International journal of clinical practice. Supplement最新文献

The risk of ulcer complications rises steeply with dose for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) but estimates of the overall incidence of bleeding ulcer are unreliable. Drug utilisation data, epidemiological data on the frequency of bleeding ulcer and death, and the relative risks associated with different NSAIDs, indicate that the number of cases of bleeding ulcer attributable to NSAIDs in the United Kingdom is approximately 2,400. Substitution of ibuprofen at a dose of 2.4 g/day for all other NSAIDs would reduce the number of events attributable to NSAIDs from 2,431 to 695 annually. At a dose of 1200 mg/day, substituting ibuprofen or another safe NSAID would be likely to reduce events to zero. Similarly, substitution of ibuprofen 2.4 g/day for all other NSAIDs would reduce attributable ulcer mortality to 80. The total number of excess cases attributable to aspirin is 753 annually. If prophylactic aspirin was prescribed solely at a dose of 75 mg/day, the number of cases would fall to 445 annually and the number of related deaths from 87 to 51 annually. NSAIDs and aspirin account for approximately one-third and previous ulcer for about one-fifth of the overall risk of bleeding ulcer and its complications.

There is a clear relationship between single doses of ibuprofen over the range 50-400 mg and the peak analgesic effect and the duration of analgesia. The smallest clinically useful dose of ibuprofen is 200 mg. Ibuprofen 400 mg has been shown to be as effective as aspirin 600 or 900 mg/day in models of moderate pain but superior to aspirin or paracetamol in more sensitive models such as dental pain. The duration of action of ibuprofen 400 mg is at least 6 hours compared with 4-6 hours for ibuprofen 200 mg or paracetamol. In patients undergoing oral surgery, ibuprofen 200 mg was broadly comparable with naproxen 220 mg and ibuprofen 400 mg comparable with ketoprofen 25 mg. The combination of ibuprofen and hydrocodone is more effective than either drug alone in patients undergoing abdominal and gynaecological surgery. The absorption of ibuprofen acid is influenced by formulation, and certain salts of ibuprofen (lysine, arginine, potassium) and solubilised formulations have an enhanced onset of activity. These differences are clinically important, offering a shorter time to onset of relief of tension headache compared with paracetamol.

This review updates previous systematic reviews to explore the overall levels of risk of serious upper gastrointestinal complications of treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and to investigate the importance of dose in explaining variations in risk. Thirty-six eligible case control studies were published between 1985 and 2000 and involved 19,648 cases and 105,373 controls. Eight eligible cohort studies included around 400,000 exposed subjects and 1 million non-exposed controls. The pooled unadjusted odds ratio from case control studies (compared with non-use of NSAIDs) for serious gastrointestinal complications is 4.06 (CI95% 3.47, 4.75); the pooled odds ratio from cohort studies is 2.29 (CI95% 1.50, 3.51). Unadjusted odds ratios range from 1.81 for ibuprofen to 7.46 for piroxicam. These data require careful interpretation because the statistical power of analyses of individual NSAIDs is lower than that for the class as a whole. There is a rank order of risk for different NSAIDs at low doses but at higher doses the odds ratios tend to converge. Ibuprofen is associated with a lower risk of serious gastrointestinal complications than other NSAIDs; this advantage is probably lost at higher doses (>1800 mg/day).

This paper describes two studies in children with fever in which the safety of ibuprofen was compared with that of paracetamol. The Boston University Fever Study aimed to assess the risk of rare but serious adverse events in febrile children. There were 795 admissions among 84,192 children during the study. There were no significant differences between the drugs in the risk of admission or the risk of secondary endpoints (admissions for asthma or cellulitis, or physician visits for abdominal pain or dyspepsia) and no evidence of clinically significant impairment of renal function. However, ibuprofen was associated with a significantly lower risk of physician visits for asthma: the incidence associated with ibuprofen was 3.0% (CI95% 2.1, 4.1) compared with 5.1% (CI95% 3.5, 7.1) for paracetamol (P = 0.02). The second study was a case control study to investigate a possible association between antipyretic medication, varicella infection and necrotising fasciitis. We identified 52 children aged under 19 years who were admitted to hospital with varicella and Group A streptococcal infection and 172 matched controls with uncomplicated varicella. The risk of invasive Group A streptococcal infection was associated with demographic and environmental factors and persistent high fever. There was no association with the use of ibuprofen or paracetamol alone, but the use of both agents was significantly associated with streptococcal infection. These studies demonstrate that children with fever tolerate treatment with ibuprofen as well as treatment with paracetamol. Neither agent is associated with an increased risk of necrotising soft tissue infections.

Non-steroidal anti-inflammatory drugs (NSAIDs) suppress the activity of both isoforms of cyclo-oxygenase (COX). Inhibition of COX-1, the constitutive isoform, is primarily responsible for the adverse gastrointestinal effects of the NSAIDs whereas inhibition of COX-2, the inducible isoform, accounts for their therapeutic effects. COX-2 inhibitors such as celecoxib and rofecoxib appear to be as effective as non-selective NSAIDs in the treatment of chronic inflammatory disease but their analgesic efficacy and their safety at the higher doses required for analgesia are less certain. There is consistent evidence that COX-1 plays a major role in the early pain response following injury and that analgesia is increased when both COX-1 and COX-2 are inhibited simultaneously. Early postoperative nociception may cause hyperalgesia at a later time by a process of central plasticity. In an experimental model of pain, ibuprofen promptly suppresses prostaglandin E2 concentrations whereas celecoxib has no discernible effect until 90-120 minutes postoperatively, when COX-2 activity is induced. Both drugs significantly reduce pain compared with placebo but celecoxib appears to have a slower onset of action. The analgesic effect of ibuprofen is well characterised for acute pain and short-term treatment is well tolerated.

Indomethacin has long been used to treat patent ductus arteriosus but it is associated with a relatively high risk of adverse effects; recent evidence suggests that ibuprofen is effective and may be safer. In a randomised trial to compare the efficacy and safety of ibuprofen and indomethacin in the treatment of patent ductus arteriosus, 144 infants received three doses of ibuprofen lysine (10, 5 and 5 mg/kg) at 24-hour intervals or indomethacin 0.2 mg/kg at 12-hour intervals. Ductal closure occurred in 70% of children treated with ibuprofen and 66% of those given indomethacin on the first treatment (P = 0.41). Nineteen children underwent surgical ligation, equally distributed between the treatment groups (P = 0.81). Urine production was significantly greater than in children given indomethacin from day 3 to day 7 and the serum creatinine concentration was significantly lower from day 7. Ductal closure was associated with higher serum concentrations of ibuprofen and a concentration of 10-12 mg/l appears to be the minimum level for efficacy. In a randomised, placebo-controlled, double-blind trial of prophylaxis with ibuprofen, the rate of patent ductus arteriosus associated with ibuprofen was 19% compared with 42% with placebo. Urine output was comparable in the two groups except on day 1, when it was significantly lower among infants given ibuprofen. Ibuprofen is therefore as effective as indomethacin in the treatment of patent ductus arteriosus, and effective as prophylaxis, in premature infants.

Low-dose ibuprofen is as effective as aspirin and paracetamol for the indications normally treated with over-the-counter (OTC) medications and is associated with the lowest risk of gastrointestinal toxicity of any non-steroidal anti-inflammatory drug. By contrast, even low-dose aspirin is associated with an appreciable risk of gastrointestinal toxicity. Paracetamol is well tolerated and effective in treating mild to moderate pain but there is growing concern about a possible risk of gastrointestinal toxicity and a possible link with asthma in children. The PAIN (Paracetamol, Aspirin, Ibuprofen New tolerability) study was a blinded randomised comparison of the tolerability of OTC analgesics in the treatment of common types of acute pain encountered in the community. A total of 8,677 adults were randomised to treatment with ibuprofen 1200 mg/day, paracetamol 3 g/day or aspirin 3 g/day for 1-7 days. The most common indications for treatment were musculoskeletal conditions (31-33%), colds or flu (19-20%), backache (15-17%), sore throat (11-12%) and headache (10-11%). Significant adverse events were more common with aspirin (10.1%) than ibuprofen (7.0%) (P<0.001) or paracetamol (7.8%). Significant gastrointestinal events were less frequent with ibuprofen (4.0%) than with aspirin (7.1%, P<0.001) or paracetamol (5.3%) (P=0.025). For every 100 patients treated, five more will experience significant adverse events if they are taking aspirin rather than ibuprofen, and four more than if they were taking paracetamol.

Ibuprofen was the product of a long research programme during the 1950s and 1960s to develop a 'super aspirin' for the treatment of rheumatoid arthritis which was as effective as current alternatives but safer. Selected for development in 1964 after several promising compounds had proved disappointing at the clinical stage, ibuprofen was found to have a short elimination half-life and exceptional gastrointestinal tolerability. Ibuprofen was introduced in the United Kingdom in 1966 and in the United States in 1974, and was the first non-steroidal anti-inflammatory drug (NSAID) licensed for over-the-counter use in the UK in 1983 and in the US the following year. Ibuprofen is a non-cyclo-oxygenase selective NSAID but recent evidence suggests additional anti-inflammatory properties are due to modulation of leucocyte activity, reduced cytokine production, inhibition of free radicals and signalling transduction. Ibuprofen may also exert a central analgesic action in the dorsal horn. Future roles for ibuprofen may include protection against certain cancers and Alzheimer's disease.

The risk of gastrointestinal mucosal injury with non-steroidal anti-inflammatory drugs (NSAIDs) is dose-dependent. Epidemiological studies have clearly demonstrated a rank order of risk of ulcer complications for commonly used NSAIDs, with ibuprofen consistently associated with the lowest risk and piroxicam with the highest. Antacids, H2 receptor antagonists and misoprostol all have drawbacks as prophylaxis. Of the cyclo-oxygenase (COX)-2 selective NSAIDs, rofecoxib is associated with a lower risk of gastrointestinal toxicity but there is uncertainty about the long-term risk associated with celecoxib. Rofecoxib has been associated with a significantly higher incidence of myocardial infarction than naproxen that may counteract the benefit of greater gastrointestinal safety. At over-the-counter doses, the short duration of use and the low dose reduce the risk of a serious adverse event compared with chronic use at prescribed doses. Intermittent therapy with low-dose NSAIDs has proved extremely safe and it has not been determined whether COX-2 selective agents offer a safety advantage compared with such treatment.