Zomepirac: A Review of its Pharmacological Properties and Analgesic Efficacy

Summary

Synopsis: Zomepirac^1,2 is an analgesic which is closely related chemically to the non-steroidal anti-inflammatory agent, tolmetin. In short term studies mainly involving patients with acute pain of moderate severity, zomepirac was at least as effective as usual therapeutic doses of aspirin, codeine alone or with aspirin, phenacetin and caffeine, dextropropoxyphene with paracetamol, or orally administered pentazocine. Additionally, zomepirac may provide analgesia comparable to that with standard doses of intramuscular morphine in patients with acute pain of moderate intensity, but in severe pain states strong analgesics may be more appropriate.

Zomepirac has also been studied in patients with chronic orthopaedic pain or osteoarthritic pain for up to several months, without the need for increased doses. It appears to be at least as effective as usual doses of aspirin when used in this way, with a lower incidence of some side effects such as gastrointestinal disturbances and hearing disorders. Preliminary studies suggest that zomepirac may also be effective in patients with chronic cancer pain who have not been previously maintained on strong analgesics, but further experience is needed to clarify its usefulness in this difficult treatment area.

From animal studies and limited long term experience in man, it appears that zomepirac is not likely to produce tolerance, or physical or psychological dependence.

Thus, it appears that zomepirac is a useful alternative in a variety of acute and chronic pain states in which analgesics such as aspirin, dextropropoxyphene with paracetamol or orally administered pentazocine would be considered appropriate. Whether its usefulness extends beyond this spectrum, into more severe pain states, needs further clarification.

Pharmacodynamic Studies: In vitro studies using homogenised bovine seminal vesicles and human platelets have shown that, in common with aspirin and other non-steroidal anti-inflammatory agents, zomepirac is a potent inhibitor of prostaglandin synthesis. It has typical antinociceptive activity in a standard animal model, showing similar potency (on a weight-for-weight basis) to subcutaneously administered morphine and greater potency than orally administered aspirin, paracetamol and pentazocine and subcutaneously administered codeine and pentazocine in the acetylcholine-induced writhing test in mice, which also detects narcotic-type analgesic activity. However, zomepirac is devoid of activity in other standard animal tests which are specifically designed to detect narcotic-type analgesic activity. Zomepirac showed more potent anti-inflammatory activity than aspirin in a range of animal models to detect both acute (adjuvant-induced arthritis and carrageenan-induced oedema tests in rats) and chronic (adjuvant-induced arthritis test in rats) anti-inflammatory activity, but its anti-inflammatory effects have not been investigated in man.

As with other prostaglandin synthetase inhibitors, zomepirac produces dose-dependent increases in gastrointestinal blood loss in healthy subjects and in patients. Ulcerogenic activity has been demonstrated in animals, but the incidences of gastrointestinal bleeding and peptic ulcer have been low in patients who have received long term zomepirac therapy to date.

Zomepirac has an antiplatelet effect similar to that found with aspirin, but the duration of this effect after discontinuation is shorter with zomepirac (about 12 hours) than with aspirin (4 to 7 days). Studies in healthy subjects have indicated that zomepirac has no clinically significant effects on other haematological parameters, including haemoglobin concentration, haematocrit, platelet count, prothrombin time and red blood cell survival time. Elevations of blood urea nitrogen and creatinine have occasionally been found in patients receiving long term zomepirac therapy.

Studies in animals and patients receiving long term zomepirac therapy for chronic pain have suggested that zomepirac has little or no dependence liability or abuse potential, but only wider use over longer periods will determine this with certainty.

Pharmacokinetic Studies: On the basis of urinary recovery data, zomepirac is almost completely absorbed after oral administration of dosages of 25 to 200mg to healthy subjects. Mean peak plasma concentrations of 2.47, 4.42 and 7.94μg/ml were attained 44, 57 and 80 minutes after a single oral dose of 50, 100 or 200mg, respectively. Bioavailability is the same after ingestion of tablets, capsules or an aqueous solution. In common with aspirin and other non-steroidal anti-inflammatory agents, zomepirac is extensively bound (98.5 %) to plasma albumin.

The elimination half-life of zomepirac is about 4 hours following a single dose, but may be increased following multiple doses. Zomepirac is excreted almost exclusively in the urine, the major metabolite being the glucuronide conjugate, which accounts for about 57 % of radioactivity after a 25mg dose. Hydroxyzomepirac and 4-chlorobenzoic acid are minor metabolites. About 22 % of the dose is excreted in the urine in unchanged form. Zomepirac metabolites (type not stated) are approximately 200 to 300 times less active than zomepirac as inhibitors of human platelet aggregation in vitro.

Therapeutic Trials: Zomepirac has been evaluated in several single dose or short term studies in patients with acute pain of moderate (most patients) to severe intensity due to headache, oral surgery, a variety of other surgical procedures, episiotomy, or orthopaedic disorders. Most of these studies were of a similar design and have made reasonable attempts to overcome the inherent difficulties in evaluating an analgesic drug.

In single-dose studies in patients with acute pain, zomepirac 50mg was less effective than zomepirac 100mg in providing analgesia. Zomepirac 100mg produced greater analgesia than aspirin 650mg, dextropropoxyphene 100mg + paracetamol 650mg, codeine 60mg, or 2 capsules of aspirin 227mg + phenacetin 162mg + caffeine 32mg (APC), and provided similar analgesia to APC (1 capsule) + codeine 60mg.

In multiple-dose studies, zomepirac 50 or 100mg every 4 hours when required for pain was as effective as APC (1 capsule) + codeine 30 or 60mg, or orally administered pentazocine 50mg, and usually caused fewer side effects than these agents.

Zomepirac 100 or 200mg has been compared with morphine, in intramuscular doses of up to 16mg, in single-dose crossover studies involving patients with moderate (most patients) to severe postoperative pain. 100 and 200mg doses provided similar analgesic effects, suggesting either a ‘ceiling effect’ of analgesic activity or lack of sensitivity of the pain model. These studies indicated that oral zomepirac was about one-sixth as potent as intramuscular morphine (on a weight-for-weight basis) with a slower onset but longer duration of action. However, the effectiveness of zomepirac was reduced in the small number of patients with severe pain included in such studies, and its usefulness in severe pain states needs further clarification.

The long term use of zomepirac in patients with chronic pain has also been reported. Studies in patients with pain secondary to osteoarthritis have indicated that daily doses of about 300 to 400mg of zomepirac provide at least equivalent analgesia to standard doses of aspirin. Although studies to date in patients with chronic cancer pain have indicated that zomepirac may be effective, experience is limited; further studies in such patients, who have not previously been maintained on strong analgesics, are required to determine the contribution which zomepirac can make to this difficult treatment area.

Side Effects: Zomepirac has been well tolerated in most patients studied to date, but further data are needed to determine clearly its profile of side effects in patients receiving long term therapy. In patients receiving zomepirac for more than 1 week, the most frequently reported side effect was nausea, occurring in approximately 12 % of the patients. Other gastrointestinal disturbances occurring in between 3 and 9 % of the patients were gastrointestinal distress, diarrhoea, abdominal pain, dyspepsia, constipation, flatulence and vomiting. Central nervous system side effects (dizziness or insomnia) occurred in between 3 and 9 % of patients. The incidence of gastrointestinal bleeding and peptic ulcer appears to be below 1 %.

In a long term comparative study, zomepirac produced a profile of side effects generally similar to that with aspirin, but the incidence of adverse reactions (apart from urogenital symptoms) was generally lower. In particular, the incidences of tinnitus 3.5 % compared with 15.3%) and hearing loss (1.0% compared with 6.9%) were considerably reduced in patients receiving zomepirac than in patients receiving aspirin.

Dosage and Administration: The recommended dosage of zomepirac is 100mg every 4 to 6 hours as required for pain. In mild pain, 50mg every 4 to 6 hours may be adequate. Single doses of more than 100mg are not recommended.

The daily dose of zomepirac should not exceed 600mg in patients with acute pain or 400mg in patients with chronic pain in whom treatment is expected to be continued for more than 3 months.

As zomepirac has similar side effects to aspirin, it should be used with caution in patients with a history of upper gastrointestinal disease or coagulation disorders. Zomepirac is contraindicated in patients with active peptic ulcer or with a history of hypersensitivity to aspirin.