Diclofenac Sodium

Publisher Website
Google Scholar
Abstract
Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) advocated for use in painful and inflammatory rheumatic and certain non-rheumatic conditions. It is available in a number of administration forms which can be given orally, rectally or intramuscularly. Conveniently, dosage adjustments are not required in the elderly or in those patients with renal or hepatic impairment. The drug has a relatively short elimination half-life, which limits the potential for drug accumulation. In numerous clinical trials the efficacy of diclofenac is equivalent to that of the many newer and established NSAIDs with which it has been compared. As an analgesic it has a fast onset and long duration of action. When administered intramuscularly it is at least comparable to, and frequently superior to, many narcotic and spasmolytic combinations in renal and biliary colic. Extensive clinical experience has been gained with diclofenac, clearly establishing its safety profile. It is well tolerated compared with other NSAIDs and rarely produces gastrointestinal ulceration or other serious side effects. Thus, diclofenac can be considered as one of the few NSAIDs of ‘first choice’ in the treatment of acute and chronic painful and inflammatory conditions. Diclofenac suppresses acute and chronic inflammation, pain and hyperthermia in various animal models, and in these models the drug has generally proven more potent, weight for weight, than aspirin, ibuprofen, naproxen and phenylbutazone, less potent than piroxicam, and similar to indomethacin. The therapeutic index (ratio of gastrointestinal irritant and therapeutic dosages) of diclofenac is generally good in animals, but varies relative to other non-steroidal anti-inflammatory drugs (NSAIDs) according to the model used. However, controlled studies in healthy subjects show that usual therapeutic dosages of diclofenac cause less gastrointestinal damage than aspirin, feprazone, indomethacin and naproxen but more than fenclofenac. The anti-inflammatory activity of diclofenac, and most of its other pharmacological effects, are generally thought to be related to its inhibition of prostaglandin synthesis. Diclofenac is a potent inhibitor of cyclo-oxygenase in vitro and in vivo, thereby decreasing the synthesis of prostaglandins, prostacyclin and thromboxane products. This is reflected in animals and humans in vivo by reduced concentrations of various prostaglandins in urine, gastric mucosa and synovial fluid during treatment with diclofenac. Also, in common with other NSAIDs, diclofenac is a potent reversible inhibitor of the secondary phase of induced platelet aggregation. However, diclofenac at usual therapeutic dosages has little effect on bleeding time in humans. The drug also affects polymorphonuclear leucocyte function, thereby reducing chemotaxis, superoxide production and protease production. Diclofenac is rapidly and efficiently absorbed after conventional oral, rectal or intramuscular administration. After intramuscular administration peak plasma concentrations are attained after 10 to 30 minutes. With the enteric-coated formulation peak concentrations are reached after 1.5 to 2.5 hours, and this is delayed by food to 2.5 to 12 hours. After a single 50mg dose of these formulations, mean peak plasma concentrations of unchanged diclofenac are 0.7 to 1.5 mg/L. No clear peak concentrations are found after a single 100mg dose of sustained release diclofenac, although the mean concentration was about 0.1 mg/L at 2 hours. Peak plasma concentrations and area under the plasma concentration-time curve are linearly related to dose over the range of 25 to 150mg, regardless of administration route, and no accumulation occurs after repeated doses. Like other NSAIDs, diclofenac is highly (≥ 99.5%) protein bound. The mean total volume of distribution is 0.12 to 0.17 L/kg and that of the central compartment is 0.04 L/kg. The drug efficiently penetrates inflamed synovial fluid where high concentrations are maintained compared with plasma concentrations. Diclofenac and its metabolites cross the placenta in animals, and small amounts may be found in the breast milk of women. Diclofenac undergoes significant first-pass metabolism and only 60% of the drug reaches systemic circulation unchanged following oral administration. It is eliminated principally by hepatic metabolism and subsequent urinary and biliary excretion of glucuronide and sulphate conjugates of the metabolites. The principal metabolite in humans is 4′-hydroxydiclofenac, which possesses negligible anti-inflammatory activity compared with the parent drug; the amount excreted in urine accounts for 20 to 30% of the dose and that in bile for 10 to 20%. In healthy volunteers, mean plasma clearance of diclofenac is 16 L/h, and the mean elimination half-life of the terminal phase is 1.1 to 1.8 hours. The mean elimination half-life after a radiolabelled dose is about 30 hours for the tracer. Age and renal or hepatic impairment do not appear to have any significant effect on plasma concentrations of unchanged diclofenac, although metabolite concentrations may be increased by severe renal impairment. Diclofenac 75 to 150mg daily administered orally or rectally has been well studied in controlled clinical trials in patients with rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, showing similar analgesic and anti-inflammatory efficacy to usual therapeutic dosages of other NSAIDs, e.g. acemetacin, aspirin, carprofen, diflunisal, fenclofenac, flurbiprofen, ibuprofen, indomethacin, indoprofen, isoxicam, ketoprofen, mefenamic acid, naproxen, piroxicam, proglumetacin, proquazone, sulindac and tiaprofenic acid. As would be expected in such a large number of comparisons, statistically significant differences were found for some assessment parameters, but these differences were not of any clinical significance. In these controlled trials efficacy was usually examined over several weeks to several months. Longer term efficacy (up to several years) has been confirmed in non-comparative studies involving many thousands of patients. Most improvement occurred in the first 6 months, and an ‘excellent to good’ response was found in 60 to 90% of patients. Once improvement has occurred with diclofenac 150mg daily, the dosage can usually be reduced to 100mg daily without loss of efficacy. Diclofenac 75 to 150mg daily administered orally or intramuscularly appears effective in the treatment of acute gout and is as effective as phenylbutazone 600mg daily and indomethacin 150mg daily. In a single study, diclofenac 2 to 3 mg/kg/day appeared more effective and better tolerated than aspirin 50 to 100 mg/kg/day in patients with juvenile rheumatoid arthritis. Diclofenac 75 to 150mg daily administered orally, rectally or intramuscularly is an effective analgesic and anti-inflammatory agent in the treatment of various rheumatic conditions (e.g. tendinitis, bursitis, sciatica, myalgia) and acute soft tissue injuries (e.g. strains, sprains). It is also effective in treating the signs and symptoms of dysmenorrhoea. Diclofenac is as effective as, and occasionally superior to, usual therapeutic dosages of other NSAIDs such as flufenamic acid, ibuprofen, indomethacin, ketoprofen, naproxen and piroxicam. The onset of analgesia was frequently more rapid with diclofenac. Diclofenac (administered orally, rectally or intramuscularly as single doses of 50 to 100mg or up to 150mg daily) is an effective analgesic agent in cases such as dental or minor surgical pain, postpartum pain and headache. It was at least as effective as usual therapeutic dosages of NSAIDs (e.g. indomethacin) and narcotic analgesics [e.g. oxycodone, dihydrocodeine plus paracetamol (acetaminophen), pentazocine, pethidine], but was devoid of the CNS effects associated with narcotics. Again, the onset of analgesia was frequently noted to be more rapid with diclofenac. Intramuscularly administered diclofenac 50 to 100mg provides rapid and long lasting analgesia in patients with renal or biliary colic. It is at least as effective as, and superior to, many narcotic and spasmolytic combinations [e.g. pethidine 100mg, hyoscine (scopolamine) butylbromide 20mg]. Even when narcotic analgesics show similar efficacy, diclofenac possesses superior tolerability, being devoid of significant CNS effects. Orally, rectally and intramuscularly administered diclofenac 0.25 to 0.5 mg/kg in children and 50 to 150mg in adults is an effective antipyretic agent, but must be used with caution in intensive care patients with compromised renal or circulatory function as oliguria or circulatory shock may rarely occur. The tolerability profile of diclofenac is well established, as wide experience has been gained with the drug in clinical practice. About 12% of patients experience side effects, which are usually mild and transient, and 1.5% to 2% have the drug withdrawn. Side effects usually occur in the first 6 months of treatment, and they are not more frequent in the elderly. As with other NSAIDs, gastrointestinal problems are the most frequent effects, followed by minor CNS symptoms and allergic or local reactions. Diclofenac is well tolerated compared with other NSAIDs, and no other agent of this class appears to have a side effect profile which is clearly superior to diclofenac. Aspirin produces more frequent and more severe gastrointestinal effects than diclofenac, and tinnitus and hearing loss are only extremely rarely associated with diclofenac. Indomethacin clearly produces more CNS effects than diclofenac, and gastrointestinal complaints are also somewhat more frequent with indomethacin. The tolerability of diclofenac appears similar to other commonly used NSAIDs such as ibuprofen, ketoprofen and naproxen. As with any drug which has been used so extensively, a number of extremely rare or serious adverse effects have been associated with diclofenac. Gastrointestinal ulceration appears rarely associated with diclofenac compared with many other NSAIDs: there were only 8 reports in 85,361 patients (0.009%) treated with the drug. Although rare and isolated cases of hepatitis, severe renal damage and severe haematological complications have been reported, other NSAIDs have also been associated with these problems. In addition, diclofenac is rarely or never associated with some other serious side effects caused by other commonly used NSAIDs, e.g. acute pancreatitis, aseptic meningitis, or severe cutaneous or phototoxic reactions. Changes in laboratory test values may occur during diclofenac therapy, but these are usually minor, transient and unrelated to therapy. However, persistently abnormal or worsening renal, hepatic or haematological test values should be followed up carefully, as with any drug, since they may in rare cases be related to therapy. Diclofenac does not appear to interact with oral anticoagulants, parenteral gold, penicillamine, chloroquine, azathioprine, prednisolone, cefadroxil, doxycycline, codeine and oral hypoglycaemics. Antacids delay the absorption of diclofenac but do not affect the overall extent of absorption. Plasma concentrations of diclofenac are decreased by concomitant aspirin administration. Diclofenac decreases the clearance of lithium, and plasma lithium concentrations can become toxic during coadministration. It is probably inadvisable to administer diclofenac, or any NSAID, with triamterene or methotrexate. Diclofenac has been noted to increase plasma concentrations of digoxin. The initial dosage of conventional or enteric-coated tablets of diclofenac is 150mg daily in 2 or 3 divided doses with meals, and in most patients therapeutic control can be maintained on 100mg daily. In children the dosage is 2 to 3 mg/kg/day. Diclofenac can be used in rheumatic conditions such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis and bursitis, and in other inflammatory or painful conditions such as strains and sprains, dysmenorrhoea, back pain, sciatica and postoperative pain. A sustained release formulation can be administered once daily, and suppositories can be administered once or twice daily. Intramuscular diclofenac 75mg can be given for the urgent relief of acute pain such as renal or biliary colic. A further dose may be administered after 30 minutes if necessary, but as with oral administration the daily dosage should not exceed 150mg. Diclofenac is not recommended for children less than 18 months of age, and only when essential in pregnant or lactating women. Dosage reductions are not required in the elderly or in patients with hepatic or renal insufficiency. However, these patients should remain under close supervision as should those with a history of gastrointestinal disease.