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Diclofenac in the treatment of ankylosing spondylitis: Review of worldwide clinical experience and report of a double-blind comparison with indomethacin

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Abstract

Diclofenac sodium, a phenylacetic acid derivative, is a nonsteroidal anti-inflammatory drug (NSAID) that has been proven both safe and effective in numerous worldwide clinical trials in the treatment of several rheumatoid conditions, including ankylosing spondylitis. In both double-blind and open-label studies, diclofenac has demonstrated efficacy comparable or superior to that of indomethacin and phenylbutazole, the antiinflammatory agents considered standards of therapy for this painful, disfiguring form of arthritis.

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... The overall risk of bias in these studies was considered high due to lack of information on randomization, allocation concealment, blinding, and loss to follow-up. Given the data heterogeneity, a meta-analysis was not possible [46,[51][52][53][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95]. ...
... In only one of the 19 studies, indomethacin caused more adverse events than oxaprozin [80]. In the analysis by organ system, indomethacin was also associated with a higher rate of neurological adverse events than aceclofenac, oxaprozin, and diclofenac [80,83,86]. No difference was observed in adverse events rate (renal, cardiovascular, hepatic, hematological, respiratory, or dermatologic) in patients with axSpA. ...
... Considering five RCTs of non-selective NSAIDs versus placebo and three of iCOX2 versus placebo, neither the meta-analysis nor individual studies found an increase in respiratory, hematological, dermatologic, or neurological adverse events [44][45][46][47][48]. Additionally, no significant differences were found in the comparison of iCOX2 versus traditional NSAIDs [38,40,44,45,48,49]. In the comparison of NSAIDs with other NSAIDs, selective or not for COX-2, only indomethacin was associated with a greater number of neurological adverse events [80,83,86]. Despite data from general population have suggested some hepatotoxic effect of NSAIDs, no specific RCTs were found for NSAIDs versus placebo in patients with axSpA [116]. ...
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Spondyloarthritis (SpA) is a group of chronic inflammatory systemic diseases characterized by axial and/or peripheral joints inflammation, as well as extra-articular manifestations. Over some decades, nonsteroidal anti-inflammatory drugs (NSAIDs) have been the basis for the pharmacological treatment of patients with axial spondyloarthritis (axSpA). However, the emergence of the immunobiologic agents brought up the discussion about the role of NSAIDs in the management of these patients. The objective of this guideline is to provide recommendations for the use of NSAIDs for the treatment of axSpA. A panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis of randomized clinical trials for 15 predefined questions. The Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations were used, and at least 70% agreement of the voting panel was needed. Fourteen recommendations for the use of NSAIDs in the treatment of patients with axSpA were elaborated. The purpose of these recommendations is to support clinicians’ decision making, without taking out his/her autonomy when prescribing for an individual patient.
... A detailed description of the search results and characteristics of included studies can be found in the original publication 22 . We initially identified 7883 records; 177 qualified for full review and 39 were finally included in this review ( Figure 1) [38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77]78,79,80,81,82 . Randomized and quasi-randomized studies. ...
... Thirty-five RCT and 2 quasi-RCT involving 4908 participants (range 14-611, mean 133), published between 1966 and 2006, were included. Twenty-four studies (65%) were published before 1990 38,39,40,44,45,46,51,52,53,54,55,56,57,58,60,61,62,63,64,65,67,68,73,74,77,78,79 . The mean age of participants (reported in 26/37 trials) was 40.5 years (SD 11.1) and 81% were men (reported in 36 studies). ...
... The on February 5, 2016 -Published by www.jrheum.org Downloaded from NSAID vs NSAID (n = 24) 42,44,45,46,49,51,52,53,55,57,58,61,62,63,64,66,67,68,69,70,73,74,75,77,79,81 , naproxen vs other NSAID (n = 3) 41,70,80 , and low-vs high-dose NSAID (n = 5) 41,49,50,76,80 ]. Eight remaining studies could not be included in the metaanalysis because of study design (i.e., being cohort studies 43,71,72 ), there was no specification of the number of participants per treatment arm 38,39,47,60,78 , there were no other trials in the same comparison 82 , or it was not possible to extract quantitative data 65 . ...
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Objective: To determine the benefits and harms of nonsteroidal antiinflammatory drugs (NSAID) in axial spondyloarthritis (axSpA). Methods: Systematic review using Cochrane Collaboration methodology. Inclusion criteria: randomized controlled trials (RCT) and quasi-RCT (to June 2014), investigating NSAID versus any control for axSpA, and observational studies of longterm effects (≥ 6 mos) of NSAID on radiographic progression or adverse events. Main outcomes were pain, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index, radiographic progression, number of withdrawals because of adverse events, and number of serious adverse events. Risk of bias was assessed. Results: Thirty-five RCT, 2 quasi-RCT, and 2 cohort studies were included. Twenty-nine RCT and 2 quasi-RCT (n = 4356) were included in pooled analyses [traditional NSAID vs placebo (n = 5), cyclooxygenase-2 (COX-2) vs placebo (n = 3), COX-2 vs traditional NSAID (n = 4), NSAID vs NSAID (n = 24), naproxen vs other NSAID (n = 3), and low- vs high-dose NSAID (n = 5)]. Compared with placebo, both traditional and COX-2 NSAID were consistently more efficacious at 6 weeks and equally safe after 12 weeks. No significant differences in benefits or harms between the 2 NSAID classes and no important differences in benefits or withdrawals because of adverse events between different NSAID were found, especially if studies with high risk of bias were excluded. Single studies suggest NSAID may retard radiographic progression, especially by continuous rather than on-demand NSAID use. Conclusion: High-quality evidence indicates that both traditional and COX-2 NSAID are efficacious for treating axSpA, and harms are not different from placebo in the short term. Various NSAID are equally effective.
... [44,45] Buna karfl›n bireysel etkinlik, yan etki ve ilaç etkileflimlerinde de¤ifliklikler bildirilmifltir. [46][47][48] ASAS grubu aksiyel SpA'da tümör nekrozis faktör (TNF)-alfa bloke edici tedavileri kullanmadan önce önerilen veya tolere edilen maksimum anti-inflamatuar dozdaki en az 2 farkl› NSA‹‹ tedavisinin (kontrendikasyon olmad›¤› müddetçe) kullan›lmas›n› önermektedir. [40] 15. ...
Article
Background: Axial spondyloarthritis (axSpA) comprises ankylosing spondylitis (radiographic axSpA) and non-radiographic (nr-)axSpA and is associated with psoriasis, uveitis and inflammatory bowel disease. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line drug treatment. Objectives: To determine the benefits and harms of NSAIDs in axSpA. Search methods: We searched CENTRAL, MEDLINE and EMBASE to 18 June 2014. Selection criteria: Randomised controlled trials (RCTs) or quasi-RCTs of NSAIDs versus placebo or any comparator in adults with axSpA and observational cohort studies studying the long term effect (≥ six months) of NSAIDs on radiographic progression or adverse events (AEs). The main comparions were traditional or COX-2 NSAIDs versus placebo. The major outcomes were pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), radiographic progression, number of withdrawals due to AEs and number of serious AEs Data collection and analysis: Two review authors independently selected trials for inclusion, assessed the risk of bias, extracted data and assessed the quality of evidence for major outcomes using GRADE. Main results: We included 39 studies (35 RCTs, two quasi-RCTs and two cohort studies); and 29 RCTs and two quasi-RCTs (n = 4356) in quantitative analyses for the comparisons: traditional NSAIDs versus placebo, cyclo-oxygenase-2 (COX-2) versus placebo, COX-2 versus traditional NSAIDs, NSAIDs versus NSAIDs, naproxen versus other NSAIDs, low versus high dose. Most trials were at unclear risk of selection bias (n = 29), although blinding of participants and personnel was adequate in 24 trials. Twenty-five trials had low risk of attrition bias and 29 trials had low risk of reporting bias. Risk of bias in both cohort studies was high for study participation, and low or unclear for all other criteria. No trials in the meta-analyses assessed patients with nr-axSpA.Traditional NSAIDs were more beneficial than placebo at six weeks. High quality evidence (four trials, N=850) indicates better pain relief with NSAIDs (pain in control group ranged from 57 to 64 on a 100mm visual analogue scale (VAS) and was 16.5 points lower in the NSAID group (95% confidence interval (CI) -20.8 to -12.2), lower scores indicate less pain, NNT 4 (3 to 6)); moderate quality evidence (one trial, n = 190) indicates improved disease activity with NSAIDs (BASDAI in control group was 54.7 on a 100-point scale and was 17.5 points lower in the NSAID group, 95% CI -23.1 to -11.8), lower scores indicate less disease activity, NNT 3 (2 to 4)); and high quality evidence (two trials, n = 356) indicates improved function with NSAIDs (BASFI in control group was 50.0 on a 100-point scale and was 9.1 points lower in the NSAID group (95% CI -13.0 to -5.1), lower scores indicate better functioning, NNT 5 (3 to 8)). High (five trials, n = 1165) and moderate (three trials, n = 671) quality evidence (downgraded due to potential imprecision) indicates that withdrawals due to AEs and number of serious AEs did not differ significantly between placebo (52/1000 and 2/1000) and NSAID (39/1000 and 3/1000) groups after 12 weeks (risk ratio (RR) 0.75, 95% CI 0.46 to 1.21; and RR 1.69, 95% CI 0.36 to 7.97, respectively). BASMI and radiographic progression were not reported.COX-2 NSAIDS were also more efficacious than placebo at six weeks. High quality evidence (two trials, n = 349) indicates better pain relief with COX-2 (pain in control group was 64 points and was 21.7 points lower in the COX-2 group (95% CI -35.9 to -7.4), NNT 3 (2 to 24)); moderate quality evidence (one trial, n = 193) indicates improved disease activity with COX-2 (BASDAI in control groups was 54.7 points and was 22 points lower in the COX-2 group (95% CI -27.4 to -16.6), NNT 2 (1 to 3)); and high quality evidence (two trials, n = 349) showed improved function with COX-2 (BASFI in control group was 50.0 points and was 13.4 points lower in the COX-2 group (95% CI -17.4 to -9.5), NNT 3 (2 to 4)). Low and moderate quality evidence (three trials, n = 669) (downgraded due to potential imprecision and heterogeneity) indicates that withdrawals due to AEs and number of serious AEs did not differ significantly between placebo (11/1000 and 2/1000) and COX-2 (24/1000 and 2/1000) groups after 12 weeks (RR 2.14, 95% CI 0.36 to 12.56; and RR 0.92, 95% CI 0.14 to 6.21, respectively). BASMI and radiographic progression were not reported.There were no significant differences in benefits (pain on VAS: MD -2.62, 95% CI -10.99 to 5.75; three trials, n = 669) or harms (withdrawals due to AEs: RR 1.04, 95% CI 0.60 to 1.82; four trials, n = 995) between NSAID classes. While indomethacin use resulted in significantly more AEs (RR 1.25, 95% CI 1.06 to 1.48; 11 studies, n = 1135), and neurological AEs (RR 2.34, 95% CI 1.32 to 4.14; nine trials, n = 963) than other NSAIDs, these findings were not robust to sensitivity analyses. We found no important differences in harms between naproxen and other NSAIDs (three trials, n = 646), although other NSAIDs appeared more effective for relieving pain (MD 6.80, 95% CI 3.72 to 9.88; two trials, n = 232). We found no clear dose-response effect on benefits or harms (five studies, n = 1136). Single studies suggest NSAIDs may be effective in retarding radiographic progression, especially in certain subgroups of patients, e.g. patients with high CRP, and that this may be best achieved by continuous rather than on-demand use of NSAIDs. Authors' conclusions: High to moderate quality evidence indicates that both traditional and COX-2 NSAIDs are efficacious for treating axSpA, and moderate to low quality evidence indicates harms may not differ from placebo in the short term. Various NSAIDs are equally effective. Continuous NSAID use may reduce radiographic spinal progression, but this requires confirmation.
Non-opioids are first-line drugs for long-term pain therapy. They are effective and have a low incidence of side-effects. There are differences between non-opioids, allowing for differential indications in order to improve efficacy as well as safety. While patients with low back pain and osteoarthritis are often treated well using pure analgesics, patients with rheumatoid arthritis, and in particular those with ankylosing spondylitis, require the most potent anti-inflammatory drugs. Patients with cancer pain of moderate-to-severe intensity also benefit from them, but this is limited by the progression of the disease and the ceiling effect of non-steroidal anti-inflammatory drugs (NSAIDs). Regular endoscopic investigation of the upper gastro-intestinal tract should be considered for the prevention of fatal side-effects in patients at risk. The choice of drugs for treatment must be based on outcome studies of high quality. According to the selection of studies presented, a few drugs can be ranked, those with highest safety first: ibuprofen, tenidap, fenbufen, aceclofenac, indomethacin, ketorolac, diclofenac, tenoxicam, piroxicam and ASA.
Article
This summary of a Cochrane review presents what we know from research about the safety of using pain-relieving drugs in people with rheumatoid arthritis who also have either heart or kidney disease, or both. What is rheumatoid arthritis and what is pain management? When you have rheumatoid arthritis, your immune system, which normally fights infection, inflames the lining of your joints making them painful, stiff and swollen. People with rheumatoid arthritis often need to use painkillers and anti-inflammatories such as paracetamol or ibuprofen to control this pain and inflammation. Pain can be managed with several drugs including non-steroidal anti-inflammatory drugs (NSAIDs), (e.g. ibuprofen, diclofenac and COX-2s (e.g. celecoxib)); opioids and opioid-like drugs (e.g. tramadol, morphine and others), paracetamol (also known as acetaminophen), and neuromodulators (including anti-depressants, anti-convulsants, and muscle relaxants). The review shows that in people with rheumatoid arthritis and heart or kidney problems: We do not have precise information about side effects and complications because no studies were found that looked at side effects of pain drugs in these people. There are well documented side effects with many commonly used pain medications such as stomach, kidney and heart problems associated with NSAID use, and gastrointestinal problems associated with the use of opioids.
Article
The efficacy and tolerance of 1200 mg/day oxaprozin and 100 mg/day diclofenac sodium were compared in 40 patients with ankylosing spondylitis in a 6-week open study. Overall improvement was seen in the patients in both treatment groups. Oxaprozin-treated patients showed significant improvement in spontaneous pain of the vertebral spine and in morning stiffness after 6 weeks' treatment. There were no statistically significant differences between the treatment groups. Therapy was discontinued in 10 patients; five treated with oxaprozin (three because of intolerance and two because of worsening of symptoms) and five taking diclofenac sodium (four because of intolerance and one because of worsening of symptoms). Five (25%) oxaprozin-treated patients and six (30%) diclofenac sodium-treated patients had side-effects, with gastro-intestinal disturbances and dizziness reported most frequently. There were no statistically significant differences between the groups in the frequency of side-effects. These results indicate that oxaprozin is a promising therapeutic agent for ankylosing spondylitis.
Article
Patients with active ankylosing spondylitis of at least 6 months' duration were stabilised on diclofenac 50mg, given 2, 3 or 4 times daily in a 4-week open-label run-in. Patients were then randomised to receive a diclofenac 50mg/misoprostol 200 micrograms fixed combination tablet (n = 331) or diclofenac 50mg (n = 339) for 8 weeks at the same dosage frequency as in the open-label phase. For the intent-to-treat cohorts differences between treatment groups in the primary measures of efficacy were statistically significant. This between-group difference was thought to be attributable to the high incidence of 'unknown' outcomes, particularly in the diclofenac/misoprostol recipients. No significant differences were observed in the modified intention-to-treat or evaluable cohorts, which excluded patients with an 'unknown' outcome. No significant between group differences were observed in the change from baseline in the ankylosing spondylitis assessments. A difference was apparent between groups in the incidence of adverse events, particularly abdominal pain and diarrhoea (18.1 and 17.2%, respectively, in diclofenac/misoprostol recipients versus 12.4% each in diclofenac recipients). However, it was thought that the 4-week open-label phase of the study, during which patients received only diclofenac, may have selected for diclofenac-tolerant patients. Thus, in the treatment of ankylosing spondylitis, the diclofenac/misoprostol fixed tablet was as effective as diclofenac. Furthermore, diclofenac/misoprostol was well tolerated.
This study compares the effectiveness of tiaprofenic acid with diclophenac sodium over a 7-day period with respect to pain, facial swelling, and trismus. Sixty patients who required general anesthesia for removal of bilateral impacted third molar teeth were included. Intraoperatively, they received intramuscular injections of either tiaprofenic acid or diclophenac sodium followed respectively by tiaprofenic acid tablets for 5 days and placebo for an additional 2 days or diclophenac sodium tablets for the full 7 days. Surgical and anesthetic techniques were standardized. Pain levels were compared hourly for 4 hours postoperatively and thereafter twice daily for 7 days. Changes in facial swelling and trismus were compared on days 2 and 7 postoperatively. No statistically significant difference was found between the two treatment groups with respect to pain or facial swelling. Only with respect to recovery in mouth-opening ability (trismus) from day 2 to day 7 did diclophenac sodium reveal a statistically significant advantage (p = 0.0452).
Article
We sought to identify differences in the description of adverse drug experiences in reports of randomized clinical trials (RCTs) from the United States and Japan, using diclofenac and simvastatin as test drugs. Reports were identified in Medline (Index Medicus 1966-1990), EMBASE (Excerpta Medica 1974-1990), JAPICDOC (1979-1990), and JOIS-III (JMEDICINE 1980-1990). In each search keywords describing study design were paired with the drugs' generic names, chemical names, and development numbers. Twenty-seven U.S. reports (18 for diclofenac and 9 for simvastatin) and 22 Japanese reports (17 for diclofenac and 5 for simvastatin) identified in these four databases were selected for review. For each paper we identified the relation of the article to the data (preliminary, primary, and secondary reports, reviews), the means of identifying adverse reactions, the principal outcomes of the trials, and a variety of descriptive measures relating to study design, authorship, and elements of presentation. With few exceptions, Japanese reports were not indexed in English-language databases, and studies from the United States were not carried out in the Japanese databases. The Japanese literature consisted exclusively of primary reports of clinical trials, whereas the U.S. literature was dominated by review articles and secondary reports of data from trials not fully published elsewhere. Japanese reports contained more detail on adverse experiences but reported principally those attributed to the drugs by attending clinicians. U.S. reports by contrast offered little detail but tended to include all adverse experiences, whether or not clinically attributed to drugs. A preponderance of U.S. articles reported significant differences between drugs in safety or treatment efficacy, whereas only one third of the Japanese articles did so for the same agents. Reports from both countries offered few details of the methods used to gather information on adverse drug experiences, and as a result the reported absolute frequencies of such events are difficult to compare between trials or to generalize to other settings. In conclusion, the reporting of adverse reactions in clinical trials is inadequate in both the United States and Japanese literature. The shortcomings are complementary in that reports of U.S. trials contain insufficient detail and Japanese reports do not interpret or synthesize experience. Clinical research into drug safety in both countries could be improved through the adoption of simple standards of clarity and consistency in the monitoring and reporting of drug adverse effects.
Article
Our purpose is to review the developments in the treatment of ankylosing spondylitis in 2004. Tumor necrosis factor blockers have been shown to have rapid and persistent efficacy with limited additional toxicity up to 4 years with continuing therapy, but cessation of therapy results in relapse in most patients. Therapy is cost-effective. There are some differences between the different tumor necrosis factor blockers currently available. Other biologic therapies are not as promising. Algorithms have been developed to aid in early diagnosis. This may be relevant for future therapeutic strategies. Tumor necrosis factor blockers are effective and safe in active spinal disease, but simple measures such as exercise and nonsteroidal anti-inflammatory drug therapy are still considered the basis of standard therapy. Early disease diagnosis is becoming easier, and is likely to be important for optimal therapeutic responses. Future research will include the effect of tumor necrosis factor blockade on structural disease progression.
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To assess available management strategies in ankylosing spondylitis (AS) using a systematic approach, as a part of the development of evidence based recommendations for the management of AS. A systematic search of Medline, Embase, CINAHL, PEDro, and the Cochrane Library was performed to identify relevant interventions for the management of AS. Evidence for each intervention was categorised by study type, and outcome data for efficacy, adverse effects, and cost effectiveness were abstracted. The effect size, rate ratio, number needed to treat, and incremental cost effectiveness ratio were calculated for each intervention where possible. Results from randomised controlled trials were pooled where appropriate. Both pharmacological and non-pharmacological interventions considered to be of interest to clinicians involved in the management of AS were identified. Good evidence (level Ib) exists supporting the use of non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs for symptomatic treatment. Non-pharmacological treatments are also supported for maintaining function in AS. The use of conventional antirheumatoid arthritis drugs is not well supported by high level research evidence. Tumour necrosis factor inhibitors (infliximab and etanercept) have level Ib evidence supporting large treatment effects for spinal pain and function in AS over at least 6 months. Level IV evidence supports surgical interventions in specific patients. This extensive literature review forms the evidence base considered in the development of the new ASAS/EULAR recommendations for the management of AS.
Article
The purpose of this study was to review the evidence regarding the efficacy and safety of pharmacological therapies currently available for the treatment of ankylosing spondylitis (AS). A literature search using MEDLINE from 1966 through to April 2005 and a hand search of abstracts from the American College of Rheumatology (ACR) meetings for 2001 through to 2004 were performed. References of articles retrieved were also searched. The MEDLINE search yielded 570 citations and 157 abstracts from ACR were identified. Eighty-four studies were randomised controlled trials (RCTs); 53 fulfilled the inclusion criteria (pharmacological treatment of AS and RCT) and were included in this review. Statistical pooling of data was not performed because of the disparate outcome measures used. Eight RCTs found nonselective NSAIDs and two RCTs found cyclo-oxygenase (COX)-2-selective NSAIDs to be superior to placebo for relief of pain and improvement in physical function. Twenty-nine RCTs showed comparable efficacy and safety between nonselective NSAIDs. One RCT showed no difference between methylprednisolone 1g and 375mg. Seven RCTs assessing the efficacy of sulfasalazine (sulphasalazine) and two RCTs of methotrexate provided contradictory evidence as to their benefit for treatment of AS. One RCT showed intravenous pamidronate 60mg to be more effective than 10mg intravenously for the treatment of axial pain. All six RCTs of anti-tumour necrosis factor (TNF)-α agents demonstrated superiority to placebo for the treatment of axial and peripheral symptoms. Nonselective as well as COX-2-selective NSAIDs can be used for pain control in patients with AS. Other proven treatment options include sulfasalazine for the treatment of peripheral joint symptoms, while limited evidence supports the use of pamidronate or methotrexate, which require further studies. Anti-TNFα agents have been found very effective for the treatment of both peripheral and axial symptoms in patients with AS, but their use is limited by cost and uncertainty over long-term efficacy and safety.
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The introduction of anti-TNFalpha therapy into the field of rheumatology has led to dramatic improvements in patient care, perhaps the most remarkable being in the management of ankylosing spondylitis. As experience with these compounds grows, their place in therapeutic strategy is becoming clearer, and it has been possible to develop evidence- and expertise-based recommendations for the management of ankylosing spondylitis to aid the clinician in patient care. This review outlines treatment advances in ankylosing spondylitis, including the use of anti-TNFalpha agents, and how these have been incorporated into clinical recommendations for daily use.
Article
Ankylosing spondylitis (AS) is a chronic systemic rheumatic disease that primarily affects the sacroiliac joints and spine. Even with the development of tumor necrosis factor-alpha inhibitors, which have revolutionized the treatment of this disease, the combination of nonsteroidal anti-inflammatory drugs (NSAIDs), physical therapy, and a life-long exercise program still form the first step in its management. Multiple clinical trials have addressed the efficacy and safety of both nonselective and selective NSAIDs. Gastrointestinal toxicity remains their major side effect, with increased concern about the potential of cardiovascular toxicity, especially with the selective cyclooxygenase-2 inhibitors. A specific set of recommendations has been proposed for the management of AS.
Article
In a multicentre double blind study 5 physicians each treated 10 patients with ankylozing spondylitis for 2 weeks by Voltaren or Indometacin (daily dose 150 mg). The following were the results of the treatments: in comparison with the Indometacin group the action on characteristic parameters was better with Voltaren insofar as only the percentage changes were taken into consideration. But on the basis of the absolute figures for the mean values, and because of the great variances, practically no difference between the 2 treatments was demonstrable. Also in the general judgment of the physicians the treatment with Voltaren was more successful. Nevertheless the difference from Indometacin is not significant. There was, however, a difference in the number of undesirable side effects. 2 patients (7%) treated by Voltaren, and 6 patients (20%) treated by Indometacin, complained of side effects. On each occasion the patient discontinued the treatment on account of stomach pains.
Article
Synopsis: Diclofenac sodium1, a phenylacetic acid derivative, is a non-steroidal, anti-inflammatory, analgesic agent advocated for use in rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and allied conditions, and in the treatment of pain resulting from minor surgery, trauma and dysmenorrhoea. Published data indicate that diclofenac 75 to 150mg daily (25 to 50mg 3 times daily) is comparable in efficacy with ordinary aspirin 3 to 5g daily and indomethacin 75 to 150mg daily in rheumatoid arthritis and with indomethacin in osteoarthritis. Available data suggest that in patients with osteoarthritis diclofenac sodium is comparable in efficacy and tolerability with naproxen, ibuprofen, sulindac and diflunisal. As oral diclofenac is generally given in 3 divided daily doses it may be at a disadvantage relative to less frequent administration with naproxen, diflunisal and sulindac in rheumatoid arthritis, although there is some evidence of diclofenac’s efficacy when administered twice daily, or once daily as a slow release tablet. The drug is also available as suppositories and ampoules for intramuscular injection. No one of the non-steroidal anti-inflammatory agents is the most suitable drug for all patients requiring such therapy, and diclofenac should be considered along with other drugs of its type in the arthritic patient. Pharmacology: Diclofenac sodium has been shown to be active in suppressing inflammation in non-specific animal models including carageenan-induced rat paw oedema, oedema induced by kaolin, mustard or croton oil and in suppressing granuloma formation in rats and ultraviolet-induced erythema in guinea-pigs. In these tests diclofenac has demonstrated activity at least comparable (weight for weight) with that of indomethacin and greater than that of aspirin, phenylbutazone, naproxen and flufenamic acid. Diclofenac sodium has been demonstrated to have antipyretic activity and to be an effective analgesic in rats and mice and in therapeutic trials in patients with rheumatoid arthritis, osteoarthritis or pain of varying origin. Controlled studies in healthy volunteers, employing 51Cr-labelled erythrocytes or endoscopy, have found commercially available oral preparations of diclofenac sodium to cause milder gastric mucosal changes than naproxen and less gastrointestinal blood loss than aspirin, naproxen or feprazone. However, the relevance of these findings after brief periods of administration to healthy subjects, to prolonged use in the treatment of arthritis diseases is not known. In vitro, diclofenac sodium is a potent inhibitor of the secondary phase of platelet aggregation by adenosine disphosphate, but at usual therapeutic dosages oral diclofenac has little effect on platelet aggregation, or activated prothrombin time. Diclofenac sodium is a potent, competitive and irreversible inhibitor of prostaglandin synthetase in vitro and in vivo and it is considered that much of its anti-inflammatory activity is attributable to this property. Pharmacokinetics: Studies with single doses of oral and intravenous diclofenac sodium indicate that the orally administered drug is completely absorbed whether given as a solution or as an enteric-coated tablet. Single 50mg doses of enteric-coated tablets result in maximum plasma concentrations of about 1500ng/ml at 1.5 to 2 hours after ingestion. Plasma concentrations are significantly decreased by the concomitant administration of therapeutic doses of aspirin. Diclofenac sodium is eliminated principally by metabolism and subsequent urinary and biliary excretion of glucuronide and sulphate conjugates of the metabolites. The principal metabolite in man is the 4’-hydroxy derivative of diclofenac sodium. The amount excreted in urine accounts for 20 to 30 % of the dose and that in bile for 10 to 20%. The mean terminal elimination half life is 1.2 to 1.8 hours. In animals this metabolite possesses about 1/30th the anti-inflammatory activity of the parent drug. Studies with single intravenous doses of 14C-labelled diclofenac in 4 patients with varying degrees of renal impairment indicate that the area under the plasma level-time curve (AUC) is markedly increased only when the creatinine clearance is 3ml/min or less, but the AUC for unchanged diclofenac sodium is not influenced by renal function. In severe renal impairment, steady-state concentrations of total metabolites for 2 daily doses of 50mg can be expected to be 4 times higher than in subjects with normal renal function. Therapeutic Trials: In patients with active rheumatoid arthritis or osteoarthritis, diclofenac sodium has been compared with placebo, ordinary aspirin, indomethacin, ibuprofen, naproxen, phenylbutazone, sulindac, diflunisal and clofezone. Diclofenac 75 to 150mg has been demonstrated to be superior to placebo in patients with active rheumatoid arthritis with respect to pain relief, decreased duration of morning stiffness, increase in grip strength, decrease in joint tenderness and decrease in the circumference of the proximal interphalangeal and other involved joints. Therapeutic trials comparing diclofenac 75 to 150mg with ordinary aspirin 4 to 5g daily have been of the within-patient type, generally of short duration and have had no drug-free period between the active drug periods. No significant differences between the therapeutic efficacy of diclofenac and aspirin 4 to 5g daily was demonstrable, but diclofenac tended to be more efficacious than lower doses of aspirin. In all studies there was a tendency, which in some instances was significant, for aspirin to cause more adverse effects than diclofenac. As in most short term studies which have compared indomethacin with other non-steroidal anti-inflammatory drugs in rheumatoid arthritis, no statistically significant difference could be demonstrated between diclofenac 75 to 150mg daily and an equal dose of indomethacin with respect to the usual assessment criteria. However, in several studies indomethacin has caused more frequent adverse effects than diclofenac. In 6-month studies there was a clear tendency for diclofenac to be superior with respect to most assessment criteria as the study progressed. No statistically significant differences between the efficacy of diclofenac and naproxen, ibuprofen or phenylbutazone was found in limited studies. The frequency of side effects has been similar with diclofenac and each of the other drugs studied. In patients with osteoarthritis, short term studies comparing diclofenac 75 to 150mg and indomethacin 75 to 150mg have not found significant differences between the drugs, but some studies conducted over a period of 12 to 24 weeks found diclofenac to be superior to indomethacin with respect to analgesic activity or overall improvement. Diclofenac 75 to 150mg daily has been found to be at least as effective as relatively low doses of ibuprofen (600 to 1800mg daily) whilst no trends indicating a better effect with either drug were evident in a comparison of diclofenac 75 to 150mg and sulindac 200 to 400mg daily. Comparisons between diclofenac and naproxen have produced varying results. Design faults such as small patient numbers or lack of comparability of groups between centres in these studies necessitate further well designed trials to determine the relative merits of diclofenac and naproxen when both drugs are administered twice daily. Long term open studies in large numbers of patients in general practice indicate an excellent or good response in about 70 to 85% of patients with rheumatoid arthritis or osteoarthritis respectively. Open non-comparative studies in patients with ankylosing spondylitis suggest that marked or moderate symptomatic improvement occurs in 55 to 66% of patients treated for 2 to 4 weeks. Diclofenac sodium administered either orally or intramuscularly has been studied in the relief of pain and various other symptoms in patients who have undergone minor oral surgery, tonsillectomy or anorectal surgery. Diclofenac has also been studied in post partum pain and that associated with sports injuries or other accidental trauma. Because of poor design, studies in postoperative pain provide little valid data, but suggest that diclofenac provides adequate analgesia in about three-quarters of patients. Onset of analgesia occurs 30 to 45 minutes after ingestion in most patients. In the alleviation of pain and swelling following tooth extraction, diclofenac 75mg daily was at least as effective as indomethacin 75mg and oxyphen-butazone 600mg daily. Diclofenac 150mg daily was superior to oxyphenbutazone 600mg daily in reducing swelling associated with sports injuries. Side Effects: As with other non-steroidal anti-inflammatory drugs introduced in recent years, diclofenac has been better tolerated than moderate doses of aspirin. Gastrointestinal side effects are the most frequently reported adverse effects of diclofenac and occur in about 10% of patients. The frequency of side effects appears not to be closely related with either dosage or age. The incidence of side effects with diclofenac 75 to 125mg daily has generally been lower than with aspirin 3 to 5g daily or indomethacin 75 to 125mg daily and similar to that with naproxen, sulindac, ibuprofen or diflunisal. As with other recently introduced nonsteroidal anti-inflammatory drugs, there have been a few reports of gastrointestinal bleeding possibly associated with diclofenac. Dosage: In adults the initial dosage is 25 to 50mg 3 times daily. The maintenance dosage should be adjusted to the minimum required for adequate control of symptoms. The tablets should be swallowed whole with or after a meal.
Article
Diclofenac sodium, a phenylacetic acid derivative, is a non-steroidal, anti-inflammatory, analgesic agent advocated for use in rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and allied conditions, and in the treatment of pain resulting from minor surgery, trauma and dysmenorrhoea. Published data indicate that diclofenac 75 to 150mg daily (25 to 50mg 3 times daily) is comparable in efficacy with ordinary aspirin 3 to 5g daily and indomethacin 75 to 150mg daily in rheumatoid arthritis and with indomethacin in osteoarthritis. Available data suggest that in patients with osteoarthritis diclofenac sodium is comparable in efficacy and tolerability with naproxen, ibuprofen, sulindac and diflunisal. As oral diclofenac is generally given in 3 divided daily doses it may be at a disadvantage relative to less frequent administration with naproxen, diflunisal and sulindac in rheumatoid arthritis, although there is some evidence of diclofenac's efficacy when administered twice daily, or once daily as a slow release tablet. The drug is also available as suppositories and ampoules for intramuscular injection. No one of the non-steroidal anti-inflammatory agents is the most suitable drug for all patients requiring such therapy, and diclofenac should be considered along with other drugs of its type in the arthritic patient.
Article
In the face of deficiencies in our present system of introducing new drugs, clinicians must be committed to monitoring patients carefully. They must not be caught up in the hyperbole and excitement of the latest new drug, but instead should allow the crucible of time to teach them and the rest of the medical community the ultimate truths about this drug in all situations. They must not let the package circular be their only guide to therapy, for it reflects only what has been accomplished under limited conditions. By knowing their patients well and by learning to proficiently use selected drugs that they have become familiar and comfortable with, conscientious practitioners will approach the present state of the art in meeting the needs of their patients.
Article
SUMMARY A double-blind between-patient comparison of diclofenac sodium (Voltaren) 150 mg daily and sulindac 400 mg daily in 62 patients with active ankylosing spondylitis was carried out. After a seven-day wash-out period in which current anti-inflammatory drugs were tailed off, patients were entered into the trial and treated for four weeks. Both drugs significantly reduced the activity of the disease. There were no statistically significant differences between the effects of the two drugs, although diclofenac appeared to be marginally more effective. In respect of finger-floor distance, the difference was statistically significant (P <0.01) in favour of diclofenac. Subjective assessment by the patient and the physicians both favoured diclofenac but the difference was not statistically significant. Adverse reactions were mild and occurred slightly more frequently in the sulindac group. No significant laboratory abnormalities were found. The present work has shown that diclofenac has a useful role in the management of ankylosing spondylitis.
Le Voltaren 100 suppositoirc en rhumatologie Bilan clinique a propos de 16419 nouvelles observations recueillies par 2895 omniprati-ciens en France
  • M Alcalay
  • Jl Bussiere
  • Peltier
Alcalay M, Bussiere JL, Peltier A: Le Voltaren 100 suppositoirc en rhumatologie. Bilan clinique a propos de 16419 nouvelles observations recueillies par 2895 omniprati-ciens en France. Gaz med Fr 1980;87:2036