Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis

PURPOSE: To assess the efficacy and safety of nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of cancer pain by meta-analyses of the published randomized control trials (RCTs). PATIENTS AND METHODS: Twenty-five studies met inclusion criteria for analysis. Of these, 13 tested a single-dose effect, nine multiple-dose effects, and three both single- and multiple-dose effects of 16 different NSAIDs in a total of 1,545 patients. Baseline pain intensity (when provided) of moderate or higher was indicated in 81% of patients. RESULTS: Single-dose NSAID studies found greater analgesic efficacy than placebo, with rough equivalence to 5 to 10 mg of intramuscular morphine. Pain scores differed insignificantly for aspirin versus three other NSAIDs. Analgesic responses to low- and high-dose NSAIDs suggested a dose-response relationship, but this was not statistically significant. Recommended and supramaximal single doses of three NSAIDs produced comparable changes in pain scores, which indicates a ceiling analgesic effect. Common side effects included upper gastrointestinal symptoms, dizziness, and drowsiness. The incidence of side effects showed a trend to increase with dose, without a ceiling effect, and to increase with multiple doses. Single or multiple doses of weak opioids (WO) alone or in combination (WO/C) with nonopioid analgesics did not produce greater analgesia than NSAIDs alone. Single doses of WO/C analgesics produced more side effects than NSAIDs alone, although both side effect incidence and patient dropout rates were equal when multiple doses were administered. CONCLUSION: These findings question whether the traditional World Health Organization (WHO) second analgesic step (addition of a weak opioid when pain is inadequately treated by a nonopioid analgesic alone) is warranted. A lack of comparable studies precluded testing the hypothesis that NSAIDs are particularly effective for malignant bone pain.     

The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone

To determine the safety and efficacy of viscosupplementation with hylan G-F 20, a cross-linked hyaluronan preparation, used either alone or in combination with continuous non-steroidal anti-inflammatory drug (NSAID) therapy, a randomized, controlled, multicenter clinical trial, assessed by a blinded assessor, was conducted in 102 patients with osteoarthritis (OA) of the knee. All patients were on continuous NSAID therapy for at least 30 days prior to entering the study. Patients were randomized into three parallel groups: (1) NSAID continuation plus three control arthrocenteses at weekly intervals; (2) NSAID discontinuation but with three weekly intra-articular injections of hylan G-F 20; and (3) NSAID continuation plus three injections, one every week, intra-articular injections of hylan G-F 20. Outcome measures of pain and joint function were evaluated by both the patients and an evaluator at baseline and weeks 1, 2, 3, 7 and 12, with a follow-up telephone evaluation at 26 weeks. At 12 weeks all groups showed statistically significant improvements from baseline, but did not differ from each other. A statistical test for the equivalence, the q-statistic, demonstrated that viscosupplementation with hylan G-F 20 was at least as good or better than continuous NSAID therapy for all outcome measurements except activity restriction. At 26 weeks both groups receiving hylan G-F 20 were significantly better than the group receiving NSAIDs alone. A transient local reaction was observed in three patients after hylan G-F 20 injection; only one patient withdrew from the study as a result and all recovered without any sequela. Hylan G-F 20 is a safe and effective treatment for OA of the knee and can be used either as a replacement for or an adjunct to NSAID therapy.     

Short-term effects of flurbiprofen and diclofenac on refractive outcome and corneal haze after photorefractive keratectomy

PURPOSE: To evaluate the short-term effects of topical nonsteroidal anti-inflammatory drugs (NSAIDs) on refractive outcome and corneal haze after excimer laser photorefractive keratectomy (PRK) according to the degree of myopia and to compare the results with those of topical steroids. SETTING: Seoul National University Hospital, Seoul, Korea. METHODS: Patients were divided into two groups: low to moderate myopia (-6.00 diopters [D] or less) and high myopia (greater than 6.00 D). Then, each patient was randomly assigned to one of three drug subgroups for initial management (4 months post-PRK): corticosteroids (fluorometholone 0.1%); flurbiprofen sodium 0.03% (Ocufen); diclofenac sodium 0.1% (Decrol). Follow-up was 6 months. RESULTS: In eyes with low to moderate myopia, the steroid and diclofenac subgroups had significantly different refractions 2 and 4 months postoperatively but no difference at 6 months; subjective haze grading was consistently lower in the steroid subgroup than in the NSAID subgroups (flurbiprofen, diclofenac) after 2 months. In eyes with high myopia, the steroid subgroup had significantly less myopic regression after 3 weeks and lower subjective haze after 2 months than the NSAID subgroups. The steroid subgroup had severe myopic regression or corneal haze less frequently than the NSAID subgroups. CONCLUSION: Topical NSAIDs were less effective than topical steroids in reducing myopic regression and haze after PRK, especially in highly myopic eyes.     

The treatment of osteoarthritis of the knee with pulsed electrical stimulation

OBJECTIVE: The safety and effectiveness of pulsed electrical stimulation was evaluated for the treatment of osteoarthritis (OA) of the knee. METHODS: A multicenter, double blind, randomized, placebo controlled trial that enrolled 78 patients with OA of the knee incorporated 3 primary efficacy variables of patients' pain, patients' function, and physician global evaluation of patients' condition, and 6 secondary variables that included duration of morning stiffness, range of motion, knee tenderness, joint swelling, joint circumference, and walking time. Measurements were recorded at baseline and during the 4 week treatment period. RESULTS: Patients treated with the active devices showed significantly greater improvement than the placebo group for all primary efficacy variables in comparisons of mean change from baseline to the end of treatment (p < 0.05). Improvement of > or = 50% from baseline was demonstrated in at least one primary efficacy variable in 50% of the active device group, in 2 variables in 32%, and in all 3 variables in 24%. In the placebo group improvement of > or = 50% occurred in 36% for one, 6% for 2, and 6% for 3 variables. Mean morning stiffness decreased 20 min in the active device group and increased 2 min in the placebo group (p < 0.05). No statistically significant differences were observed for tenderness, swelling, or walking time. CONCLUSION: The improvements in clinical measures for pain and function found in this study suggest that pulsed electrical stimulation is effective for treating OA of the knee. Studies for longterm effects are warranted.     

Nonsteroidal anti-inflammatory drugs and corticosteroids for the management of canine osteoarthritis

Anti-inflammatory medications have long been prescribed for relief of the pain and discomfort associated with OA. This occurs despite the recognized side effects associated with use of NSAIDs and corticosteroids. Available evidence suggests that NSAIDs provide this relief through a combination of central and peripheral actions. Recent discovery of two isoforms of cyclooxygenase has increased our understanding of NSAID activity and may result in identification of drugs that potentially will have fewer side effects. A review of NSAIDs used in veterinary medicine indicates that relatively little is known regarding their role in treating OA, although controlled studies involving carprofen and etodolac have increased our knowledge of the efficacy of specific NSAIDs used for this purpose.     

A double-masked comparison of Naprelan and nabumetone in osteoarthritis of the knee. Naprelan Study Group

The efficacy and safety of Naprelan (naproxen sodium) 1000 mg once daily (QD) and nabumetone 1500 mg QD were compared in a multicenter, randomized, parallel-group, placebo-controlled, double-masked, 4-week study of adult outpatients with active osteoarthritis (OA) of the knee. Nabumetone 1500 mg was chosen for comparison because it is commonly prescribed in a QD dosing regimen for OA. After a washout period free of nonsteroidal anti-inflammatory drugs, 279 patients were enrolled and assigned randomly to treatment with either Naprelan 1000 mg QD (n = 92), nabumetone 1500 mg QD (n = 93), or placebo (n = 94). All treatments were evaluated for efficacy and safety at baseline and at weeks 2 and 4 of the treatment period or at discontinuation. Demographic characteristics were comparable among all treatment groups. As might be expected in a study of OA of the knee, a majority of patients enrolled were women (68.8%), and many were obese (mean weight, 195.6 lb; mean height, 66 in). Significantly fewer patients (13) treated with Naprelan prematurely discontinued the study than did patients treated with placebo (27); there was a lower rate of discontinuation for insufficient therapeutic effect in the Naprelan group compared with the nabumetone and placebo groups. Using an intent-to-treat model, the overall distribution of scores in all three primary efficacy assessments (investigator's global assessment of OA, patient's global assessment of OA, and walking pain) at week 2 and at the last visit was significantly better for the Naprelan group compared with both the nabumetone and placebo groups. The mean improvement from baseline was also significant for Naprelan compared with the nabumetone and placebo groups for all three assessments at week 2 and for investigator's global assessment of OA and walking pain at the last visit. The nabumetone-treated group showed significant improvement over the placebo-treated group in only one primary assessment: mean change from baseline in patient's global assessment of OA at week 2. At week 2, significant differences favoring Naprelan versus nabumetone and placebo were measured in overall distribution of scores for joint tenderness and nighttime pain. Distribution of quality of sleep and inactivity stiffness scores also improved relative to placebo at week 2. At the last visit, nighttime pain scores were still significantly better for patients receiving Naprelan versus nabumetone and placebo. Patients receiving nabumetone had statistically significant improvement from baseline in inactivity stiffness compared with placebo at week 2. There were no clinically important differences among treatment groups in the occurrence of adverse events or laboratory abnormalities. The results of this 4-week study of Naprelan 1000 mg QD compared with nabumetone 1500 mg QD demonstrate at least equal efficacy (superior efficacy was demonstrated for several parameters) and equal safety in adult outpatients with active OA of the knee.     

Pharmacotherapy and osteoarthritis

Therapy for osteoarthritis (OA) is aimed at relieving symptoms and at maximizing function. Therapies can be considered as either symptom modifying OA drugs (SMOADs) or as disease modifying OA drugs (DMOADs). Currently available agents fall into the category of SMOADs. Analgesic medications, particularly paracetamol and capsaicin, have proven efficacy in OA and are recommended first line therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) do appear to provide extra symptomatic benefit for some patients but have greater toxicity. Newer generation NSAIDs may have safety advantages which remain to be confirmed in practice. Further therapies are being developed which aim to prevent cartilage damage and/or aid cartilage restoration, but these DMOADs remain in the experimental stage.     

Efficacy and safety of tramadol HCl in breakthrough musculoskeletal pain attributed to osteoarthritis

OBJECTIVE: To evaluate the efficacy of tramadol as adjunctive therapy in patients with musculoskeletal pain attributed to osteoarthritis (OA) who experienced breakthrough pain while taking a nonsteroidal antiinflammatory drug (NSAID). METHODS: This single center, parallel, placebo controlled, 2 phase study was conducted in adults who experienced breakthrough OA pain while undergoing stable NSAID therapy. In a 24 h open label phase, patients took 100 mg of tramadol followed by 50 mg every 6 h (total 250 mg) in addition to their daily NSAID regimen. Supplemental analgesics were prohibited. Patients who met entry criteria and were willing to continue therapy were randomized to a 13 day double blind phase of adjunctive therapy with tramadol (50-100 mg every 4-6 h as needed for pain) or placebo; NSAID therapy was continued. The primary efficacy endpoint was the time to exit from the study because of therapeutic failure (i.e., insufficient pain relief or an inability to perform activities of daily living). RESULTS: The time to exit from the study because of insufficient pain relief tended to be longer in the tramadol group (250 mg/day) compared with the placebo group (p = 0.066). At the end of the double blind phase, pain at rest was significantly less severe in tramadol treated patients (p = 0.046). In addition, severity of pain on motion tended to be less severe in tramadol treated patients (p = 0.059). General severity of current pain and ability to perform activities of daily living were not significantly different with tramadol or placebo. Patients' overall assessment of therapy (p = 0.022) and investigator's rating of global improvement (p = 0.004) were significantly better with tramadol than with placebo. CONCLUSION: Tramadol may have a role as adjunctive treatment for breakthrough pain in patients receiving NSAID therapy for musculoskeletal pain attributed to OA.     

The status of human filariasis in north-western zone of Bauchi State, Nigeria

PURPOSE: To review the efficacy of nonmedicinal, noninvasive therapies in hip and knee osteoarthritis. DATA SOURCES: Search of English-language literature from 1966 through 1993 using MEDLINE by cross-referencing "osteoarthritis" (therapy subheadings) with "controlled trial," "comparative study," or "trial(s)." STUDY SELECTION: Fifteen controlled trials of diathermy (deep heat), exercise, acupuncture, transcutaneous electrical nerve stimulation, topically applied capsaicin, low-energy laser, and pulsed electromagnetic fields were found. No experimental studies of superficial heat and cold, orthotic devices, vibration, or weight loss were identified. RESULTS: Exercise reduces pain and improves function in patients with osteoarthritis of the knee. No support exists in the literature for pre-exercise ultrasound treatment. Single, well-designed studies suggest that topically applied capsaicin and laser treatment reduce pain associated with knee osteoarthritis. Data on the other three therapies were sparse (transcutaneous electrical nerve stimulation, pulsed electromagnetic fields) or inconsistent (acupuncture). CONCLUSIONS: More data are needed to determine the optimal exercise regimen for treating knee osteoarthritis and to evaluate the role of topical capsaicin, laser therapy, acupuncture, transcutaneous electrical nerve stimulation, and pulsed electromagnetic fields. No data specifically address the role of any of these therapies in hip osteoarthritis.     

Hyaluronic acid treatment (viscosupplementation) for OA of the knee

Viscosupplementation may be useful in the treatment of OA of the knee when other medical forms of therapy are contraindicated, toxic, or have failed. It may have a role in managing the patient with moderate to severe OA of the knee before considering total knee arthroplasty (Table 2). Viscosupplementation or medical treatment does not replace the need for thigh muscle strengthening or for overweight patients to lose weight. Whether or not efficacy will demand or warrant earlier or repeated use of hyaluronic acid-like products remains to be seen.     

Polyamine-enhanced NMDA receptor activity: effect of ethanol

Gastrointestinal symptoms and lesions are often associated with the clinical use of non-steroidal antiinflammatory drugs (NSAIDs). An open-label, single arm multicenter Italian study evaluated if misoprostol, a prostaglandin E1 analogue with gastroduodenal mucosal protective activity, was effective in the prevention and treatment of NSAID-induced gastroduodenal lesions. Patients affected by rheumatoid arthritis (RA) or osteoarthritis (OA), in treatment with NSAIDs and suffering from gastric symptoms or gastroduodenal lesions related to NSAID use, were admitted to the study. Gastrointestinal and arthritic symptoms were assessed before and after 4 weeks co-administration of an NSAID (the most frequent was diclofenac, used in 35% of the RA and in 22% of the OA patients, followed by piroxicam and tenoxicam respectively) + misoprostol (200 mcg two times daily in 58% of the cases, 200 mcg three times daily in 39%, 200 mcg four times daily in 3%). On admission and after 4 weeks of therapy a gastrointestinal endoscopy was performed to evaluate the condition of the gastroduodenal mucosa. Final results showed that: (i) NSAID-related gastric lesions were more frequent than duodenal lesions; (ii) when patients were given misoprostol and NSAIDs, 96% of them did not develop gastric lesions and 97% did not develop duodenal lesions; (iii) even when NSAID therapy was continued, gastric or duodenal lesions induced by NSAIDs healed or in any case did not worsen in 92% and 91% respectively of the cases; (iv) during the period of coadministration of NSAIDs+misoprostol, NSAID-related UGI symptoms disappeared or improved in 77% of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Management of osteoarthritis in older adults

Management of osteoarthritis (OA) is directed primarily towards relief of pain and functional limitation. This article discusses a range of nonpharmacologic modalities, including education, social support, weight reduction, and exercise. Drug treatment should begin with adequate doses of acetaminophen. Guidelines for appropriate use of NSAIDs also are suggested in this article. Intraarticular steroids help a proportion of patients, particularly those with OA of the knee or thumb base; the role of intraarticular therapies remains uncertain. Surgery (total joint replacement) remains an excellent treatment for patients in whom medical treatment has failed to provide adequate symptom relief. Future developments are likely to include earlier intervention using drugs with the potential to modify the course of the disease.     

Analgesic efficacy of paracetamol and its combination with codeine and caffeine in surgical pain--a meta-analysis

The objective of this study was to quantify the analgesic efficacy of paracetamol and its combination with codeine or caffeine through a systematic overview and meta-analysis of relevant randomized controlled trials (RCTs). Systematic retrieval of relevant clinical trials was carried out using computerized searches, historical searches and communication with manufacturers. The results of RCTs were pooled to estimate (i) the difference in percentage improvement of total pain relief (TOTPAR%) and the sum of pain intensity difference (SPID%); (ii) the proportions of patients obtaining moderate to excellent pain relief relative to placebo (ResRR) and (iii) the ratio of patients requiring analgesic re-medication (RemRR). Head-to-head comparisons were also undertaken for paracetamol versus its combination with codeine or caffeine. A total of 80 RCT reports describing 103 placebo comparisons and 26 head-to-head comparisons were identified. The total pain relief score in the single dose studies increased by 38 percentage points for paracetamol and by 24 points for placebo. The difference (d) in TOTPAR% between the two was highly significant (d = 14, 95% CI: 12, 16). For the difference in SPID%, d = 12, 95% CI: 11, 13. Patients were more than twice as likely to obtain moderate to excellent pain relief on paracetamol than on placebo (ResRR = 2.39, 95% CI: 1.89, 3.02), and less likely to require re-medication (RemRR = 0.78, 95% CI: 0.69, 0.88). There was no significant (P > 0.05) dose-response relationship. The analgesic efficacy of paracetamol 600 mg was enhanced with the addition of codeine 60 mg (using TOTPAR% as outcome) in both indirect and head-to-head comparisons. SPID%, but not ResRR and RemRR, data supported this conclusion. Much weaker effects were observed with the caffeine combination. Adverse effects were mild. Surprisingly, drowsiness was seen more often with paracetamol and paracetamol-codeine combinations than with placebo. The relative risks (95% CI) were 1.83 (1.29, 2.59) and 2.39 (1.58, 3.57), respectively. In conclusion paracetamol is an effective analgesic for post-surgical pain. Caffeine adds little to the analgesic effect of paracetamol. However, there is some evidence that codeine 60 mg adds to the analgesic effects of paracetamol 600 mg, using pain relief or pain intensity scores as outcomes, but this is not necessarily translated into an increase in number of patients who obtain moderate to excellent pain relief.     

A comparison of topical ketorolac, systemic flurbiprofen, and placebo for the inhibition of bone loss in adult periodontitis

Systemic non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce alveolar bone loss in periodontitis. This study assesses the efficacy of a topical NSAID rinse, containing ketorolac tromethamine as the active agent. Adult periodontitis patients (n = 55) were studied in this 6-month randomized, double blind, parallel, placebo and positive-controlled study. Each patient had a least 3 sites at high risk for bone loss as assessed by low dose bone scan. Groups, balanced for gender, were assigned to one of three regimens: bid ketorolac rinse (0.1%) with placebo capsule; 50 mg bid flurbiprofen capsule (positive control) with placebo rinse; or bid placebo rinse and capsule. Prophylaxes were provided every 3 months. Monthly examinations assessed safety, gingival condition, and gingival crevicular fluid PGE2. Standardized radiographs were taken at baseline and at 3 and 6 months for digital subtraction radiography. A significant loss in bone height was observed during the study period in the placebo group (-0.63 +/- 0.11; P < 0.001), but not in the flurbiprofen (-0.10 +/- 0.12; P = 0.40) or ketorolac rinse (+0.20 +/- 0.11 mm; P = 0.07) groups. Nested ANOVA revealed that ketorolac and flurbiprofen groups had less bone loss (P < 0.01) and reduced gingival crevicular fluid PGE2 levels (P < 0.03) compared to placebo. ANOVA suggests (P = 0.06) that ketorolac rinse preserved more alveolar bone than systemic flurbiprofen at the dose regimens utilized. These data indicate that ketorolac rinse may be beneficial in the treatment of adult periodontitis.     

Topical NSAIDs for musculoskeletal conditions. A review of the literature

In recent years a growing number of topical nonsteroidal anti-inflammatory drugs (NSAIDs) have become available. This has been prompted in large part by the high incidence of serious gastrointestinal adverse events associated with the use of systemic NSAIDs, and the premise that minimisation of plasma concentrations of active drug may result in fewer systemic adverse effects. Evidence in humans and animals with topical NSAIDs demonstrates lower plasma concentrations than with systemically administered drugs, while those in soft tissues are still of a magnitude considered consistent with exerting an anti-inflammatory effect. In joints, however, the evidence is less strong, and there is still dispute whether in this case the drug reaches the joint predominantly via the transcutaneous or systemic route. There has been a sufficient number of studies of soft tissue conditions to demonstrate the superiority of topical NSAIDs over placebo and to suggest equivalent efficacy in comparison with some oral NSAIDs. For arthropathies, however, the literature is more sparse. Although several studies claim a benefit for topical NSAIDs against placebo, the results are less conclusive and further study is required. Trials of topical agents against intra-articular corticosteroids and rubefacients are either lacking or inconclusive. The adverse event profile of topical agents is reasonable: minor cutaneous effects occur in up to 2% of patients but tend to be self-limiting. Gastrointestinal events appear from the existing literature to be infrequent and minor, although long term studies are required. Bronchospasm and renal impairment have been reported and may be more frequent in patients who have experienced these effects with oral agents. The initial costs of topical agents tend to be higher than those of oral agents but a cost-effectiveness analysis suggests an overall benefit: this issue requires further clarification.     

A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have well-known gastrointestinal and renal toxic reactions. Effects of NSAIDs on blood pressure are less appreciated. A meta-analysis was performed to determine the hypertensive effects of NSAIDs and rank them by magnitude of change in mean arterial pressure (MAP). METHODS: A literature search of published English-language studies of NSAIDs and their effects on blood pressure was done. Studies were included if they met the following criteria: (1) the studies were intervention studies; (2) NSAIDs at any dose or aspirin at doses of 1.5 g/d or greater were included; (3) documentation of blood pressure was provided; and (4) the studies were 24 hours in duration. Studies were excluded if 20% or more of their participants dropped out or if the dose of antihypertensive drugs was adjusted while the subjects were taking NSAIDs. The major outcome was change in MAP while patients were receiving NSAIDs. Each NSAID arm was extracted from its trial. Information on possible confounders, including subject age, trial quality, amount of dietary salt intake, and whether study subjects were hypertensive or normotensive, was recorded. We calculated the average change in MAP on each NSAID, adjusting for confounders. RESULTS: Fifty-four studies with 123 NSAID treatment arms met inclusion criteria. The mean age of subjects was 46 years. Of the 1324 participants, 1213 subjects (92%) were hypertensive. The effects of NSAIDs on blood pressure were found solely in hypertensive subjects. Among these, the increase in MAP after adjusting for amount of dietary salt intake was 3.59 mm Hg for indomethacin (57 treatment arms), 374 mm Hg for naproxen (four arms), and 0.49 mm Hg for piroxicam (four arms). The MAP decreased by 2.59 mm Hg for placebo (10 arms), 0.83 mm Hg for ibuprofen (six arms), 1.76 mm Hg for aspirin (four arms), and 0.16 mm Hg for sulindac (23 arms). The effects on MAP by using placebo, sulindac, and aspirin were statistically significantly different from indomethacin. CONCLUSIONS: In short-term use, NSAIDs vary considerably in their effect on blood pressure. Of the drugs studied, indomethacin and naproxen were associated with the largest increases in blood pressure. The average effects of piroxicam, aspirin, ibuprofen, and sulindac were negligible.     

The impact of ibuprofen on the efficacy of antihypertensive treatment with hydrochlorothiazide in elderly persons

BACKGROUND: Nonsteroidal antiinflammatory drugs (NSAIDs) may alter blood pressure through their inhibitory effects on prostaglandin biosynthesis. Such potential hypertensive effects of NSAIDs have not been adequately examined in the elderly, who are the largest group of NSAID users. METHODS: We performed a randomized, double-blind, two-period crossover trial of ibuprofen (1800 mg per day) vs placebo treatment in patients older than 60 years of age with hypertension controlled with hydrochlorothiazide. While continuing their usual thiazide dosage, subjects were randomized to a 4-week treatment period (ibuprofen or placebo) followed by a 2-week placebo wash-out period and a second 4-week treatment period with the alternative therapy. Supine and standing systolic and diastolic blood pressures were measured weekly. RESULTS: Of 25 randomized subjects, 22 completed the study protocol (mean age = 73 +/- 6.7 years). Supine systolic blood pressure and standing systolic blood pressure were increased significantly with ibuprofen treatment, compared with placebo. Mean supine systolic blood pressures were 143.8 +/- 21.0 and 139.6 +/- 15.9 mmHg on ibuprofen and placebo, respectively (p = .004). Mean standing systolic blood pressures were 148.1 +/- 19.9 and 143.4 +/- 17.9 mmHg on ibuprofen and placebo, respectively (p = .002). CONCLUSION: We conclude that 1800 mg per day of ibuprofen does induce a significant increase in systolic blood pressure in older hypertensive patients treated with hydrochlorothiazide. NSAID therapy may negatively impact the control of hypertension in elderly patients.     

Epidermoid carcinoma of the esophagus in caustic esophageal stenosis

A prospective study of the effectiveness of the topical application of non-steroidal anti-inflammatory drugs (NSAIDs) as a gel preparation was carried out in 26 women with severe breast pain. The results showed a satisfactory relief of pain in 81% of the women: 11 of 13 with cyclical pain, eight of 11 with non-cyclical pain, and in two women with severe scar pain after lumpectomy and radiotherapy. Topical NSAID gel was applied as required; the relief of severe pain was rapid and no side effects were reported. These factors compare favourably with established recommended treatments which usually involve months of continuous treatment, tailoring of drug dosages and a significant incidence of intolerable side effects. This study has shown that topical NSAID application is an effective, safe, acceptable and easily administered treatment for severe cyclical and non-cyclical breast pain.     

Direct observation of DNA translocation and cleavage by the EcoKI endonuclease using atomic force microscopy

OBJECTIVES: To determine whether antibiotic prophylaxis reduces respiratory tract infections (RTI) and overall mortality in an unselected adults intensive care population. SEARCH STRATEGY: Systematic literature search in peer-reviewed journals indexed in MEDLINE, examination of relevant proceedings of scientific meetings and personal contact with trialists. SELECTION CRITERIA: All randomised clinical trials (RCTs), published and unpublished, comparing different forms of antibiotic prophylaxis used to reduce RTIs and mortality in unselected adult intensive care units (ICUs) populations. DATA COLLECTION AND ANALYSIS: Out of the 32 RCTs eligible for this review data have been extracted from published reports and then complemented with information provided by study investigators for 29 trials. Data were available only from published reports in the remaining three RCTs. For each trial the following information has been sought: a) method of randomisation; b) use of blinding techniques; c) number of randomised patients; d) number of patients with RTIs; e) number of deaths; f) number of patients excluded from the published analysis; g) number of RTIs and number of deaths among excluded patients. Pooled estimates of treatment effects across trials have been calculated after grouping RCTs in two main, mutually exclusive, categories: a) 15 trials testing the effect of a combination of a topical and a systemic antibiotic against no prophylactic treatment; b) 17 trials where the experimental treatment was a topical antimicrobial preparation. Crude proportions of RTIs and mortality were used to calculate the overall treatment effect. We also computed the number of ICU patients who need to be treated in order to prevent one infection and one death. MAIN RESULTS: Overall 32 RCTs including 5639 patients were identified. Pooled estimates of the 15 RCTs (including 3273 patients) testing the effect of the topical and systemic antibiotic combination indicate a strong significant reduction of both RTIs (OR = 0.36, 95% CI = 0.30-0.43) and total mortality (OR = 0.80, 95% CI = 0.68-0.93). Five and 23 patients need to be treated to prevent one infection and one death, respectively, using this treatment. When data on the effect of the combination based on topical antimicrobials were pooled from the 17 available trials (including 2366 patients) a marked reduction on RTIs (OR = 0.57, 95% CI = 0.46-0.69) also emerged but no corresponding effect on overall mortality (OR = 1.01; 95% CI = 0.84-1.22) was found. CONCLUSIONS: After 15 years of clinical research this meta-analysis of 32 RCTs shows that a regimen of antibiotic prophylaxis based on a combination of a systemic and topical antibiotic can reduce both RTIs and overall mortality in ICU patients in a way that is both statistically significant and humanly worthwhile. Over and above their personal opinions intensivists should take this evidence into account when defining their policies.     

NSAID-induced polyp regression in familial adenomatous polyposis patients

NSAIDs inhibit prostaglandin synthesis. In 1983, Waddell et al first reported that sulindac, a NSAID (Clinoril), caused regression of rectal adenomatous polyps in several patients with familial adenomatous polyposis, an inherited form of colorectal cancer. Subsequently, NSAIDs have been used as chemopreventive agents in animal carcinogenesis models and adenoma regression had been confirmed in human trials with sulindac. This article summarizes these developments and describes possible mechanisms of colorectal neoplasia chemoprevention.