Diclofenac

Diclofenac
2-[(2,6-dichloro phenyl)amino]benzene acetic acid
CAS number 15307-86-5	ATC code M01AB05, M02AA15, S01BC03
Chemical formula	C₁₄H₁₁Cl₂N O₂
Molecular weight	296.152
Bioavailability	approx. 50%, depending on mode of application
Metabolism	hepatic
Elimination half life	1.2-2 hr
Excretion	?
Pregnancy category	B (1st. and 2nd. trimenon), X (third trimenon)
Legal status	Rx-only, not a controlled substance
Routes of Application	oral, rectal, i.m.-injection, i.v.-injection (renal- and gallstones)

Diclofenac (marketed as Voltaren®, Voltarol® and Cataflam®) is a non-steroidal anti-inflammatory drug (NSAID) taken to reduce inflammation, such as in arthritis or acute injury. It can also be used to reduce menstrual pain. 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 currently one of the drugs most often used to treat painful conditions. It is available in stomach acid resistant formulations (25 and 50mg), fastly disintegrating oral formulations (50mg), slow release and CR forms (75, 100 or 150mg), suppositories (50 and 100mg), and injectable forms (50 and 75mg). Diclofenac is also available OTC in some countries : Voltaren® dolo (12.5mg Diclofenac as Potassium salt) in Switzerland and Germany, and preparation with 25mg Diclofenac are OTC in New Zealand. OTC use is approved for minor aches and pains and fever associated with common infections.

Diclofenac is available as a generic drug in a number of formulations.

Mechanism of action

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

Diclofenac, it seems, 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 molar basis.

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 (approx. 10-fold) and is said to have therefore a somewhat lower incidence of gastrointestinal complaints than noted with indomethacin and aspirin.

The action of one single dose is mauch longer (6 to 8 hours) than the very short halflife of the drug indicates. This could be due to a particular high concentration achieved in synovital fluids.

Common Uses

Diclofenac is used for musculoskeletal complaints, especially arthritis (rheumatoid arthritis and osteoarthritis), and pain management in case of kidney stones and gallstones. An additional indication is the treatment of acute migraine attacks. Diclofenac is used commonly to treat mild to moderate postoperative or posttraumatic pain, particular when inflammation is also present. Its an effective drug against menstrual pain.

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 form of Diclofenac (Solareze®) is available against sunburns. Some countries also approved the external use of Diclofenac to treat muskoskeletal conditions.

OTC use against minor aches and pains and fever associated with common infections is also licensed in some countries.

Off Label/Investigational Uses

Diclofenac is often used to treat chronic pain associated with cancer, particular if inflammation is also present. Good results (sometimes better than those with opioids) have been seen in female breast cancer and in the pain associated with bony metastasis. Diclofenac can be combined with opioids if needed. In Europe Combaren® exists, a fixed combination of Diclofenac and Codeine (50mg each) for cancer treatment. Combinations with psychoactive drugs such as Chlorprothixene and/or Amitriptyline have also been investigated and found useful in a higher number of cancer patients.

Fever due to malignant lymphogranulamatosis Morbus Hodgkin often reponds to Diclofenac.

Diclofenac has been found to increase the blood pressure in patients withs Shy-Drager-syndrome (autonomous hypotension) often seen in diabetic patients. Currently, this use is highly investigational and cannot be recommended as routine treatment.

Contraindications

Hypersensitivity against Diclofenac
History of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following the use of Aspirin or an other NSAID
In the third trimenon of pregnancy
Active stomach- and/or duodenal ulceration or gastrointestinal bleeding
Inflammative intestinal disorders as M. Crohn or Colitis ulcerosa.
Severe insufficience of the heart (NYHA III/IV)
Severe liver insufficience (Child-Pugh Class C).
Severe renal insufficience (Kreatinin-Clearance <30 ml/min)

Side Effects

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 longterm treatment (Misoprostol, Ranitidine 150mg at bedtime or omeprazol 20mg at bedtime).
Liver and renal damage occur infrequently, but are usually reversible. Hepatitis may occur rarely without any warning symptoms and may be fatal. Interestingly, patients with osteoarthritis develop more often symptomatic liver disease than patients with rheumatoid arthritis. Monitor liver and kidney function regularly during longterm treatment.
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. Monitor all patients closely. Diclofenac is a weak and reversible inhibitor of thrombocytic aggregation needed for normal coagulation of the blood. Exert caution in treating patients also receiving anticoagulants (coumarines or heparine) or those with hemophilia.
Rarely, but life-threatening : shock-like-syndrome including hypotension, tachycardia, cold sweating, anxiety, laryngospam, bronchospasm, and urticaria. Immediate treatment is necessary and can be life-saving. This reaction is most often noted within 30 to 60 minutes after the first application of Diclofenac. Parenteral use (i.m. or i.v.) is particular dangerous in this regard. The reaction may also been seen in the longterm treatment with Diclofenac.
Sometimes central nervous symptoms (nervousness, insomnia, headaches, vertigo) are also seen. Initially, the patient's ability to drive or control machines may be compromised.
The strong antipyretic activity may obscure the course of infections

Interactions

Other NSAIDs, corticoids and alcohol : risk of gastrointestinal ulceration and bleeding increased
ACE-Inhibitors and Amiloride/Triamterene : risk of severe hyperkalema and renal damage increased
Methotrexat : increased effects and side-effects of Methotrexat
Oral Antidiabetic Drugs : possibly increased hypoglycemia
Anticoagulants : increased risk of bleeding

Dosage

The usual dose in adults depend on the condition to be treated:

muskoskeletal conditions : initially 3 times 50mg oral or rectal. In longterm treatment try to reduce the daily dose to 3 to 4 times 25mg oral.
postoperative and posttraumatic pain, menstruation pain : 3 times 50mg oral or rectal, in severe cases up to 300mg rectally each day for a few days
migraine attacks : 50mg Diclofenac as Potassium salt every 4 to 6 hours (not to exceed 200mg daily) or 100mg rectally up to 300mg daily. Terminate treatment as soon as the attack subsides.
renal-/gallbladder stones : single rapid i.v.-injection of 50mg. The patients must have plenty of fluids to achieve an effect.
minor aches and pains and fever : 12.5 to 25mg Diclofenac (Potassium salt) up to 3 times daily (OTC maximum is 75mg daily).

Environmental problems

Use of diclofenac in animals has been reportedTemplate:Fn to have led to a sharp decline in the vulture population in the Indian subcontinent, up to 95% in some areas. The mechanism is probably renal failure, a known side-effect of diclofenac. Vultures eat the carcasses of animals that have been administered diclofenac, and are poisoned by the accumulated chemical.

Reference

Template:Fnb Oaks JL, Gilbert M, Virani MZ, Watson RT, Meteyer CU, Rideout BA, Shivaprasad HL, Ahmed S, Chaudhry MJ, Arshad M, Mahmood S, Ali A, Khan AA. Diclofenac residues as the cause of vulture population decline in Pakistan. Nature 2004;427:630-3. PMID 14745453.

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