Diclofenac Sodium: A Review of its Pharmacological Properties and Therapeutic Use in Rheumatic Diseases and Pain of Varying Origin

Summary

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.