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.     

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.     

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.     

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.     

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.     

Diflunisal in general practice

Summary

A large-scale, double-blind comparative study was carried out in general practice to assess the relative efficacy and tolerance of diflunisal and aspirin in patients suffering from acute painful conditions such as sprains and strains, osteoarthritis, etc. Patients received either 250?mg or 500?mg diflunisal twice daily, or 600?mg aspirin 4-times daily for 5 days. The results of subjective assessments of pain relief from the daily records of 1902 patients (967 on diflunisal, 935 on aspirin), and the overall assessment of response by both doctors and patients, showed that diflunisal was significantly better than aspirin. Gastric side-effects were more common and more severe in patients receiving aspirin, and more often led to withdrawal of treatment.     

Suprofen. A review of its pharmacodynamic and pharmacokinetic properties, and analgesic efficacy

Suprofen (sutoprofen) is a non-steroidal anti-inflammatory analgesic, closely related structurally to drugs such as ibuprofen, ketoprofen and naproxen. In patients with acute pain, single oral doses of suprofen are at least as effective as: usual therapeutic doses of aspirin; codeine alone or combined with aspirin; dextropropoxyphene alone or in various combinations; oxycodone combined with aspirin; dipyrone; pentazocine; paracetamol (acetaminophen); diflunisal; ibuprofen; indomethacin; or mefenamic acid. In chronic pain due to osteoarthritis, suprofen is as effective as usual dosages of aspirin or dextropropoxyphene during long term therapy, and as effective as diclofenac, ibuprofen, indomethacin and naproxen during short term treatment. As with other non-steroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects, although discontinuation due to gastrointestinal effects may be necessary less frequently with suprofen than with aspirin, dextropropoxyphene or combinations of the two. Suprofen appears to be a useful alternative to mild analgesics, analgesic combinations or the older more established non-steroidal anti-inflammatory drugs in the treatment of patients with acute or chronic pain. However, further definition of its efficacy and tolerability is required, especially in comparison with newer non-steroidal anti-inflammatory analgesics.     

Difunisal in general practice.

A large-scale, double-blind comparative study was carried out in general practice to assess the relative efficacy and tolerance of difunisal and aspirin in patients suffering from acute painful conditions such as sprains and trains, osteoarthritis, etc. Patients received either 250 mg or 500 mg difunisal twice daily, or 600 mg aspirin 4-times daily for 5 days. The results of subjective assessments of pain relief from the daily records of 1902 patients (967 on diflunisal, 935 on aspirin), and the overall assessment of response by both doctors and patients, showed that diflunisal was significantly better than aspirin. Gastric side-effects were more common and more severe in patients receiving aspirin, and more often led to withdrawal of treatment.     

Platelet aggregation in patients treated with diflunisal

Summary

The effect of the non-steroidal analgesic diflunisal on platelet aggregation and clinical haemorrhage at a dosage 250?mg twice or 3-times daily, sufficient to relieve musculo-skeletal pain and other painful conditions, was studied in 15 patients and 5 normal subjects. Platelet aggregation was carried out with ADP and collagen before and during treatment with diflunisal. The results indicated that diflunisal is an effective analgesic with no significant adverse effect on platelet function or clinical bleeding.     

Rectal versus oral absorption of diflunisal in man

Rectal absorption of diflunisal from various dosage forms was studied in man. The rectal dosage forms included fatty and macrogol suppositories, an aqueous suspension and solutions with various solvents in order to achieve complete dissolution of diflunisal. A comparison was made with an orally administered suspension. The plasma concentrations of diflunisal were measured by means of HPLC analysis after a single dose of 250 mg diflunisal in a cross-over study in 7 volunteers.Compared with oral administration, rectal absorption conditions are limited as a consequence of the poor solubility characteristics of diflunisal. Therefore attempts were made to improve absorption conditions by varying the nature of the rectal dosage form. The addition of alkali and solvents such as polyethylene glycol and glycofurol, did result in an increase of the rate of absorption, whereas the bioavailability 8 h after administration did rise up to 80% as compared with oral dosing. In the case where suppositories are employed, a fatty vehicle rather than a water-soluble base should be chosen in order to stimulate the driving force for absorption. It is concluded that 500 mg diflunisal suspended in a 4 ml fatty mass results in peak plasma concentrations comparable with an oral dose of 250 mg diflunisal.     

Diclofenac sodium

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of diclofenac sodium are reviewed. Diclofenac, the first nonsteroidal anti-inflammatory agent (NSAID) to be approved that is a phenylacetic acid derivative, competes with arachidonic acid for binding to cyclo-oxygenase, resulting in decreased formation of prostaglandins. The drug has both analgesic and antipyretic activities. Diclofenac is efficiently absorbed from the gastrointestinal tract; peak plasma concentrations occur 1.5 to 2.0 hours after ingestion in fasting subjects. Even though diclofenac has a relatively short elimination half-life in plasma (1.5 hours), it persists in synovial fluid. The drug is metabolized in the liver and is eliminated by urinary and biliary excretion. In clinical trials, diclofenac was as effective as aspirin, diflunisal, indomethacin, sulindac, ibuprofen, ketoprofen, and naproxen in improving function and reducing pain in patients with rheumatoid arthritis. For treatment of osteoarthritis, diclofenac was equivalent in efficacy to aspirin, diflunisal, indomethacin, sulindac, ibuprofen, ketoprofen, naproxen, flurbiprofen, mefenamic acid, and piroxicam. Diclofenac was as effective as indomethacin or sulindac in treating ankylosing spondylitis. The most frequent adverse effects reported for diclofenac were gastrointestinal, but these effects were fewer and less serious than occurred with aspirin or indomethacin; in addition, diclofenac caused fewer central nervous system reactions than indomethacin. Diclofenac is administered in divided doses with meals. The recommended total daily dosage is 100 to 150 mg (osteoarthritis and ankylosing spondylitis) or 150 to 200 mg (rheumatoid arthritis). Diclofenac is effective, but no more so than other NSAIDs. It is structurally distinct and offers another choice in the treatment of rheumatological conditions.     

Naproxen up to date: a review of its pharmacological properties and therapeutic efficacy and use in rheumatic diseases and pain states.

Naproxen is a propionic acid derivative with analgesic and anti-inflammatory activity which has been widely used in the treatment of rheumatic diseases. Naproxen has been well studied in rheumatoid arthritis and is as effective as aspirin but better tolerated, thus enabling more patients to continue with treatment. For this reason some clinicians now prefer to try propionic acid derivatives, such as naproxen, before aspirin in arthritic patients. In comparative studies with other non-steroidal anti-inflammatory drugs, such as indomethacin, ibuprofen, fenoprofen and others, all drugs were usually of similar overall efficacy although naproxen was sometimes preferred: but as with other non-steroidal anti-inflammatory agents, not all patients will respond to naproxen and in such cases other agents should also be tried until the most satisfactory drug is found for each patient. Naproxen is also effective in degenerative joint diseases of the hip and knee, although further well designed studies are needed to more clearly define its relative place compared with newer drugs such as diclofenac or diflunisal. Results of other comparative studies have shown that naproxen is a suitable alternative to phenylbutazone or indomethacin in ankylosing spondylitis and to aspirin in juvenile rheumatoid arthritis. Naproxen appears to be effective in reducing pain and swelling in acute gout and is an effective analgesic in patients with pain following surgery or trauma and in pain of dysmenorrhoea. Naproxen has generally been better tolerated than aspirin or indomethacin at the dosages used. Because of its relatively long plasma half-life, naproxen can with convenieice be given twice daily, and there is some evidence that once daily dosage is as effective in rheumatoid arthritis.     

Skin and plasma levels of acetylsalicylic acid: a comparison between topical aspirin/diethyl ether mixture and oral aspirin in acute herpes zoster and postherpetic neuralgia

Objective: The aim of this investigation was to elucidate whether the analgesic effect was due to the local aspirin or to the systemic drug. This was done by comparing skin and plasma levels of acetylsalicylic acid (ASA) and salicylic acid (SA) after topically administered ASA/diethyl ether (ADE) mixture in acute herpetic neuralgia (AHN) and postherpetic neuralgia (PHN). The analgesia and the plasma and skin levels of ASA were also determined after oral administration of aspirin. Methods: Nineteen patients, 11 (57.9%) with AHN and␣8 (42.1%) with PHN were given, on different days, a single 500-mg oral dose of ASA or a topical dose (750 mg) of (ADE) daubed onto the painful skin. The analgesic effect was assessed by means of a visual analogue scale (VAS). Overall pain relief was graded as: excellent, good, fair, or poor. AHN as well as PHN patients had severe pain at baseline (6.83 and 5.93). Levels of ASA and SA in plasma and in the stratum corneum after adhesive tape stripping of the treated area were determined by HPLC. Results: After ADE application, the analgesic effect was very rapid and VAS scores were lower than at baseline. Pain significantly decreased by 82.6% after topical and 15.4% after oral ASA. After ADE, 95% of the patients had excellent or good pain relief, but after oral administration 79% of the patients had a poor response. Pain relief was similar in the two subgroups after ADE. Skin concentrations of ASA, but not of SA, after ADE were about 80- to 100-fold those after oral administration. Levels of ASA and SA in plasma after oral administration were similar to those previously found, but after ADE were undetectable or very low. Patients with excellent pain relief showed a trend towards higher ASA skin concentrations. Conclusions: The analgesic effect can be obtained only after topical administration, because by this route the skin levels of ASA are much higher than after oral administration. The mechanism is exclusively local; there are no active drugs in plasma after topical administration. Received: 7 July 1997 / Accepted in revised form: 15 January 1998     

Comparative analgesic activity of various naturally occurring cannabinoids in mice and rats

The analgesic effectiveness of ⁹-tetrahydrocannabinol (THC), a crude marihuana extract (CME), cannabinol (CBN), cannabidiol (CBD), morphine SO⁴ and aspirin following oral administration was directly compared in mice using the acetic-induced writhing and hot plate tests and the Randall-Selitto paw pressure test in rats. THC and morphine were equipotent in all tests except that morphine was significantly more potent in elevating pain threshold in the uninflamed rat hind paw. In terms of THC content, CME was nearly equipotent in the hot plate and Randall-Selitto tests, but was 3 times more potent in the acetic acid writhing test. On the other hand, CBN, like aspirin, was only effective in reducing writhing frequency in mice (3 times more potent than aspirin) and raising pain threshold of the inflamed hind paw of the rat (equipotent with aspirin). CBD did not display a significantly analgesic effect in any of the test systems used. The results of this investigation seem to suggest that both THC and CME possess narcotic-like analgesic activity similar to morphine, while CBN appears to be a non-narcotic type analgesic like aspirin.     

A comparative oral analgesic study of indoprofen, aspirin, and placebo in postpartum pain

The purpose of this study was to evaluate the analgesic efficacy and adverse effect liability of single oral doses of indoprofen, 50 mg, 100 mg, and 200 mg, compared with aspirin, 300 mg and 600 mg, and placebo in the relief of moderate to severe postpartum pain. Two hundred-ten patients entered a randomized, double-blind, parallel group study and were evaluated over a six-hour period by a single nurse-observer. There was a significant imbalance in the distribution of pain types across treatments that compromises the interpretation of the results. In addition to analyzing the data from all patients, the subsets with episiotomy/cesarean section pain and uterine cramp pain were examined separately. The latter group had too few patients to permit distinction between drugs. The 100 mg and 200 mg doses of indoprofen were significantly (P less than or equal to .05) more effective than placebo for many variables including the following summary values: sum of pain intensity difference (SPID), sum of hourly relief values (TOTPAR), and % SPID for all patients as well as in the subset of patients with episiotomy/cesarean section pain. Aspirin, 600 mg, was also significantly more effective than placebo for many of the same measures of analgesia in the episiotomy/cesarean section subset. Pairwise differences were also seen between placebo and aspirin, 300 mg, but on fewer variables. Indoprofen, 100 mg, was significantly more effective than aspirin, 600 mg, at hour 6 for pain intensity difference (PID) in the episiotomy/cesarean section subset. The effect of indoprofen appeared to plateau above 100 mg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analgesic efficacy of non-steroidal anti-inflammatory drugs in experimental pain in humans

1. The aim of this study was to establish a simple and reliable experimental pain model that could distinguish the analgesic effects of non-steroidal anti-inflammatory drug (NSAID) treatment from placebo in human volunteers. 2. The reproducibility and reliability over time of subject pain ratings was compared using cutaneous electrical stimuli applied to either the thenar eminence or the ear lobe at varying intensities and modes. Subjects were asked to respond firstly, when the stimulus became clearly sharp and painful ('first pain') and secondly, when the sensation became deep and burning and no further increase in stimulus intensity could be tolerated ('second pain'). 3. Constant voltage stimuli were found to be more reproducible than constant current stimuli. Both phasic (intermittent) and tonic (continuous) stimulation modalities produced 'first' and 'second pain' sensations. The latter sensation was more reproducible, and was perceived as a burning pain which is akin to clinical pain. 4. Analgesics from the NSAID class were found to attenuate reliably only 'second pain' sensations. The analgesic effects of ibuprofen (ibuprofen vs placebo: 0.12 +/- 0.09 vs 0.02 +/- 0.07 volt h(-1), P = 0.03; 95% confidence interval for differences (CI): 0.03-0.18) and diflunisal (diflunisal vs placebo: 0.29 +/- 0.40 vs 0.005 +/- 0.27 volt h(-1), P = 0.0001; CI: 0.168-0.407), respectively, could be distinguished from placebo.     

Buffering the stomach content enhances the absorption of diflunisal in man

Diflunisal, a lipophilic salicylate, is absorbed more slowly in healthy volunteers than aspirin. In this paper we report on attempts to influence diflunisal absorption by buffering the gastric milieu. Sodium bicarbonate given together and 30 min after diflunisal tablets significantly (p less than 0.05) shortened the time to reach peak plasma concentration (tmax greater than 15 per cent), raised maximum plasma concentration slightly (Cmax 6 per cent) and increased the area under the plasma concentration-time curve (AUC greater than 8 per cent). Other pharmacokinetic parameters, including terminal half-life and renal elimination of the compound, were not considerably influenced. These findings indicate that the absorption of diflunisal was enhanced by increased gastric pH, presumably a result of an increased solubility of diflunisal in the stomach together with faster transport into the small intestine. In one volunteer, after intravenous administration diflunisal plasma concentrations declined in a triphasic manner with a terminal half-life of 12.8 h. The volume of distribution was approximately 10 per cent of body weight. Based on the ratio of AUC after equivalent i.v. and oral diflunisal doses, the absolute bioavailability was 89.5 per cent.     

Stability of amoxicillin trihydrate-potassium clavulanate in original containers and unit dose oral syringes

The stability of reconstituted amoxicillin trihydrate-potassium clavulanate oral suspension both in original containers and pre-packaged in commercially available oral syringes stored at various temperatures was determined. Amoxicillin trihydrate 125 mg/5 mL-potassium clavulanate 31.25 mg/5 mL and amoxicillin trihydrate 250 mg/5 mL-potassium clavulanate 62.5 mg/5 mL were reconstituted according to the manufacturer's instructions. The reconstituted suspensions in the original containers and in five brands of oral syringes were stored at 5 degrees C and 25 degrees C and -10 degrees C, 5 degrees C, and 25 degrees C, respectively, for 0, 2, 4, 7, and 14 days. The concentrations of amoxicillin trihydrate and potassium clavulanate remaining after storage were assayed in triplicate by reverse-phase high-performance liquid chromatography, using a stability-indicating method. An F statistic was calculated to determine whether different syringe brands had significantly different effects on drug stability. Amoxicillin trihydrate was stable for at least 10 days in the original containers and all types of oral syringes at 5 degrees C. However, potassium clavulanate was stable for 11.1 days in original containers and less than 5 days in all types of oral syringes at 5 degrees C. The effect of syringe brand on the stability of drugs over time at specific storage conditions and temperature was significant for potassium clavulanate at 5 degrees C and for both amoxicillin trihydrate and potassium clavulanate at 25 degrees C. The manufacturer's guidelines for storage of reconstituted amoxicillin trihydrate-potassium clavulanate oral suspension in the original containers should not be applied to dosages repackaged in unit dose oral syringes.     

The analgesic efficacy of suprofen in periodontal and oral surgical pain

Suprofen is a new, orally effective nonsteroidal antiinflammatory analgesic of the propionic acid chemical class. Three separate single-dose studies were performed to evaluate the efficacy of suprofen in acute pain associated with periodontal surgery and removal of impacted third molars. Study medications were: A--suprofen 200 mg, codeine 60 mg, propoxyphene HCl 65 mg, and placebo; B--suprofen 400 mg and 200 mg, aspirin 650 mg, and placebo; C--suprofen 400 mg and 200 mg, aspirin 650 mg with codeine 60 mg, aspirin 650 mg alone, and placebo. Analgesic and side effect data were collected over a 6-hour period after patients medicated for moderate to severe pain. All studies were randomized, double-blinded, and parallel-group in design. Suprofen was significantly more effective than codeine 60 mg, propoxyphene HCl 65 mg, and aspirin 650 mg. Suprofen 400 mg appeared to be clinically more effective than the aspirin-codeine combination and the difference was statistically significant for most of the analgesic variables. Of the 224 patients who received suprofen in the 3 studies, 16 reported drowsiness and 1 reported constipation.     

Clinical evaluation of fluid extract of Chamomilla recutita for oral aphthae

Recurrent aphthous stomatitis is a difficult to treat and quite common chronic inflammatory disease of the oral mucosa. This study evaluates the fluid extract from Chamomilla recutita's safety and effectiveness in pain relief from aphthous stomatitis and other painful ulcers of the oral mucous membrane. The analgesic effect was considered excellent by 82% and good by 18% of the patients, as demonstrated with the Analogical Visual Scale for chronic and experimental pains after 5, 10, and 15 minutes. Tolerance was evaluated as excellent by 97% and good by 1% of the subjects. The fluid extract from Chamomilla recutita, due to its analgesic effect, may give these patients a better quality of life.