Systemic Nonsteroidal Anti-inflammatory Drugs Research Articles

Pharmacotherapy for regional musculoskeletal pain.

Studies performed on drug therapy in regional musculoskeletal pain conditions are of varying quality, and this is related to several methodological problems. The efficacy of analgesic medications is well established from clinical practice. However, both weak and especially strong opioid analgesics are associated with adverse reactions and also with dependency and abuse. The use of anti-depressants and skeletal muscle relaxants is only weakly supported by results from controlled clinical trials. The efficacy of both systemic and topical non-steroidal anti-inflammatory drugs (NSAIDs) has been examined in several Cochrane reviews of various regional musculoskeletal pain conditions. Studies of COX-2 selective NSAIDs have not been performed in conditions with regional musculoskeletal pain, but it is assumed that COX-2 selective inhibitors will not differ from dual COX inhibitors regarding efficacy. Therefore, some of the recent controversies related to gastrointestinal safety and possible risk of myocardial infarctions are also discussed.

Multimodal analgesia and intravenous nutrition preserves total body protein following major upper gastrointestinal surgery

Background and Objectives: This study examined whether perioperative multimodal analgesia (MMA) improves the effectiveness of intravenous nutrition (IVN) as a means of preventing protein wasting following major upper abdominal surgery (UAS). The MMA regimen utilized combined epidural opioid/local anesthetic and the systemic nonsteroidal anti-inflammatory drug (NSAID) ketorolac for 48 hours. Methods: In a prospective, randomized, nonblinded study, 47 patients scheduled for major UAS were allocated to receive the following: MMA [plusmn] intravenous lipid-based nutrition (IVN) or patient-controlled analgesia with opioids (PCA) [plusmn] IVN. Pain scores, nitrogen balance, total body protein (TBP), arterial blood gases, and various hormones were measured. Results: Pain control was significantly better in the MMA patients at rest and coughing. Only the MMA + IVN group maintained TBP, mean ([plusmn]95% confidence interval) preoperative day 1, 10.5 ([plusmn]1.0) kg; day 14, 10.7 ([plusmn]1.2) kg, whereas TBP decreased in the other groups (P = .04). Nitrogen balance was significantly greater in patients receiving IVN on day 7 (P = .01), but there was no effect related to the analgetic regimen. Decreased PaO2 seen on postoperative day 2 was not prevented by MMA. The hormonal response to surgery was not influenced by treatment modality, apart from a return to postprandial insulin levels on postoperative day 7 in those patients receiving IVN (P = .002). Conclusions: In conclusion, we have shown that the combination of MMA and IVN prevents protein loss and improves pain control after major UAS. Our results suggest that after UAS, MMA significantly reduced pain and, in combination with IVN, preserves total body protein and fat. This is the first direct evidence of such effects associated with a commonly used multimodal regimen. Reg Anesth Pain Med 2002;27:15-22.

Konsequenzen und Kosten der NSA-Gastropathie in Deutschland1

In an appreciable percentage of cases the use of systemic nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with adverse reactions ranging from lesions of the gastrointestinal mucosa to life-threatening perforations, ulcers and bleeding (PUB). Yet the consequences and costs of preventing and treating these adverse effects in Germany have never been investigated. We therefore recruited 18,177 patients who were issued 66,637 non-acetyl-acid NSAID prescriptions in the period between January 1996 and June 1998 (MediPlus, IMS Health) and compared the unit and cost rates of predefined gastrointestinal drug groups in the first 30 days with their rates on day 90 following NSAID prescription. We calculated hospital stays due to NSAID-induced PUB on the basis of the age- and sex-standardized PUB background risk of NSAID users in Germany, the relative NSAID risk from published meta-analysis, and the number of daily NSAID doses supplied by pharmaceutical wholesalers to public pharmacies in 1998. All reported resources were adjusted by the NSAID-free background rate. The following contributed to the total DM 101 million expenditure of the German statutory health-insurance fund (GKV): NSAID-associated H2-receptor antagonists (DM 31 million), proton pump inhibitors (DM 29 million), other antacids and ulcer drugs (DM 15 million), antidiarrheals and digestants (DM 12 million), spasmolytics, anticholinergic and gastroprokinetic agents (DM 10 million), prostaglandin ulcer drugs (DM 2 million), antiemetic and antinausea drugs (DM 1 million) and bismuth ulcer drugs (<DM 1 million). This compares with 10,700 NSAID-related hospital admissions for PUB in the GKV resulting in 157,000 hospital days and costs of DM 125 million. Conclusion: Under current practice, nearly a quarter of a billion DM annually is invested for the treatment NSAID-induced side effects, at an estimated 1,100 to 2,200 NSAID-associated deaths a year among the about 73 million members of the GKV. Anti-inflammatory drugs with a significantly lower gastrointestinal risk may help to resolve a serious quality- assurance problem in public health.

Effects of Magnoliae Cortex and Zizyphi Fructus Extract Mixtures on the Progression of Experimental Periodontitis in Beagle Dogs

Periodontal disease is an inflammatory process caused by periodontopathic microorganisms in dental plaque. Numerous studies have interested in the use of antimicrobial agents to eradicate or decrease number of putative periodontal pathogenic microorganisms. Another approach has focused on the use of chemotherapeutic agents to modulate the host response. In the view of general reluctance to use antibiotics for the treatment of chronic infections with such a wide prevalence, interest has been directed largely towards the antiseptics. Most commonly used antiseptics in clinical periodontics are bisbiguanides, phenolic compounds, quaternary ammonium compounds, and etc. While these agents have been used for many years, they have exhibited many drawbacks such as tooth staining, development of resistant strains and desquamation of oral epithelium1-3). Systemic non-steroidal anti-inflammatory drugs (NSAIDs) therapy have been shown to arrest periodontal disease progression in animal models4-7) and clinical trials8-11). Although relative low dose systemic NSAIDs therapy has been successfully used to slow the rate of periodontal disease progression, its use also involves side effects such as gastrointestinal trouble12). In a previous study, it was suggested that magnolia and honokiol isolated from the stem bark of Magnolia obovate Thunb. have a significant antimicrobial activity against periodontopathic bacteria13). It was reported that Zizyphi fructus extract may prevent glucan production by cariogenic bacteria14) and prevent production of IL-1 βand PGE215, 16). This study focuses on the effect of oral administration of Magnoliae cortex and Zizyphi fructus extract mixtures on the disease progression in beagle dogs with ligature-induced experimental periodontitis.

Combination of Diclofenac and Intrathecal Morphine for Cesarean Delivery

In Response: We appreciate Pavy et al.'s comments on our study. Although the rationale behind our study and that of Pavy et al.'s [1] is the same, the study designs are considerably different and certainly limit comparisons. In our study, we did not objectively differentiate the components of pain after cesarean delivery. However, it is our opinion that the results of Pavy et al. (2), that contraction pain was similar in study and control patients, clearly reflect pharmacokinetic limitations of their therapeutic regimen. It is unreasonable to expect similar effects for indomethacin suppositories and diclofenac intramuscular injections. Plasma levels determined by suppositories are much lower and delayed compared with those determined by intramuscular administration. Diclofenac suppositories are shown to be ineffective as a supplement to our small-dose intrathecal morphine technique, especially in the first 6 h postpartum (unpublished data). We do not agree that such a large dose of intrathecal morphine, as proposed by Pavy et al., is necessary to provide a comfortable postoperative period after cesarean delivery. In our study, no patient receiving diclofenac and morphine requested additional analgesic in the first 24 h postpartum. Although pain on movement was not objectively assessed, our patients were encouraged to ambulate 8 h postdelivery and were free to request pain medication. In their study, however, even with such a large dose of morphine (10 times larger) combined with indomethacin, some patients still requested additional analgesics. Pavy et al. counted on the effect of a very large dose of morphine and probably on a minor, yet clinically significant effect, of indomethacin, whereas we counted on a very small dose of morphine and on a significant effect of diclofenac. In our opinion, the advantages claimed by Pavy et al. in terms of efficacy of their therapeutic regimen are not clear. A major problem we see with the dose of morphine proposed by Pavy et al., which should limit the acceptance of their technique in clinical practice, is the high incidence of side effects. All but one of their patients exhibited itching on the first postoperative day; unfortunately, the authors did not report the severity of such a side effect. Additionally, some patients exhibited severe nausea (visual analog scale score 100) on the first postoperative day; unfortunately the authors again did not report the incidence. We have used this technique for >2 yr in >24,000 patients, with excellent clinical results and wide acceptance by patients, surgeons, and nursing staff. We strongly suggest that the smallest possible effective dose of intrathecal opioids should be used to avoid side effects, including respiratory depression. We agree with Pavy et al. that this will only be possible by using a multimodal approach to pain control. In that case, systemic nonsteroidal antiinflammatory drugs play a major role. A closer look at their mechanism of actions, especially at the clinical implications of their pharmacokinetics, is certainly worthwhile. Jose C. A. Carvalho, MD, PhD, FANZCA Antonio R. Amaro, MD Elizabeth L. Cappelli, MD Monica M. S. C. Cardoso, MD Ademar A. Prado, MD Department of Anesthesiology; Hospital e Maternidade Santa Joana; 04031-000 Sao Paulo, Brazil

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.

Visual Outcomes Prognosticators in Juvenile Rheumatoid Arthritis-associated Uveitis

Purpose: The purpose of the study is to delineate the visual prognosticators in juvenile rheumatoid arthritis-associated uveitis.Methods: The records of 43 patients with juvenile rheumatoid arthritis-associated uveitis who were observed for at least 6 months were studied retrospectively. Bivariate and multivariate statistical models were applied to more than 40 parameters to determine the relative odds of visual rehabilitation among patients with each characteristic.Results: Thirty-seven (86%) patients were females and 6 (14%) males. The mean known age of uveitis onset was 13 years, with females having, on average, 4 years earlier onset of disease compared to males (P = 0.04). Ninety-three percent had chronic, 5% had recurrent, and 2% had an acute monophasic disease course. Of the 76 affected eyes, 93% were nongranulomatous and 97% had iridocyclitis. The mean overall duration of uveitis was 146 months, with females suffering from a significantly longer duration of active disease than did males (P < 0.001). Nineteen (44%) patients underwent cataract extraction, and 16 (37%) underwent vitrectomy. Thirty (70%) of the patients experienced visual improvement with their therapy. When controlling for potential confounders, male sex (P = 0.006), shorter duration of uveitis (P = 0.007), older age at disease onset (P = 0.02), and a shorter delay in presentation to a subspecialist (P = 0.02) were associated significantly with visual acuity improvement. Visual acuity at presentation (P = 0.001), use of systemic nonsteroidal anti-inflammatory drugs (P = 0.01), older age at disease onset (P = 0.02), absence of glaucomatous neuropathy (P = 0.02), and male sex (P = 0.03) were correlated strongly with a final visual acuity outcome of 20/40 or better.Conclusion: Juvenile rheumatoid arthritis-associated uveitis is a serious disease with a guarded visual prognosis. It is hoped that increased awareness of its prognosticators will lead to treatment and referral patterns that have the best chance of minimizing the likelihood of visual impairment in patients with juvenile rheumatoid arthritis.

Metacarpophalangeal joint synovial pad fibrotic proliferation in 63 horses.

Medical records, radiographs, and sonograms of 63 horses with metacarpophalangeal joint synovial pad proliferation were examined retrospectively. All horses had lameness, joint effusion, or both signs associated with one or both metacarpophalangeal joints. Bony remodeling and concavity of the distodorsal aspect of the third metacarpal bone (Mc3) just proximal to the metacarpal condyles was identified by radiography in 71 joints (93%); 24 joints (32%) had radiographic evidence of a chip fracture located at the proximal dorsal aspect of the proximal phalanx. Fifty-four joints (71%) were examined by ultrasound. The mean +/- SD sagittal thickness of the synovial pad was 11.3 +/- 2.8 mm. Seventy-nine percent of the horses had single joint involvement with equal distribution, between the right and left forelimbs. Sixty-eight joints in 55 horses were treated by arthroscopic surgery. Sixty joints (88%) had debridement of chondral or osteochondral fragmentation from the dorsal surface of Mc3 beneath the synovial pad and 30 joints (44%) had a bone chip fracture removed from the medial or lateral proximal dorsal eminence of the proximal phalanx. Complete or partial excision of both medial and lateral synovial pads was completed in 42 joints. Only the medial synovial pad was excised or trimmed in 21 joints, and 5 joints had only the lateral pad removed. Eight joints in eight horses were treated by stall rest, administration of intra-articular medication and systemic nonsteroidal anti-inflammatory drugs. Follow-up information was obtained for 50 horses treated surgically and for eight horses treated medically. Forty-three (86%) that had surgery returned to racing; 34 (68%) raced at an equivalent or better level than before surgery. Three (38%) of the medically treated horses returned to racing; only one horse raced better than the preinjury level. Horses that returned to racing at a similar or equal level of performance were significantly younger in age than horses returning at a lower level or not racing (P < or = .05). Overall, horses with synovial pad proliferation treated by arthroscopic surgery had a good prognosis for return to racing at a level equal or better than before injury.

Episcleritis and Scleritis: Diagnosis and Therapy

Episcleritis and scleritis are distinct forms of external ocular inflammation with different clinical and therapeutic considerations and prognostic implications. Episcleritis is a self-limited disease involving the superficial aspect of the sclera, with symptoms usually limited to mild discomfort. Scleritis is a potentially blinding disease that is usually severely painful. It is frequently associated with a systemic autoimmune disorder, such as rheumatoid arthritis, Wegener's granulomatosis, or Crohn's disease, and may be the first clinically apparent manifestation of that disorder. Necrotizing scleritis is a severely destructive form of the disease caused by local and often a systemic vasculitis. Although episcleritis infrequently requires therapy, scleritis requires systemic anti-inflammatory therapy. Systemic nonsteroidal anti-inflammatory drugs and corticosteroids are the mainstay of scleritis therapy with necrotizing scleritis frequently requiring systemic cytotoxic immunosuppressive therapy. The co...

Aspirin and acetaminophen reduced both Fos expression in rat lumbar spinal cord and inflammatory signs produced by carrageenin inflammation

This study, performed in freely moving rats, evaluates the effects of the two most prescribed analgesics, aspirin and acetaminophen, on carrageenin inflammation and the associated c-Fos expression in the rat lumbar spinal cord. Maximal dorsal horn c-Fos expression is observed 3 h after carrageenin (6 mg/150 μl of saline), with Fos-like (Fos-LI) neurones being predominantly located in laminae I–II and V–VI (41 ± 3% and 39 ± 5% of the total number of Fos-LI neurones per section for the control group, respectively) of the dorsal horn. Pretreatment with aspirin (75 or 150 mg/kg, i.v.) reduced the number of Fos-LI neurones induced by carrageenin-inflammation (28 ± 2% and 45 ± 1% reduction, respectively; P < 0.001 for both). Acetaminophen (75 or 150 mg/kg, i.v.) reduced the number of Fos-LI neurones (19 ± 1% and 43 ± 1% reduction, respectively; P < 0.001 for both). When considering the lower dose (75 mg/kg), the effects of aspirin were significantly more marked than those of acetaminophen ( P < 0.001). There was a tendency for both aspirin and acetaminophen to have a more pronounced effect on the number of Fos-LI neurones located in deeper laminate, these differential effects being significant for 75 mg/kg of aspirin ( P < 0.01) and 150 mg/kg of acetaminophen ( P < 0.01). Both the two doses of aspirin and acetaminophen greatly reduced the inflammatory signs associated with the intraplantar injection of carrageenin. Furthermore there was a positive correlation between the effects of aspirin and acetaminophen on the number of Fos-LI neurones and the inflammatory signs which developed after carrageenin. Our results suggest that the effects of both drugs are mainly due to a peripheral site of action without rejecting an additional central site of action of systemic non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. In addition, our results suggest that the approach we used could be a useful tool to evaluate systematically and quantitatively the effects of NSAIDs. Finally, the effects obtained with the low dose of acetaminophen question the classical view of textbooks claiming that such a compound had no anti-inflammatory effect and are in agreement with previous observations in humans (Skjelbred and Lökken 1979; Skjelbred et al. 1984).

Topical Cyclosporine for Treating Necrotizing Scleritis

Anterior scleritis is a serious, potentially sight-threatening inflammatory disease that may present in diffuse, nodular, or necrotizing forms. Topical corticosteroid treatment is often inadequate, and patients with this condition require systemic non-steroidal anti-inflammatory drugs, corticosteroids, or immunosuppressive agents. 1 Systemic cyclosporine has been successfully used for treating severe scleritis, but significant nephrotoxicity, hypertension, hepatoxicity, tremor, hirsutism, and gingival hyperplasia have been associated with its use. 1,2 Recently, topical cyclosporine has been reported to be of benefit in various eye diseases, including scleritis, 2 and we now report another case. Report of a Case. We examined a 68-year-old white woman with a 6-week history of an inflamed right eye that had not responded to a regimen of topical prednisolone acetate and flurbiprofen sodium (0.03%), along with oral indomethacin (25 mg three times a day). She was found to have a large, inflamed superonasal scleral nodule with reactive ptosis ( Figure 1 ). Her

Treatment Strategies for Scleritis and Uveitis Associated With Inflammatory Bowel Disease

We treated 19 patients with anterior uveitis, episcleritis, or scleritis associated with inflammatory bowel disease. Adequate control of ocular inflammation was achieved in 16 patients (84%). Ocular inflammation was adequately controlled with corticosteroids alone, without systemic adverse effects, in only three patients, all of whom had anterior uveitis associated with ulcerative colitis. Systemic nonsteroidal anti-inflammatory drugs proved beneficial in six of seven patients, and one additional patient benefited from another anti-inflammatory drug (hydroxychloroquine sulfate). Systemic cytotoxic immunosuppressive therapy was used in the remaining seven patients, six of whom had bilateral disease. Ocular inflammation was controlled in six of these patients. Azathioprine was beneficial for scleritis but was less effective for anterior uveitis, especially in Crohn's disease, thus necessitating the use of another cytotoxic agent. HLA-B27-positive anterior uveitis was more refractory to corticosteroid therapy and was more likely to require systemic cytotoxic immunosuppressive therapy. With the medical and surgical strategies described, vision was improved or maintained in all patients in the study group.

Cataract Surgery in Patients with Sarcoidosis-associated Uveitis

The authors analyzed the incidence of cataract development and the visual outcome of cataract surgery performed on patients with sarcoidosis-associated uveitis who were treated at the Immunology Service at the Massachusetts Eye and Ear Infirmary during a 17-year period. The records of 102 patients with sarcoidosis-associated uveitis who were treated with topical and regional corticosteroids, systemic nonsteroidal anti-inflammatory drugs, systemic steroids, or with systemic immunosuppressive chemotherapy were reviewed. Cataract surgery was performed on those eyes in which cataract developed, resulting in decreased visual acuity of 20/100 or less. The incidence of cataract development and visual results of cataract extraction and intraocular lens implantation were analyzed. In this cohort of 102 patients, visually significant cataracts that warranted surgery developed in 10 (16 eyes). In addition, four patients (5 eyes) had a visually significant cataract at the time of first evaluation. A total of 14 patients (21 eyes) underwent cataract surgery. Posterior chamber lens implantation accompanied cataract surgery in 19 (90.5%) of 21 eyes. The average final visual acuity of the 21 eyes after cataract surgery was 20/51, and 61% of the eyes achieved a stable visual acuity of 20/40 or better. The major causes of the decreased visual acuity in patients who had less than 20/40 visual acuity were sequelae of chronic posterior uveitis, cystoid macular edema, epiretinal membrane, and glaucomatous optic nerve damage. Posterior chamber lens implantation and cataract surgery in patients with sarcoidosis-associated uveitis can be well tolerated when absolute control of the inflammation is achieved. Pre-existing retinal pathology and glaucoma as a result of uncontrolled inflammation resulting in permanent ocular structural damage were found to be the most important factors for determining the postoperative final visual acuity.

An Analysis of Therapeutic Decision for Scleritis

To compare the long-term efficacy of different systemic therapeutic regimens for patients with noninfectious anterior scleritis to establish guidelines for institution of therapy. Therapeutic failure of systemic nonsteroidal anti-inflammatory drugs (NSAIDs), systemic steroidal anti-inflammatory drugs, and systemic nonsteroidal immunosuppressive drugs was evaluated in 132 patients with noninfectious anterior scleritis (diffuse, nodular, or necrotizing types). In patients with diffuse scleritis, therapeutic failure for initial regimens occurred in 7% of patients treated with NSAIDs, in 16% of patients treated with steroids, and in 27% of patients treated with immunosuppressive drugs. In patients with nodular scleritis, therapeutic failure for initial regimens occurred in 9% of patients treated with NSAIDs, in 28% of patients treated with steroids, and in 25% of patients treated with immunosuppressive drugs. Addition or substitution of steroids or immunosuppressive drugs as second- or third-line therapies helped control the scleritis. In patients with necrotizing scleritis, therapeutic failure for initial regimens occurred in 100% of patients treated with NSAIDs, in 91% of patients treated with steroids, and in 26% of patients treated with immunosuppressive drugs. In patients with diffuse and nodular scleritis, NSAIDs should be the initial choice; in case of therapeutic failure, steroids should be added or substituted as second-line therapy, tapering and discontinuing them as soon as possible while maintaining remission with continued NSAIDs; in case of therapeutic failure, immunosuppressive drugs should be added or substituted as third-line therapy. In patients with necrotizing scleritis, immunosuppressive drugs should be the initial choice.

Cataract Development and Cataract Surgery in Patients with Juvenile Rheumatoid Arthritis-associated Iridocyclitis

The authors used an aggressive stepladder, steroid-sparing, therapeutic algorithm in the care of patients with iridocyclitis associated with juvenile rheumatoid arthritis (JRA) to preserve vision, limit cataract formation, and improve probability of successful visual rehabilitation when cataract surgery became necessary. The authors treated 60 patients with JRA-associated iridocyclitis with topical and regional corticosteroids, systemic nonsteroidal anti-inflammatory drugs, systemic steroids, and systemic immunosuppressive chemotherapy to achieve total quiescence of intraocular inflammation. Cataract surgery (phacoemulsification extracapsular cataract extraction) combined with pars plana vitrectomy was performed on those eyes with cataract sufficient to limit visual acuity to 20/200 or less, after maintenance of complete freedom from inflammation for at least 3 months. The incidence of cataract development and the visual outcome of cataract surgery were analyzed in those patients for whom a minimum follow-up of 1 year was available. Eventually, 10 of the 60 patients required systemic immunosuppressive chemotherapy in the stepladder therapeutic approach to achieve complete abolition of all active inflammation. Of 72 phakic eyes without cataract, significant cataract developed in 13 (18%) while under our care. The average postoperative stable visual acuity in this group was 20/40. Sixteen eyes of 12 additional patients had visually significant cataract at the time of our first evaluation of them. The average postoperative stable visual acuity in this group of patients after cataract surgery was 20/40. Iridocyclitis associated with JRA is an insidiously blinding disease, with 12% of individuals affected by this problem eventually blinded by the inflammatory consequences to the eye. A therapeutic philosophy of complete intolerance for active inflammation and limited tolerance for chronic steroid use may offer the most realistic hope for the next step in progress to prevent blindness in this patient population. The results of this study suggest that such a therapeutic attitude results in diminished cataract prevalence and decreased prevalence of vision-limiting retinal pathology, with resultant improved visual outcome of the cataract surgery which is eventually needed in a small proportion of the patients.

Cutaneous Reactions to Analgesic-Antipyretics and Nonsteroidal Anti-Inflammatory Drugs

We analyzed the cutaneous reactions to systemic analgesic-antipyretics and non-steroidal anti-inflammatory drugs reported to the spontaneous reporting system of the Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED). The system has been active since 1988, with periodic intensive surveillance exercises, and 202 dermatologists have collaborated. Up to December 1991, 2,137 reactions had been collected, of which 713 were reactions to systemic analgesic-antipyretics and nonsteroidal anti-inflammatory drugs. A general profile of the reactions was identifiable. It included, in order of frequency, urticaria/angioedema, fixed eruptions, exanthemas, erythema multiforme and Stevens Johnson syndrome. Fixed eruptions and Stevens Johnson syndrome were reported with exceedingly high frequency in association with feprazone. Our system also revealed previously unreported reactions, including fixed eruption to nimesulide, fixed eruption to piroxicam and fixed eruption to flurbiprofen.

Effects of systemic non-steroidal anti-inflammatory drugs on nociception during tail ischaemia and on reperfusion hyperalgesia in rats.

1. We have investigated the effects of five non-steroidal anti-inflammatory drugs (NSAIDs) on nociception during ischaemia and on reperfusion hyperalgesia in rats. 2. We induced tail ischaemia in conscious rats by applying a tourniquet at the base of the tail until the rats exhibited co-ordinated escape behaviour when we released the tourniquet. 3. We assessed hyperalgesia by measuring the tail flick latency following tail immersion in water at 49 degrees C, before applying and immediately after releasing the tourniquet, and then at 30 min intervals for 2 h. 4. Intraperitoneal injection of NSAIDs prior to applying the tourniquet had no effect on the co-ordinated escape behaviour during ischaemia, nor on tail flick latency in the absence of prior ischaemia. However all the drugs attenuated reperfusion hyperalgesia in a log dose-dependent manner. Doses required to abolish hyperalgesia, were indomethacin 5 mg kg-1, diclofenac sodium 42 mg kg-1, ibuprofen 54 mg kg-1, dipyrone 168 mg kg-1 and paracetamol 170 mg kg-1. 5. We conclude that the mechanisms underlying nociception during ischaemia are not the same as those underlying reperfusion hyperalgesia. Moreover our procedure provides a rapid and more humane method for measuring the antinociceptive potency of NSAIDs.

A double-blind comparison of naproxen gel and placebo in the treatment of soft tissue injuries

A double-blind study was carried out in 120 patients who had received soft tissue injuries within the preceding 48 hours to compare the effectiveness of naproxen gel (10%) with placebo gel (base alone). The injuries were predominantly synovitis and tendinitis. Standard clinical evaluations of the patients' condition were made by physicians and patients on entry and after 3 and 7 days of treatment. Both treatments resulted in a significant improvement in symptoms, but naproxen gel was significantly superior to placebo gel (p less than 0.05). The response produced by naproxen was more rapid; all symptoms were significantly improved by Day 3 (p less than 0.05). The greater efficacy of naproxen was reflected in a lower usage of active drug compared with placebo which was consistent throughout the study. While the physicians' global assessments of the two gels did not differ significantly, the patients showed a preference in favour of naproxen (p less than 0.05) Naproxen gel was well tolerated; only 1 adverse event of itching occurred. It is suggested that naproxen gel offers an effective and convenient alternative to systemic non-steroidal anti-inflammatory drugs for patients where side-effects are to be avoided or when oral administration is undesirable.

Lateralization of facial pain, emotionality and affective disturbance

This study, performed in freely moving rats, evaluates the effects of the two most prescribed analgesics, aspirin and acetaminophen, on carrageenin inflammation and the associated c-Fos expression in the rat lumbar spinal cord. Maximal dorsal horn c-Fos expression is observed 3 h after carrageenin (6 mg/150 μl of saline), with Fos-like (Fos-LI) neurones being predominantly located in laminae I–II and V–VI (41 ± 3% and 39 ± 5% of the total number of Fos-LI neurones per section for the control group, respectively) of the dorsal horn.Pretreatment with aspirin (75 or 150 mg/kg, i.v.) reduced the number of Fos-LI neurones induced by carrageenin-inflammation (28 ± 2% and 45 ± 1% reduction, respectively; P < 0.001 for both). Acetaminophen (75 or 150 mg/kg, i.v.) reduced the number of Fos-LI neurones (19 ± 1% and 43 ± 1% reduction, respectively; P < 0.001 for both). When considering the lower dose (75 mg/kg), the effects of aspirin were significantly more marked than those of acetaminophen (P < 0.001). There was a tendency for both aspirin and acetaminophen to have a more pronounced effect on the number of Fos-LI neurones located in deeper laminate, these differential effects being significant for 75 mg/kg of aspirin (P < 0.01) and 150 mg/kg of acetaminophen (P < 0.01). Both the two doses of aspirin and acetaminophen greatly reduced the inflammatory signs associated with the intraplantar injection of carrageenin. Furthermore there was a positive correlation between the effects of aspirin and acetaminophen on the number of Fos-LI neurones and the inflammatory signs which developed after carrageenin.Our results suggest that the effects of both drugs are mainly due to a peripheral site of action without rejecting an additional central site of action of systemic non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. In addition, our results suggest that the approach we used could be a useful tool to evaluate systematically and quantitatively the effects of NSAIDs.Finally, the effects obtained with the low dose of acetaminophen question the classical view of textbooks claiming that such a compound had no anti-inflammatory effect and are in agreement with previous observations in humans (Skjelbred and Lökken 1979; Skjelbred et al. 1984).