Diflunisal

Abstract

Synopsis: Diflunisal 1 is a salicylic acid derivative with analgesic and anti-inflammatory activity. It has been studied in osteoarthritis, pain resulting from musculoskeletal sprains and strains and from minor surgery and cancer. The duration of its analgesic effect is longer than that of aspirin and diflunisal is effective when given twice daily. Diflunisal is not metabolised to salicylic acid and has a lesser effect than aspirin on platelet function in vivo. In osteoarthritis, diflunisal appears comparable in efficacy to moderate doses of aspirin (2 to 3g daily), but is better tolerated. It has not been compared with the most active phenylalkanoic acid derivatives such as naproxen in adequate numbers of patients. Diflunisal is comparable with glafenine in pain and with propoxyphene / paracetamol combinations and oxyphenbutazone in pain and in musculoskeletal strains and sprains. As with other non-steroidal agents, gastrointestinal complaints are the most frequently reported side effects. Pharmacology: Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. The analgesic effect of diflunisal is longer than that of aspirin, lasting for at least 8 hours and up to 12 hours. Between-patient and crossover studies have indicated that usual therapeutic doses of diflunisal cause less faecal blood loss than therapeutically equivalent doses of ordinary aspirin. Endoscopic examination during a comparison of diflunisal and aspirin in osteoarthritis, revealed a higher incidence of gastric erosions with aspirin than with diflunisal. To date there have been no comparisons with enteric-coated aspirin, aloxiprin or benorylate or with the other non-steroidal anti-inflammatory drugs. In vitro, diflunisal, like aspirin and many other non-steroidal anti-inflammatory agents, inhibits the secondary phase of platelet aggregation induced by adenosine diphosphate, adrenaline or thrombin. However, diflunisal has a lesser effect than aspirin on platelet function in vivo, possibly because of its lesser potency in inhibiting prostaglandin synthetase from human platelets. At usual therapeutic dosages diflunisal produced a significant decrease in serum uric acid. As far as can be determined from excretion of β-d-N-acetyl glucosaminidase, diflunisal has less marked acute effects on the kidney than aspirin, although the clinical relevance of these findings remains controversial. Pharmacokinetics: Diflunisal is well absorbed after oral administration, peak plasma concentrations being attained at about 2 hours. The time required to reach steady-state concentrations increases with dosage from 3 to 4 days for a 125mg dose to 7 to 9 days for a 500mg dose. The bioavailability of diflunisal is significantly decreased by aluminium hydroxide gel or an aluminium hydroxide-magnesium hydroxide mixture in fasted subjects, but this effect of antacids diminishes in fed subjects. Concomitant administration of diflunisal and aspirin 2.4g daily significantly decreases steady-state plasma concentrations of diflunisal, but this effect is thought not to be of clinical importance. Diflunisal is highly bound to plasma protein and has a relatively low volume of distribution of 7.5L in patients with normal renal function, but this increases significantly in moderate to severe renal impairment. The elimination of diflunisal is almost entirely dependent on glucuronidation of the parent compound. The phenolic glucuronide conjugate accounts for about 64 % of the radioactivity found in the urine after a single dose. Diflunisal is not metabolised to salicylic acid. About 80 to 95 % of an oral dose of diflunisal is excreted in the urine in 72 to 96 hours. Total body clearance of diflunisal is small (7.9ml/min). Less than 5 % of a single dose is recovered in the faeces. In renal impairment the terminal elimination half-life increases from the normal value of 10 hours to 115 hours when creatinine clearance is less than 2ml/min. Total body clearance of unchanged drug decreases significantly when creatinine clearance is less than 10ml/min. Diflunisal is not effectively removed from the body by haemodialysis. Therapeutic Trials: Diflunisal has been studied in osteoarthritis, pain following minor surgery and that associated with cancer and in sprains and strains of the wrist or ankle. In patients with osteoarthritis of the hip, diflunisal has been shown to be superior to placebo on the basis of objective and subjective criteria. In most of the controlled trials of diflunisal in osteoarthritis, it has been compared with ordinary aspirin in between-patient studies. In all studies diflunisal 500 to 750mg daily (twice daily dosage) has been compared with 2 to 3g daily of aspirin (4 times daily). Dosage has been titrated to individual requirements, but maximum daily dose has been 750mg diflunisal and 3g of aspirin. Most studies have involved rather small numbers of patients. Seldom has there been any statistically significant difference between the drugs with respect to analgesic activity assessed on several criteria. However, on the basis of overall opinion of response, diflunisal has sometimes been found to be superior to aspirin. A tendency for the duration of stiffness after inactivity to improve more with diflunisal than with aspirin has been noted by some investigators. If the stiffness represents an inflammatory component, as in rheumatoid arthritis, the tendency for diflunisal to be more effective is not surprising, as aspirin 2 to 3g daily would not be expected to exert an anti-inflammatory effect. In practically all studies, diflunisal has been better tolerated than aspirin, and a smaller proportion of patients receiving diflunisal have had to discontinue treatment because of adverse effects. All studies reporting on an extended open assessment of diflunisal, have found that the degree of improvement achieved during the 12-week double-blind phase has been maintained during the subsequent 12 to 36 week period. Diflunisal has been compared with ibuprofen and naproxen in patients with osteoarthritis of the hip and/or knee, but generally too few patients have been studied to permit valid conclusions regarding the relative efficacy and tolerance of the drugs. Further studies involving adequate numbers of patients and different dosage levels of diflunisal and the other non-steroidal anti-inflammatory drugs are needed to determine the relative efficacy of these drugs in osteoarthritis. To date, there have been no comparisons published with indomethacin. In patients with pain resulting from minor surgery (meniscectomy, episiotomy), diflunisal 500mg twice daily has been comparable with oxyphenbutazone 200mg 3 times daily, dextropropoxyphene 65mg plus paracetamol 650mg 3 times daily and glafenine 200mg 3 times daily. Diflunisal has been superior to placebo and a relatively low dose of codeine and comparable with glafenine in alleviating pain resulting from the removal of impacted wisdom teeth of: third molars. An unexplained high incidence of ’dry socket’ occurred in one study in patients who had been treated with diflunisal. In patients with strains or sprains involving the wrist or ankle, diflunisal 375 or 500mg twice daily has been shown to be comparable with dextropropoxyphene 65mg plus paracetamol 650mg 3 times daily and with oxyphenbutazone 200mg 2 or 3 times daily. A large trial in general practice found diflunisal to be superior to aspirin in the treatment of pain mostly in the back, shoulders, knee or neck caused most often by sprains, strains and osteoarthritis. Gastrointestinal side effects occurred more frequently with aspirin than with diflunisal and were more often severe. Side Effects: At dosages used in the treatment of osteoarthritis, diflunisal has generally been well tolerated. Gastrointestinal effects, mostly mild, have been reported in about 20% of patients in the first 12 weeks and in about 7 % in longer term studies. Central nervous system effects such as dizziness and headache have occurred in about 5% of patients, whilst tinnitus has rarely occurred. Under the conditions existing in controlled therapeutic trials, diflunisal has been better tolerated than moderate doses of aspirin. Further studies are required to determine the relative incidence of side effects of diflunisal and the propionic acid derivatives such as naproxen. As with other non-steroidal agents, gastrointestinal bleeding has occurred in some instances and long term clinical experience is required to establish the incidence relative to other drugs used to treat arthritic conditions. Dosage: The usual initial adult dose is 500mg followed by 250 to 500mg twice daily.