misoprostol increased median gastric secretion of PSTI from 11 to 33 micrograms/hour (p less than 0.05), producing concentrations in gastric juice six times higher than those found in jejunal juice and about 1/30 of the values seen in pancreatic juice. Median mucus secretion increased to a lesser extent from 29 to 38 mg/hour during misoprostol. There was no change in intragastric concentrations of protein or of epidermal growth factor during infusion of misoprostol. Infusion of pentagastrin (6 micrograms/kg/hour) had no effect on gastric secretion of mucus, PSTI, or protein. Human gastric mucus was degraded on incubation with trypsin in vitro and this was prevented by the addition of PSTI. These results suggest that gastric PSTI may protect the gastric mucus layer against refluxed pancreatic proteases. Increased output of PSTI during microprostol may contribute to the protective effect of this drug.

Misoprostol does not alter the pharmacokinetics of propranolol.

Twelve healthy volunteers took part in a randomised, double-blind, balanced, cross-over study to investigate the effect of misoprostol on the pharmacokinetics of propranolol. The subjects took propranolol 80 mg twice daily by mouth plus either misoprostol 400 micrograms twice daily or placebo by mouth for 14.5 days, followed by a 2-week washout period, followed by the alternate treatment for 14.5 days. Misoprostol had no significant effect on the t/2, Cmax or AUC of propranolol either after a single dose or at steady state.