Tolmetin: A Review of its Pharmacological Properties and Therapeutic Efficacy in Rheumatic Diseases

SummarySynopsis: Synopsis: Tolmetin1 (1-methyl-5-p-toluoylpyrrole-2-acetic acid) is a new non-steroidal anti-inflammatory, antipyretic and analgesic agent advocated for use in rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint disease and ankylosing spondylitis.Published data suggest that in rheumatoid arthritis, tolmetin 1200 to 1600mg daily is comparable in effectiveness with about one-eighth its dose of indomethacin and with moderate to high doses of aspirin (4 to 4.5g daily), but generally causes fewer and less troublesome side-effects at the dosages used. Tolmetin appears to be comparable with alclofenac 4g daily, and at least as effective as ibuprofen, but has not been compared with the other commonly used phenylalkanoic acid derivatives such as naproxen and fenoprofen. However, as no one of the non-steroidal anti-inflammatory agents is the most suitable drug for all patients requiring such therapy, tolmetin should be considered along with the other drugs of its type in the initial treatment of the arthritic patient. Tolmetin, as a pyrole acetic acid derivative like indomethacin, has compared favourably with indomethacin in degenerative joint disease and anky losing spondylitis*, but it is generally better tolerated than indomethacin in the diseases studied. Pharmacology: In experimental studies in animals, tolmetin has been shown to inhibit rat paw oedema caused by carrageenan or kaolin and to inhibit joint and inflammatory changes in established adjuvant-induced arthritis. In guinea-pigs, tolmetin delayed the appearance of ultraviolet-induced erythema.Tolmetin is a potent inhibitor of bovine seminal vesicle prostaglandin synthesis in vitro. The antipyretic effect of tolmetin has been demonstrated in rats with yeast-induced hyperthermia, and the analgesic effect in patients with pain of varying origin.Tolmetin, like many other non-steroidal anti-inflammatory agents, produces lesions in the mucosa of the stomach and small intestine. However, this effect is less marked than with aspirin or indomethacin.In healthy volunteers, tolmetin 1200mg daily causes less gastrointestinal bleeding than therapeutically equivalent doses of aspirin given for the same period. Tolmetin has not been compared in this regard with other commonly used non-steroidal anti-inflammatory agents other than indomethacin, or with other forms of aspirin.Tolmetin has a mild antiplatelet effect similar to that found with aspirin, but the duration of effect after discontinuation is shorter with tolmetin than with aspirin. Unlike aspirin, tolmetin has only a slight effect on platelet adhesiveness.Pharmacokinetic studies indicate that in humans, tolmetin is rapidly and almost completely absorbed after oral administration. Peak plasma concentrations are generally attained 20 to 60 minutes and are dose related. Like the phenylalkanoic acid derivatives, tolmetin is highly bound to serum protein and has a fairly low apparent volume of distribution.Tolmetin is quickly cleared from the plasma, mainly by metabolism, and has an elimination half-life of about 60 minutes based on the assumption that pharmacokinetics are linear. However, use of a nonlinear model results in a half-1 ife of about 5 hours. The principal metabolite, the decarboxylic acid, has no apparent anti-inflammatory activity in animals.In arthritic patients the rate constants for drug absorption and elimination are not significantly different from those in normal subjects, but the area under the plasma level curve profile is lower in arthritic patients than in healthy volunteers. Therapeutic Trials: In the treatment of rheumatoid arthritis, tolmetin has been compared in formal comparative trials with placebo, high dose aspirin, indomethacin and phenylbutazone and other non-steroidal anti-inflammatory agents including alclofenac and ibuprofen. Tolmetin has invariably been shown to be superior to placebo. In all but one of the studies comparing tolmetin and aspirin, there has been no significant difference between the drugs with regard to effectiveness, but side-effects have been less frequent with tolmetin. Similarly, there was no significant difference between tolmetin 800 to 1400mg daily and indomethacin 100 to 150mg daily, or between tolmetin 1600mg daily and phenylbutazone 400mg daily, but tolmetin was generally better tolerated than the reference drugs.Tolmetin was comparable with alclofenac in one study and with ibuprofen in another, but was rated superior to ibuprofen in a retrospective comparison.There appeared to be little therapeutic advantage in treatment with a combination of tolmetin and aspirin compared with aspirin alone, but tolmetin plus paracetamol was shown to be superior to tolmetin alone on the basis of subjective assessment. However, this advantage was less evident when assessed by objective and semi-objective criteria. Similarly, a gold-tolmetin combination was considered by investigators and patients to be superior to gold alone, but the combination produced significantly greater improvement in only a minority of more objective criteria.The addition of tolmetin to stabilised doses of prednisone enabled a significant reduction in the daily dose of the corticosteroid and also resulted in greater symptomatic improvement. Although the addition of tolmetin to a fixed dose of oral corticosteroid resulted in a higher proportion of satisfactory responses than the corticosteroid alone, there was a tendency towards a higher incidence of side-effects with the combination treatment.Long-term open studies indicated that a progressive improvement in joint symptoms and some objective measurements of disease activity can be achieved in patients treated for 12 months or more with usual dosages.In degenerative joint disease involving the hip and knee,* there was no significant difference in the efficacy of tolmetin 600 to 1200mg daily and indomethacin 75 to 150mg or aspirin 4.5g daily, although patients and physicians preferred tolmetin to aspirin and indomethacin tended to be more effective than tolmetin in relieving hip pain.Tolmetin has been shown to be at least as effective as indomethacin (at about one-eighth the dose) in patients with definite ankylosing spondylitis*, but tolmetin has yet to be compared with the phenylalkanoic acid derivatives in this condition.Results of a well conducted study in juvenile rheumatoid arthritis found no significant differences in the clinical responses to aspirin or tolmetin over a 12-week period. Side-effects: At dosages usually used in the treatment of rheumatic diseases, tolmetin has generally been well tolerated during short-term and long-term studies. The overall incidence of side-effects has been 25 to 40% of patients treated with 1200 to 1600mg daily. In controlled studies side-effects have necessitated withdrawal of treatment in about 5 to 8 % of patients. Gastrointestinal effects such as epigastric pain, dyspepsia, nausea and vomiting have been the most frequently reported adverse reactions but have generally been less troublesome with tolmetin than with aspirin. Peptic ulceration and upper gastrointestinal bleeding have been reported occasionally. Central nervous system effects have generally occurred less frequently than gastrointestinal effects, but have been less of a problem than with indomethacin. Tinnitis, deafness, dizziness and vertigo have occurred more frequently with aspirin than with tolmetin. Drug Interactions: Although tolmetin, like the phenylalkanoic acid derivatives is highly bound to plasma protein and has a low volume of distribution, studies specifically designed to determine the likelihood of interaction with warfarin, phenprocoumon and glibenclamide, have found no evidence of clinically significant interaction. Absorption of tolmetin is not influenced by concomitant administration of an antacid containing magnesium-aluminium hydroxide gel. Laboratory Test Modifications: The metabolites of tolmetin cause false positive tests for proteinuria when the tests rely on acid precipitation (e.g. sulfosalicylic acid method). No interference has been noted in tests that use dye-impregnated, commercially available reagent strips. Dosage: The usual initial adult dose is 1200mg daily in three or four divided doses**. The dosage schedule includes a dose on arising and at bedtime. However, dosage should be adjusted according to individual response. Control is usually achieved at a dosage of 600 to 1800mg daily. The recommended initial dose in children is 20mg/kg daily in divided doses. The dosage should be adjusted according to individual response, control usually being achieved at doses of 15 to 30mg/kg daily.