Diclofenac

Diclofenac (marketed as Voltaren, Voltarol, Diclon, Dicloflex Difen, Difene, Cataflam, Pennsaid, Rhumalgan, Modifenac, Abitren and Zolterol, with various drug dose combinations) is a non-steroidal anti-inflammatory drug (NSAID) taken to reduce inflammation and an analgesic reducing pain in conditions such as in arthritis or acute injury. It can also be used to reduce menstrual pain. The name is derived from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid

In the United Kingdom, India, and the United States, it may be supplied as either the sodium or potassium salt, while in some other countries only as the potassium salt. Diclofenac is available as a generic drug in a number of formulations. Over the counter (OTC) use is approved in some countries for minor aches and pains and fever associated with common infections.

Diclofenac is well-tolerated after 30 years' experience by the general human population, but may unexpectedly become intolerated in some of the elderly population of long term users.

Mechanism of action

The action of one single dose is much longer (6 to 8 hours) than the very short half-life that the drug indicates. This could partly be due to a particular high concentration achieved in synovial fluids.

The exact mechanism of action is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory/antipyretic/analgesic action is inhibition of prostaglandin synthesis by inhibition of (COX).

Inhibition of COX also decreases prostaglandins in the epithelium of the stomach, making it more sensitive to corrosion by gastric acid. This is also the main side effect of diclofenac. Diclofenac has a low to moderate preference to block the COX2-isoenzyme (approximately 10-fold) and is said to have therefore a somewhat lower incidence of gastrointestinal complaints than noted with indometacin and aspirin.

Diclofenac may also be a unique member of the NSAIDs . There is some evidence that diclofenac inhibits the lipooxygenase pathways, thus reducing formation of the leukotrienes (also pro-inflammatory autacoids). There is also speculation that diclofenac may inhibit phospholipase A₂ as part of its mechanism of action. These additional actions may explain the high potency of diclofenac - it is the most potent NSAID   on a broad basis.

There are marked differences among NSAIDs in their selective inhibition of the two subtypes of cyclo-oxygenase, COX-1 and COX-2. Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs like aspirin. In practice, use of some COX-2 inhibitors due to their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs like diclofenac have been well-tolerated by most of the population.

Indications

Combined Diclofenac sodium and misoprostol tablets.

Diclofenac is used for musculoskeletal complaints, especially arthritis (rheumatoid arthritis, osteoarthritis, spondylarthritis, ankylosing spondylitis), gout attacks, and pain management in case of kidney stones and gallstones. An additional indication is the treatment of acute migraines. Diclofenac is used commonly to treat mild to moderate post-operative or post-traumatic pain, particular when inflammation is also present, and is effective against menstrual pain.

Diclofenac suppositories

As long-term use of diclofenac and similar NSAIDs predisposes for peptic ulcer, many patients at risk for this complication are prescribed a combination (Arthrotec®) of diclofenac and misoprostol , a synthetic prostaglandin analogue, to protect the gastric mucosa.

An external, gel-based form of diclofenac (Solareze®) is available for the treatment of facial actinic keratosis which is caused by over-exposure to sunlight. Some countries have also approved the external use of diclofenac gel to treat muskoskeletal conditions.

Over-the-counter use against minor aches and pains and fever associated with common infections is also licensed in some countries.

In many countries eye-drops are sold to treat acute and chronic non-bacterial inflammations of the anterior part of the eyes (e.g. postoperative states). A common brand name is Voltaren-ophta.

Contraindications

• Hypersensitivity against diclofenac

• History of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following the use of Aspirin or another NSAID

• Third-trimester pregnancy

• Active stomach and/or duodenal ulceration or gastrointestinal bleeding

• Inflammative intestinal disorders such as Crohn's disease or ulcerative colitis

• Severe insufficiency of the heart (NYHA III/IV)

• Recently, a warning has been issued by FDA not to treat patients recovering from heart surgery

• Severe liver insufficiency (Child-Pugh Class C)

• Severe renal insufficiency (creatinine clearance <30 ml/min)

• Caution in patients with preexisting hepatic porphyria, as diclofenac may trigger attacks

• Caution in patients with severe, active bleeding such as cerebral hemorrhage

Side effects

• Diclofenac is among the better tolerated NSAIDs. Though 20% of patients on long-term treatment experience side effects, only 2% have to discontinue the drug, mostly due to gastrointestinal complaints.

Cardiac

• Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor rofecoxib in 2004, attention has focused on all the other members of the NSAIDs group, including Diclofenac. Research results are mixed with a meta-analysis of papers and reports up to April 2006 suggesting a relative increased rate of heart disease of 1.63 compared to non users. Professor Peter Weissberg, Medical Director of the British Heart Foundation said, "However, the increased risk is small and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms". Only Aspirin was found not to increase the risk of heart disease, however this is known to have a higher rate of gastric ulceration than Diclofenac.
  A subsequent large study of 74,838 users of NSAIDs or coxibs, published in May 2006 found no additional cardiovascular risk from Diclofenac use.

• Diclonefac has similar COX-2 selectivity to celecoxib . Perhaps related to this selectivity, a review of this constantly changing topic by FDA Medical Officer David Graham concluded in September, 2006 that Diclofenac does increase the risk of myocardial infarction

Gastrointestinal

• Gastrointestinal complaints are most often noted (see above). The development of ulceration and/or bleeding requires immediate termination of treatment with diclofenac. Most patients receive an ulcer-protective drug as prophylaxis during long-term treatment (misoprostol, ranitidine 150mg at bedtime or omeprazole 20 mg at bedtime).

Hepatic

• Liver damage occurs infrequently, but is usually reversible. Hepatitis may occur rarely without any warning symptoms and may be fatal. Patients with osteoarthritis more often develop symptomatic liver disease than patients with rheumatoid arthritis. Liver function should be monitored regularly during long-term treatment. If used for the short term treatment of pain or fever, diclofenac has not been found to be more hepatotoxic than other NSAIDs.

Renal

• Studies in Pakistan showed that diclofenac caused acute kidney failure in vultures when they ate the carcasses of animals that had recently been treated with it (see below at Ecological problems). Species and individual humans that are drug sensitive are initially assumed to lack genes expressing specific drug detoxification enzymes. Because elderly humans have reduced expression levels of all enzymes, elderly human metabolisms may gradually approach those of vultures, thus unexpectedly becoming more diclofenac intolerant.

• NSAIDs"are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins" in sensitive persons or animal species, and potentially during long term use in non-sensitive persons if resistance to side effects decreases with age. Unfortunately this side effect can't be avoided merely by using a COX-2 selective inhibitor because, "Both isoforms of COX, COX-1 and COX-2, are expressed in the kidney... Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs  should be used when selective COX-2 inhibitors are administered.

Other

• Bone marrow depression is noted infrequently (leukopenia, agranulocytosis, thrombopenia with/without purpura, aplastic anemia). These conditions may be life-threatening and/or irreversible, if detected too late. All patients should be monitored closely. Diclofenac is a weak and reversible inhibitor of thrombocytic aggregation needed for normal coagulation.

Formulations

Enteric Coated Diclofenac Sodium tablets by Dexel-Pharma Ltd.

Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom Voltarol can be supplied with either the sodium salt or potassium salt, while Cataflam in some other countries is the potassium salt only.

Diclofenac is available in stomach acid resistant formulations (25 and 50 mg), fast disintegrating oral formulations (50 mg), slow- and controlled-release forms (75, 100 or 150 mg), suppositories (50 and 100 mg), and injectable forms (50 and 75 mg).

Diclofenac is also available over the counter (OTC) in some countries: Voltaren dolo (12.5 mg diclofenac as potassium salt) in Switzerland and Germany, and preparations containing 25 mg diclofenac in New Zealand.