Post-operative analgesia with diflunisal.

An open study was carried out in 196 consecutive patients who had undergone orthopaedic (103) or gynaecological (93) surgical procedures to assess the effectiveness and tolerability of a single dose of 500 mg diflunisal in the relief of postoperative pain. Diflunisal was given when patients first complained of pain, and pain severity before and at intervals up to 6 hours after the dose was assessed using a 10-point analogue scale. The results showed that diflunisal was both prompt and prolonged in its effect. No pain was reported after 1 hour in 138 (71%) of the 196 patients, and after 6 hours only 13 (7%) still reported some pain. Diflunisal was equally as effective in the two groups. Side-effects were reported in 13 (7%) patients but these were ones commonly found in the post-operative situation.     

The use of diflunisal in post-operative pain: a report of double-blind Comparative trials in patients after meniscectomy

Summary

A series of double-blind randomized trials was carried out in patients suffering from moderate to severe pain after meniscectomy to assess the analgesic effectiveness of diflunisal. In a single-dose study, 150 patients received either diflunisal (125?mg, 250?mg or 500?mg), aspirin (600?mg), or placebo, and hourly assessments were made of pain severity over an 8-hour period. The results showed that 500?mg diflunisal produced comparable relief to aspirin within 3 to 4 hours, but the analgesic effect continued for longer and was still very marked after 8 hours. A multi-dose study in 120 patients receiving doses of diflunisal (375?mg or 500?mg) or placebo confirmed the overall effectiveness of twice daily treatment with diflunisal. In a comparative study against oxyphenbutazone (200?mg t.i.d.), hourly pain scores made on the first postoperative day showed that a single dose of 500?mg diflunisal produced comparable relief over a 12-hour period to that with 2 doses of 200?mg oxyphenbutazone. Overall response to multiple doses was assessed as excellent or good by all the patients receiving diflunisal. Preliminary results are reported on the use of diflunisal in other painful conditions.     

The analgesic and anti- inflammatory efficacy of diflunisal and Codeine after removal of impacted third molars

Summary

A double-blind, randomized trial was carried out in 90 patients to compare the analgesic and anti-inflammatory efficacy of 500?mg diflunisal twice daily with that of 25?mg codeine phosphate 4-times daily and of placebo in relieving pain and swelling after surgical removal of impacted third molars. Diflunisal was found to be superior to codeine and placebo on the first post-operative day, but the difference in efficacy of the drugs had diminished by the third post-operative day. In the diflunisal group of 30 patients, 10 (33%) developed ‘dry socket’ or alveolitis sicca dolorosa. Only 2 patients in the codeine group and 1 patient in the placebo group developed this very painful condition. The possible explanation of ‘dry socket’ is discussed.     

A double-blind comparison of diflunisal and aspirin in the treatment of post-operative pain after episiotomy

Summary

A double-blind randomized trial was carried out in 161 primiparous women suffering from moderate to severe post-episiotomy pain to compare the analgesic efficacy of single doses of diflunisal (125?mg, 250?mg, or 500?mg), aspirin (600?mg), and placebo. The results of pain rating assessments made before and at hourly intervals after drug administration showed that both the active drugs were more effective than placebo and produced similar pain relief over the first 4 hours. The analgesic efficacy of aspirin tailed off after 4 hours but pain relief with 500?mg diflunisal was still evident after 8 hours. Over 65% of patients in the diflunisal group had effective relief of pain at 8 hours whereas there was no significant difference between the aspirin and placebo-treated groups by the seventh and eighth hour.     

A 12-hour Evaluation of the Analgesic Efficacy of Diflunisal,Propoxyphene, A Propoxyphene-Acetaminophen Combination,and Placebo in Postoperative Oral Surgery Pain

One-hundred thirty-two outpatients with pain following oral surgery were randomly assigned, on a double-blind basis, to a single oral dose of diflunisal 500 or 1000 mg, propoxyphene napsylate 100 mg, a combination of propoxyphene napsylate 100 mg with acetaminophen 650 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 12 hours after medication. Measures of total and peak analgesia were derived from the patient's subjective reports. Diflunisal 500 and 1000 mg were significantly superior to placebo and propoxyphene alone for every measure of total and peak analgesia, and the effect of diflunisal persisted for 12 hours. Diflunisal 1000 mg was significantly superior to the propoxyphene-acetaminophen combination for all measures of analgesia. Although the propoxyphene-acetaminophen combination was significantly superior to placebo for most measures of analgesia, propoxyphene alone was significantly superior for only two measures. Adverse effects attributed to all drugs were mild and transitory.     

Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency

1 A single oral dose of 500 mg diflunisal was administered to control subjects and patients with varying degrees of renal insufficiency to estimate the disposition kinetics of this drug.

2 Diflunisal and the sum of its ester and ether glucuronides conjugates were measured fluorimetrically.

3 In normals terminal plasma half-lives (T_½β) of diflunisal and its glucuronides were very similar: 10.8 h and 11.8 h respectively. The finding that plasma half-life was shortened with declining diflunisal plasma levels suggests capacity-limited elimination.

4 In subjects with normal renal function 78.6 ± 2.7% of the administered dose was recovered in 72 h urine, mainly as the glucuronide conjugates.

5 With increasing degree of renal function impairment T_½β of diflunisal was progressively prolonged up to ten times normal probably due to slowed biotransformation. This was associated with increasing retention of the conjugated metabolites in plasma due to marked reduction of the urinary excretion of the glucuronide conjugates.

6 The apparent volume of distribution of diflunisal was very small in normals (7.3 ± 0.4 l) and was significantly increased in patients with renal insufficiency (up to 16.2 ± 2.2 l).

7 Diflunisal elimination studies performed during haemodialysis did not reveal any significant change in diflunisal plasma half-time. In vivo ultrafiltration studies during haemodialysis have shown that diflunisal is 98-99% plasma protein bound in uraemic patients.

8 The present study indicates that although diflunisal is primarily eliminated by biotransformation, T_½β is prolonged in renal insufficiency and dose adjustment will accordingly be required in patients with renal function impairment.

     

Diflunisal compared with naproxen in the treatment of osteoarthrosis of hip or knee: a double-blind trial

Summary

A randomized double-blind trial was carried out in 20 patients with osteoarthrosis of the hip or knee to compare the efficacy and tolerance of treatment with diflunisal or naproxen. During the first 4 weeks, patients received either 250?mg diflunisal or 250?mg naproxen twice daily and this was increased by 250?mg daily in 5 patients on diflunisal and in 3 on naproxen for the second 4 weeks of the trial. The results of subjective assessments made before and at the end of Week 8 showed a trend in favour of diflunisal for improvement of symptoms, except for weight-bearing pain which was improved in only 1 patient in each group. More of the patients receiving diflunisal than naproxen considered treatment to have been satisfactory, and rated their response as equally as good as or better than previous medication. Diflunisal produced significantly fewer side-effects than naproxen, the use of which was associated with a relatively high incidence of gastro-intestinal upsets, leading to the withdrawal of 2 patients at Week 4.     

Diflunisal versus aspirin: a comparative study of their effect on faecal blood loss,in the presence and absence of alcohol

Summary

Faecal blood loss was measured in normal male volunteers using ⁵¹Cr-labelled red cells. In a double-blind parallel study in 10 subjects, the effect of 250?mg diflunisal twice daily was compared with 750?mg aspirin 4-times daily. Drugs were taken during two 7-day periods separated by a 1-week control period. Mean daily faecal blood loss during the two treatment periods was 0.32 ml and 0.53 ml in the diflunisal group versus 6.87 ml and 3.20 ml in the aspirin group. Diflunisal did not significantly increase blood loss, while aspirin had a significant effect. In a double-blind crossover study in 12 subjects, the effect of 250?mg diflunisal twice daily was compared with 600?mg aspirin 4-times daily. Alcohol (120 ml, 40%) was added during the last 2 days of each 6-day treatment period. Faecal blood loss was not significantly affected by diflunisal and there was also no significant effect on blood loss when alcohol was co-administered. Aspirin significantly increased faecal blood loss and this effect was significantly enhanced by the addition of alcohol.     

Diflunisal 500-750 mg versus aspirin 2600-3900 mg in the treatment of rheumatoid arthritis

Diflunisal was compared to aspirin in a 12-week, double-blind, parallel, multicenter rheumatoid arthritis study. One hundred twenty-six (126) patients received diflunisal and 123 patients received aspirin. Both treatment groups demonstrated significant improvement from baseline in joint pain, morning stiffness, grip strength, walking time and painful and swollen joint scores. For these parameters, the only statistically significant difference between the groups was that diflunisal was more effective than aspirin for overall joint pain at week 2. The overall evaluation by patients and by investigators showed significantly better responses in those treated with diflunisal at weeks 1 and 12. Diflunisal produced significantly less gastrointestinal pain and tinnitus than aspirin. Neither drug showed unusual frequency of adverse effects as determined in the laboratory. Long-term studies using a higher-dose regimen are suggested to further define the efficacy and tolerability of diflunisal in the treatment of patients with rheumatoid arthritis.     

The chemistry,pharmacology and clinical pharmacology of diflunisal

Summary

Studies are reviewed on diflunisal, a new analgesic agent with an improved therapeutic index, compared with acetylsalicylic acid, in animals and humans. Pharmacokinetic data indicate that a twice-daily dosage regimen of diflunisal is adequate for therapeutic purposes. Diflunisal inhibits prostaglandin E synthesis, but in humans at clinically effective doses it does not alter bleeding time or platelet aggregation. Diflunisal is uricosuric at clinically effective doses. No clinically important drug interactions with diflunisal have been found to date, although some slight alterations in blood and urine drug levels have been noted. The slight increase in prothrombin time seen when diflunisal and acenocoumarol were co-administered is not considered to be of major clinical importance.     

Nephrotoxicity studies on aspirin and diflunisal

Summary

Some of the difficulties encountered in investigations of long-term drug nephrotoxicity are reviewed, and the evidence for acute and chronic renal damage induced by aspirin is discussed. Two studies were carried out to investigate the acute effects of diflunisal on the kidney, and to compare its effects with those of aspirin. Measurements were made before, during and after drug intake, of epithelial cells and lysosomal enzyme (β-d-n-acetyl glucosaminidase) excretion in urine. Diflunisal caused no change in cell excretion and no increase in enzyme excretion in 6 normal volunteers. In a comparative study against aspirin, two groups of 12 patients being treated for osteoarthrosis were observed over an 8-week period. Enzyme excretion increased in both groups and appeared to be dose related. The increase, however, was relatively greater in the aspirin group. The possible significance of these findings is discussed.     

The use of diflunisal in post-operative pain: a report of double-blind comparative trials in patients after meniscectomy.

A series of double-blind randomized trials was carried out in patients suffering from moderate to severe pain after meniscectomy to assess the analgesic effectiveness of diflunisal. In a single-dose study, 150 patients received either diflunisal (125 mg, 250 mg or 500 mg), aspirin (600 mg), or placebo, and hourly assessments were made of pain severity over an 8-hour period. The results showed that 500 mg diflunisal produced comparable relief to aspirin within 3 to 4 hours, but the analgesic effect continued for longer and was still very marked after 8 hours. A multi-dose study in 120 patients receiving doses of diflunisal (375 mg or 500 mg) or placebo confirmed the overall effectiveness of twice daily treatment with diflunisal. In a comparative study against oxyphenbutazone (200 mg t.i.d.), hourly pain scores made on the first post-operative day showed that a single dose of 500 mg diflunisal produced comparable relief over a 12-hour period to that with 2 doses of 200 mg oxyphenbutazone. Overall response to multiple doses was assessed as excellent or good by all the patients receiving diflunisal. Preliminary results are reported on the use of diflunisal in other painful conditions.     

Two trials of diflunisal in osteoarthritis

Summary

Two double-blind inter-group trials were carried out in which diflunisal was compared for 12 weeks against aspirin in 30 patients with osteoarthritis of knees or hips, and against naproxen for 8 weeks in 20 patients with osteoarthritic knees. Diflunisal appeared to be somewhat better than aspirin in terms of both effectiveness and tolerance, whilst it was similar in both respects to naproxen.     

Diflunisal in osteoarthrosis of the hip and knee

Summary

A double-blind randomized trial was carried out in 60 patients with osteoarthrosis of the hip or knee to assess the relative efficacy and tolerance of treatment with diflunisal twice daily (maximum 750?mg per day) or with aspirin given 4-times daily (maximum 3 g per day) over a period of 12 weeks. Clinical assessments were made on entry and at regular intervals of weight-bearing pain, night pain, specific function pain, inactivity stiffness, and range of joint movement. A considerable proportion of patients in both groups showed improvement in all parameters except for limitation of movement. The difference in response between the two groups was not statistically significant, neither was the patients' overall opinion of response to or clinician's assessment of therapeutic efficacy of either drug treatment at the end of the trial. Ten of the 29 patients in the aspirin group had to withdraw because of adverse reactions, mainly gastro-intestinal, compared with 4 of the 31 patients in the diflunisal group. The overall incidence of side-effects in all patients was lower in the diflunisal group, and those that were reported were less disturbing. At the end of the double-blind study, patients were given the option to continue with the particular drug treatment for a further two 13-week periods. More patients chose to remain on diflunisal than on aspirin at the end of each of the three periods and the difference was statistically significant.     

The analgesic and anti-inflammatory efficacy of diflunisal and codeine after removal of impacted third molars.

A double-blind, randomized trial was carried out in 90 patients to compare the analgesic and anti-inflammatory efficacy of 500 mg diflunisal twice daily with that of 25 mg codeine phosphate 4-times daily and placebo in relieving pain and swelling after surgical removal of impacted third molars. Diflunisal was found to be superior to codeine and placebo on the first post-operative day, but the difference in efficacy of the drugs had diminished by the third post-operative day. In the diflunisal group of 30 patients, 10 (33%) developed 'dry socket' or alveolitis sicca dolorosa. Only 2 patients in the codeine group and 1 patient in the placebo group developed this very painful condition. The possible explanation of 'dry socket' is discussed.     

Effect of probenecid on the formation and elimination kinetics of the sulphate and glucuronide conjugates of diflunisal

The effect of probenecid on the pharmacokinetics of diflunisal and its glucuronide and sulphate conjugates was studied in 8 healthy volunteers. Diflunisal 250 mg b. d. was administered p. o. for 15 days and its steady state pharmacokinetics was evaluated on Day 16 after the last dose (control phase). Probenecid 500 mg b. d. was co-administered throughout the entire study period in the treatment phase of the study.The steady state plasma concentration of diflunisal was significantly higher during the probenecid treatment phase as compared to the control phase (104.0 vs. 63.1 g·ml^–1). This was the result of a significant decrease in the plasma clearance of diflunisal from 5.8 (control) to 3.4 ml·min^–1 (probenecid co-administration). The metabolite formation clearances of both glucuronides were significantly decreased by probenecid, -45 % and -54 % for the phenolic and acyl glucuronide, respectively. The metabolite formation clearance of the sulphate conjugate was not affected by probenecid co-administration.Steady state plasma concentrations of the sulphate and glucuronide conjugates of diflunisal were 2.5- to 3.1-fold higher during probenecid co-administration, due to a significant reduction in the renal clearance of the three diflunisal conjugates. Probenecid also reduced the plasma protein binding of diflunisal, but only to a minor extent; the unbound plasma fraction of diflunisal at steady state averaged between 5 and 30 % higher during probenecid co-administration.     

Medical treatment of acute low back pain. Diflunisal compared with indomethacin in acute lumbago

Diflunisal and indomethacin were compared in patients with acute lumbago in a double-blind prospective clinical trial. The dosage of diflunisal was 500 mg twice daily (d-group) and the dosage of indomethacin 50 mg three times daily (i-group). Out of 133 patients, 66 were in the d-group and 67 in the i-group. They were followed up for a week. In addition to the patient's own daily evaluation of pain and functional disability, control visits were performed by the investigators on days 0, 3 and 7. Both of the test drugs were effective in the dosages used. Patients' pain was decreased, functional disability was improved and patients' subjective evaluation of treatment efficacy was very similar to that of the investigators. There were no differences as to the treatment efficacy, but reports of side-effects were slightly less (p less than 0.05) in the d-group than in the i-group. If patients who had no side-effects were compared, the efficacy of diflunisal was better than indomethacin (p less than 0.05). It can be said that indomethacin was essentially as effective as diflunisal, but at the expense of an increased frequency of side-effects. In the d-group two patients (3%) and in i-group six patients (9%) discontinued the therapy because of side-effects. In acute lumbago rapid relief of pain and other harmful symptoms hastens improvement. For such indications the choice of drug therapy in general practice should be based in particular on considerations of safety and lack of potential side-effects in addition to efficacy.     

A double-blind comparison of diflunisal and aspirin in the treatment of post-operative pain after episiotomy.

A double-blind randomized trial was carried out in 161 primiparous women suffering from moderate to severe post-episiotomy pain to compare the analgesic efficacy of single doses of diflunisal (125 mg, 250 mg, of 500 mg), aspirin (600 mg), and placebo. The results of pain rating assessments made before and at hourly intervals after drug administration showed that both the active drugs were more effective than placebo and produced similar pain relief over the first 4 hours. The analgesic efficacy of aspirin tailed off after 4 hours but pain relief with 500 mg diflunisal was still evident after 8 hours. Over 65% of patients in the diflunisal group had effective relief of pain at 8 hours whereas there was no significant difference between the aspirin and placebo-treated groups by the seventh and eighth hour.     

Efficacy of chlorhexidine,dexpanthenol, allantoin and chitosan gel in comparison with bicarbonate oral rinse in controlling post-interventional inflammation,pain and cicatrization in subjects undergoing dental surgery

Introduction:

Reducing post-interventional inflammation and pain in odontostomatological surgery procedures, such as tooth extractions, implants or oral biopsies is a relevant clinical goal. Chlorhexidine oral rinse is commonly used with this aim. Recently a new product containing chlorhexidine, dexpanthenol, allantoin and chitosan (Bexident Post [BP]) in a gel formulation has been developed. We evaluated the efficacy of BP in controlling postsurgical inflammation and pain and in promoting cicatrization in subjects undergoing molar extractions.

Subjects and methods:

We conducted a prospective sequential cross-over, randomized controlled study in patients undergoing surgical removal of at least two impacted mandibular third molars (teeth numbers 38 and 48) (numbers 17 and 32 in the Universal Tooth Numbering System), in two separate sessions, to determine the effect of BP in comparison with bicarbonate (BC) oral rinse (one spoonful in 200?ml of water), both used three times daily. Each subject utilized both products in a randomized sequential manner after each tooth extraction. Primary outcomes of the study were post-procedure pain and inflammation. Secondary outcomes were analgesic pill rescue use (metamizole 1 cap every 8 hours if needed) and an assessor-blinded evaluation of cicatrization with a semi-quantitative scale (good, satisfactory and insufficient). Post-procedure pain was assessed 6 hours after tooth extraction and for seven consecutive days by means of a 10?cm visual analogue scale (VAS) (from 0: no pain to 10: extreme pain). The extent of inflammation was evaluated through metric measurements of facial perimeter using standardized anatomical reference points.

Results:

A total of 47 patients (22 men and 25 women; mean age 34 years) were enrolled with a total of 94 molars extracted. Nineteen subjects applied BC as the first sequential treatment and 28 BP as the first. Before surgery no mean differences in the two treatments in inflammation measurements were observed. After surgery mean VAS pain score was similar between the two treatments in the first 6 hours (VAS score?=?6.5). A marked progressive reduction in pain intensity with the use of BP was observed throughout the treatment period in comparison with BC (7 day mean scores 3.7 vs. 5.3; p?=?0.0001). BP was superior to BC in reducing inflammation with ?50% of the inflammation-related measurement (6?mm vs. 12?mm; p?=?0.0001). Analgesic pill consumption was lower with BP in comparison with BC (13 pills vs. 24; p?p?=?0.0001). No serious side effects were reported with either treatment regimen.

Conclusion:

In this trial BP performed better than BC in controlling pain and inflammation in subjects undergoing dental surgery, reducing the consumption of analgesics and favoring better cicatrization.     

Diflunisal in the management of sprains

Summary

A double-blind randomized trial was carried out in 31 patients suffering from acute, minor ligamentous injuries to compare the efficacy of diflunisal in the relief of pain with that of oxyphenbutazone. Patients received either 500?mg diflunisal twice daily or 200?mg oxyphenbutazone 3-times daily for 3 days. The results of subjective assessments showed that by Day 3 spontaneous pain had either completely resolved or markedly improved in all patients, and that diflunisal was significantly better than oxyphenbutazone on Days 1 and 3 in relieving pain on movement of the joint.