, Volume 52, Issue 1, pp 113-124

Aceclofenac

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Abstract

Synopsis

Aceclofenac is a phenylacetic acid derivative with anti-inflammatory and analgesic properties similar to those of diclofenac. However, preclinical studies suggest that the potential of aceclofenac to cause gastrointestinal damage is less than that of diclofenac.

Double-blind comparative trials indicate that the efficacy of aceclofenac is at least equivalent to that of ketoprofen and similar to that of indomethacin and diclofenac in patients with rheumatoid arthritis, similar to that of diclofenac and piroxicam in patients with osteoarthritis of the knee and similar to that of ten-oxicam, indomethacin and naproxen in patients with ankylosing spondylitis. The analgesic efficacy of aceclofenac 100mg is more prolonged than that of paracetamol (acetaminophen) 650mg.

If the apparently improved gastrointestinal tolerability of aceclofenac compared with diclofenac is confirmed by wider clinical experience, aceclofenac will have the potential to become a preferred initial drug in an individualised NSAID regimen in patients with rheumatic disorders.

Pharmacodynamic Properties

The anti-inflammatory activity of aceclofenac has been shown to be similar to that of diclofenac in animal models of acute and chronic inflammation. In patients with osteoarthritis of the knee, basal and stimulated prostaglandin E2 (PGE2) production by blood mononuclear and polymorphonuclear cells was inhibited to a similar extent by aceclofenac 200 mg/day and diclofenac 150 mg/day for 6 months. Aceclofenac 225 mg/day for 6 days significantly decreased synovial fluid PGE2 levels in patients with knee pain and synovial effusion.

The analgesic activity of aceclofenac was similar to that of diclofenac in rodent models and the antipyretic potency of aceclofenac was about half that of diclofenac in rats with brewer’s yeast-induced hyperthermia. In vitro, aceclofenac stimulated glycosaminoglycan synthesis in osteoarthritic cartilage, indicating potential to maintain matrix synthesis and repair.

The ulcerogenic activity of a single dose of aceclofenac in rats assessed from indices of lesion severity was about 4- and 7-fold less than that of diclofenac and indomethacin, respectively. After multiple doses, the ulcerogenic effect of aceclofenac was about 1.5- to 2-fold less than that of diclofenac. During administration of aceclofenac 200 mg/day for 10 days to healthy volunteers, mean daily blood loss relative to baseline in faecal samples (following p51Cr labelling of red blood cells) was lower than that induced by diclofenac 150 mg/day.

Pharmacokinetic Properties

After oral administration of a single 100mg dose, mean maximum plasma aceclofenac concentrations (Cmax) of 6.8 to 8.9 mg/L were reached in about 1.4 to 2 hours. Cmax and the area under the plasma concentration-time curve (AUC) increased linearly after administration of single doses of aceclofenac 50, 100 and 150mg, and the pharmacokinetic properties of the drug were generally unchanged during multiple-dose administration in both young and elderly volunteers. The presence of food did not alter the pharmacokinetic parameters of aceclofenac.

The mean concentration of aceclofenac in synovial fluid is about half that in plasma. The main metabolite of aceclofenac is 4-hydroxy-aceclofenac; minor metabolites include diclofenac and 4-hydroxy-diclofenac. The low plasma concentrations and AUC values for the metabolites indicate that aceclofenac is principally responsible for the pharmacological activity. Approximately 70% of the drug is eliminated in the urine and 20% in the faeces. Mean elimination half-life values between 3.5 and 6.2 hours have been reported.

Therapeutic Efficacy

Double-blind trials have compared the efficacy of aceclofenac 100mg twice daily with that of ketoprofen 50mg 3 times daily, diclofenac 50mg 3 times daily or indomethacin 50mg twice daily in the treatment of patients with rheumatoid arthritis. All drugs significantly reduced the Ritchie index, pain and the duration of morning stiffness, and increased grip strength compared with baseline values. The drugs were generally of similar efficacy, although the onset of effect of aceclofenac appeared to be faster than that of ketoprofen. Aceclofenac 100mg twice daily showed similar efficacy to that of diclofenac 50mg 3 times daily and piroxicam 20mg once daily in improving symptoms in patients with osteoarthritis of the knee. Although the overall efficacy did not differ significantly between treatment groups according to investigators, patient-assessed pain improved in a greater percentage of aceclofenac than diclofenac recipients in one study.

Aceclofenac 100mg twice daily, tenoxicam 20mg once daily, indomethacin 100mg daily (25mg morning and noon and 50mg in the evening) and naproxen 500mg twice daily were similarly effective in alleviating pain and morning stiffness and improving spinal mobility in patients with ankylosing spondylitis.

The analgesic efficacy of single doses of aceclofenac 50, 100 and 150mg was greater than that of placebo in patients with moderate to severe tooth pain or pain caused by episiotomy or extraction of impacted third molars. Aceclofenac 100 or 150mg was longer acting than aceclofenac 50mg, and in patients with postepisiotomy pain aceclofenac 100mg was more effective than paracetamol (acetaminophen) 650mg. The duration of analgesic effect of intramuscular aceclofenac 150mg twice daily was greater than that of diclofenac 75mg twice daily in patients with acute lumbago. Pain and swelling associated with soft tissue injuries were alleviated to a similar extent by a topical formulation of a cream containing either aceclofenac 1.5% or piroxicam 1%.

Tolerability

Data regarding the incidence of adverse events associated with aceclofenac are available only from clinical trial reports. Gastrointestinal events including indigestion, diarrhoea, nausea, abdominal pain and flatulence have been reported in 2 to 24.5% of patients treated with aceclofenac. The incidence of gastrointestinal adverse effects has generally been lower with aceclofenac than the comparators; however, endoscopy was not performed in clinical trials. Although differences did not generally reach the level of statistical significance in individual studies, a meta-analysis indicated that the incidence of adverse events and overall withdrawal rate were lower and the gastrointestinal tolerability of aceclofenac better than that of other NSAIDs. The incidence of adverse events was similar between aceclofenac and placebo in placebo-controlled trials. Although available data indicate that aceclofenac has a minimal effect on liver function at therapeutic dosages, the drug modestly increased mean levels of the hepatic enzymes aspartate and alanine aminotransferase. Its effect on liver function relative to that of other NSAIDs remains to be determined.

Dosage and Administration

The usual oral dosage of aceclofenac is 100mg twice daily for the treatment of arthritic disorders and moderate to severe pain in adults. Aceclofenac, like other NSAIDs, should be administered with caution to patients with a history of peptic ulcer or dyspepsia.

Various sections of the manuscript reviewed by: E. Batlle-Gualda, Sección de Rheumatología, Hospital General Universitario de Alicante, Alicante, Spain; H. A. Bird, Clinical Pharmacology Unit, Research School of Medicine, University of Leeds, Leeds, England; I. Bjarnason, Department of Clinical Biochemistry, King’s College School of Medicine and Dentistry, London, England; A. Crema, Section of Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy; M. S. Irani, Ashford Hospital, Ashford, Middlesex, England; F. McKenna, Rheumatic Diseases Unit, Trafford General Hospital, Manchester, England; M. M. Wolfe, Brigham and Women’s Hospital, Gastroenterology Division, Boston, Massachusetts, USA; A. Yanagawa, Institute of Medical Science, St Marianna University, Kawasaki, Kanagawa, Japan.