Diclofenac

Diclofenac

Overview
Diclofenac is a non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...

 (NSAID) taken to reduce inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 and as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 reducing pain in certain conditions.

The name is derived from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid.

In the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

, India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...

, Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...

 and the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, it may be supplied as either the sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 or potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...

 salt, in China most often as the sodium salt, while in some other countries only as the potassium salt.
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Encyclopedia
Diclofenac is a non-steroidal anti-inflammatory drug
Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...

 (NSAID) taken to reduce inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 and as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 reducing pain in certain conditions.

The name is derived from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid.

In the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

, India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...

, Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...

 and the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, it may be supplied as either the sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

 or potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...

 salt, in China most often as the sodium 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.

Medical uses





Diclofenac is used to treat pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

, inflammatory disorders, and dysmenorrhea
Dysmenorrhea
Dysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...

.

Inflammatory disorder may include musculoskeletal complaints, especially arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

, rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

, polymyositis
Polymyositis
Polymyositis is a type of chronic inflammation of the muscles related to dermatomyositis and inclusion body myositis.-Signs and symptoms:...

, dermatomyositis
Dermatomyositis
Dermatomyositis is a connective-tissue disease related to polymyositis and Bramaticosis that is characterized by inflammation of the muscles and the skin.- Causes :...

, osteoarthritis
Osteoarthritis
Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...

, dental pain, TMJ
Temporomandibular joint
The temporomandibular joint is the joint of the jaw and is frequently referred to as TMJ. There are two TMJs, one on either side, working in unison. The name is derived from the two bones which form the joint: the upper temporal bone which is part of the cranium , and the lower jaw bone called the...

, spondylarthritis, ankylosing spondylitis
Ankylosing spondylitis
Ankylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...

, gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...

 attacks, and pain management
Pain management
Pain management is a branch of medicine employing an interdisciplinary approach for easing the suffering and improving the quality of life of those living with pain. The typical pain management team includes medical practitioners, clinical psychologists, physiotherapists, occupational therapists,...

 in cases of kidney stone
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...

s and gallstone
Gallstone
A gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder, but may pass distally into other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct, or the ampulla of...

s. An additional indication is the treatment of acute migraines. Diclofenac is used commonly to treat mild to moderate post-operative or post-traumatic pain, in particular when inflammation is also present, and is effective against menstrual pain and endometriosis
Endometriosis
Endometriosis is a gynecological medical condition in which cells from the lining of the uterus appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones...

.

As long-term use of diclofenac and similar NSAIDs predisposes for peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...

, many patients at risk for this complication are prescribed a combination (Arthrotec
Arthrotec
The combination diclofenac/misoprostol is a pharmaceutical product that contains:*Diclofenac sodium: Nonsteroidal anti-inflammatory drug with analgesic properties...

) of diclofenac and misoprostol
Misoprostol
Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...

, a synthetic prostaglandin analogue, to protect the gastric mucosa.

An external, gel-based formulation containing 3% of diclofenac (Solaraze) is available for the treatment of facial actinic keratosis
Actinic keratosis
Actinic keratosis is a premalignant condition of thick, scaly, or crusty patches of skin. It is more common in fair-skinned people. It is associated with those who are frequently exposed to the sun, as it is usually accompanied by solar damage...

 caused by over-exposure to sunlight. Some countries have also approved the external use of diclofenac 1% gel to treat musculoskeletal
Musculoskeletal system
A musculoskeletal system is an organ system that gives animals the ability to move using the muscular and skeletal systems...

 conditions.

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-optha.

Investigational uses


Diclofenac is often used to treat chronic pain associated with cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

, in particular if inflammation is also present (Step I of the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 (WHO) Scheme for treatment of chronic pain). Good results (sometimes better than those with opioids) have been seen in female breast cancer and in the pain associated with bony metastases. Diclofenac can be combined with opioids if needed. Combaren, a fixed combination of diclofenac and codeine (50 mg each), is available for cancer treatment in Europe. Combinations with psychoactive drugs such as chlorprothixene
Chlorprothixene
Chlorprothixene is a typical antipsychotic drug of the thioxanthene class and was the first of the series to be synthesized...

 and/or amitriptyline
Amitriptyline
Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...

 have also been investigated and found useful in a number of cancer patients.

Fever due to malignant lymphogranulomatosis (Hodgkin's lymphoma
Hodgkin's lymphoma
Hodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes...

) often responds to diclofenac. Treatment can be terminated as soon as the usual treatment with radiation and/or chemotherapy causes remission of fever.

Diclofenac has been found to increase the blood pressure in patients with Shy-Drager syndrome and diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

. Currently, this use is highly investigative and cannot be recommended as routine treatment.

Diclofenac has been found to be effective against all strains of multi drug resistant E. coli, with a MIC of 25 micrograms/mL. Therefore, it may be suggested that diclofenac has the capacity to treat uncomplicated urinary tract infections (UTI) caused by E. coli. It has also been shown to be effective in treating Salmonella infections in mice and is under investigation for the treatment of tuberculosis.

Diclofenac is an antiuricosuric.

Contraindications

  • Hypersensitivity against diclofenac
  • History of allergic reactions (bronchospasm
    Bronchospasm
    Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...

    , shock, rhinitis
    Rhinitis
    Rhinitis , commonly known as a stuffy nose, is the medical term describing irritation and inflammation of some internal areas of the nose. The primary symptom of rhinitis is nasal dripping. It is caused by chronic or acute inflammation of the mucous membrane of the nose due to viruses, bacteria or...

    , urticaria
    Urticaria
    Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...

    ) following the use of aspirin
    Aspirin
    Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

     or another NSAID
  • Third-trimester pregnancy
  • Active stomach and/or duodenal ulceration
    Peptic ulcer
    A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...

     or gastrointestinal bleeding
    Gastrointestinal bleeding
    Gastrointestinal bleeding or gastrointestinal hemorrhage describes every form of hemorrhage in the gastrointestinal tract, from the pharynx to the rectum. It has diverse causes, and a medical history, as well as physical examination, generally distinguishes between the main forms...

  • Inflammatory intestinal disorders such as Crohn's disease
    Crohn's disease
    Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...

     or ulcerative colitis
    Ulcerative colitis
    Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...

  • Severe insufficiency of the heart (NYHA III/IV)
  • Recently, a warning has been issued by the FDA not to use for the treatment of 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
    Hepatic porphyria
    Hepatic porphyrias is a form of porphyria in which the enzyme deficiency occurs in the liver.Examples include :* Acute intermittent porphyria* Porphyria cutanea tarda and Hepatoerythropoietic porphyria...

    , as diclofenac may trigger attacks
  • Caution in patients with severe, active bleeding such as cerebral hemorrhage
  • NSAIDs in general should be avoided during dengue fever
    Dengue fever
    Dengue fever , also known as breakbone fever, is an infectious tropical disease caused by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a characteristic skin rash that is similar to measles...

    , as it induces (often severe) capillary leakage and subsequent heart failure.
  • On animals which after death may be eaten by vulture
    Vulture
    Vulture is the name given to two groups of convergently evolved scavenging birds, the New World Vultures including the well-known Californian and Andean Condors, and the Old World Vultures including the birds which are seen scavenging on carcasses of dead animals on African plains...

    s or other scavenging birds.

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.
  • And see #Ecological effects below.

Cardiac

  • Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor
    COX-2 inhibitor
    COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug that directly targets COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this...

     rofecoxib
    Rofecoxib
    Rofecoxib is a nonsteroidal anti-inflammatory drug that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea...

     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
    Aspirin
    Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

     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. A very large study of 1,028,437 Danish users of various NSAIDs or coxibs, published online on June 8, 2010, found that "Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio, 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk." .
  • Diclofenac has similar COX-2 selectivity to celecoxib
    Celecoxib
    Celecoxib INN is a sulfa non-steroidal anti-inflammatory drug and selective COX-2 inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial...

    . A review by FDA Medical Officer David Graham concluded in September, 2006 that diclofenac does increase the risk of myocardial infarction
    Myocardial infarction
    Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

    .

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
    Misoprostol
    Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...

    , ranitidine
    Ranitidine
    Ranitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in treatment of peptic ulcer disease and gastroesophageal reflux disease . Ranitidine is also used alongside fexofenadine and other antihistamines for the treatment of skin conditions...

     150 mg at bedtime or omeprazole
    Omeprazole
    Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...

     20 mg at bedtime).

Hepatic

  • Liver damage occurs infrequently, and is usually reversible. Hepatitis
    Hepatitis
    Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...

     may occur rarely without any warning symptoms and may be fatal. Patients with osteoarthritis
    Osteoarthritis
    Osteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...

     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.
  • As of 12/2009 Endo, Novartis and FDA notified healthcare professionals to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium.
  • Cases of drug-induced hepatotoxicity have been reported in the first month, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
  • Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.

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.
  • 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. However, this side-effect cannot 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." However, diclofenac appears to have a different mechanism of renal toxicity.

Other

  • Bone marrow depression is noted infrequently (leukopenia
    Leukopenia
    Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....

    , agranulocytosis
    Agranulocytosis
    Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...

    , thrombopenia with/without purpura, aplastic anemia
    Aplastic anemia
    Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and 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.

  • Induces warm antibody hemolytic anemia by inducing antibodies to Rh antigens, ibuprofen
    Ibuprofen
    Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

     also does this.

  • Diclofenac may disrupt the normal menstrual cycle.

Mechanism of action


The exact mechanism of action is not entirely known, but it is thought that the primary mechanism responsible for its anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

, antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...

, and analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 action is inhibition of prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

 synthesis by inhibition of cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...

 (COX). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.

Inhibition of COX also decreases prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

s in the epithelium
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...

 of the stomach, making it more sensitive to corrosion by gastric acid
Gastric acid
Gastric acid is a digestive fluid, formed in the stomach. It has a pH of 1 to 2 and is composed of hydrochloric acid , and large quantities of potassium chloride and sodium chloride...

. 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 indomethacin and aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

.

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 be partly because it persists for over 11 hours in synovial fluid
Synovial fluid
Synovial fluid is a viscous, non-Newtonian fluid found in the cavities of synovial joints. With its yolk-like consistency , the principal role of synovial fluid is to reduce friction between the articular cartilage of synovial joints during movement.-Overview:The inner membrane of synovial joints...

s.

Diclofenac may also be a unique member of the NSAIDs. There is some evidence that diclofenac inhibits the lipoxygenase
Lipoxygenase
Lipoxygenases are a family of iron-containing enzymes that catalyse the dioxygenation of polyunsaturated fatty acids in lipids containing a cis,cis-1,4- pentadiene structure. It catalyses the following reaction:...

 pathways, thus reducing formation of the leukotriene
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...

s (also pro-inflammatory autacoids). There is also speculation that diclofenac may inhibit phospholipase A2
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...

 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.{Scholer. Pharmacology of Diclofenac Sodium. Am J of Medicine Volume 80 April 28, 1986}

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 inhibitor
COX-2 inhibitor
COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug that directly targets COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this...

s with their adverse effects
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs such as diclofenac have been well-tolerated by most of the population.

Besides the well-known and often-cited COX-inhibition, a number of other molecular targets of diclofenac that could contribute to its pain-relieving actions have recently been identified. These include:
  • Blockage of voltage-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation also known as phase inhibition)

  • Blockage of acid-sensing ion channels (ASICs)

  • Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)

History


Diclofenac originated from Ciba-Geigy (now Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...

) in 1973. Diclofenac was first introduced in the UK in 1979.

Recent research (2010) has linked use of Diclofenac to an increased chance of stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

s.

Ecological effects


Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture
Old World vulture
Old World vultures belong to the family Accipitridae, which also includes eagles, buzzards, kites, and hawks.Old World vultures are not closely related to the superficially similar New World vultures and condors, and do not share that group's good sense of smell. The similarities between the two...

 population in the Indian subcontinent, 95% decline in 2003, 99.9% decline as of 2008. The mechanism is, it is presumed, renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

, a known side-effect of diclofenac. Vultures eat the carcasses of livestock
Livestock
Livestock refers to one or more domesticated animals raised in an agricultural setting to produce commodities such as food, fiber and labor. The term "livestock" as used in this article does not include poultry or farmed fish; however the inclusion of these, especially poultry, within the meaning...

 that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical. At a meeting of the National Wildlife Board in March 2005, the Government of India announced that it intended to phase out the veterinary use of diclofenac. Meloxicam
Meloxicam
Meloxicam is a nonsteroidal anti-inflammatory drug with analgesic and fever reducer effects. It is a derivative of oxicam, closely related to piroxicam, and falls in the enolic acid group of NSAIDs...

 is a safer candidate to replace use of diclofenac. It is more expensive than diclofenac, but the price is coming down as more drug companies begin to manufacture it.

"The loss of tens of millions of vultures over the last decade has had major ecological consequences across the Indian subcontinent that pose a potential threat to human health. In many places, populations of feral dog
Dog
The domestic dog is a domesticated form of the gray wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The dog may have been the first animal to be domesticated, and has been the most widely kept working, hunting, and companion animal in...

s (Canis familiaris) have increased sharply from the disappearance of Gyps
Gyps
The Gyps vultures are a genus of Old World vultures in the bird family Accipitridae, which also includes eagles, kites, buzzards and hawks....

vultures as the main scavenger of wild and domestic ungulate
Ungulate
Ungulates are several groups of mammals, most of which use the tips of their toes, usually hoofed, to sustain their whole body weight while moving. They make up several orders of mammals, of which six to eight survive...

 carcasses. Associated with the rise in dog numbers is an increased risk of rabies
Rabies
Rabies is a viral disease that causes acute encephalitis in warm-blooded animals. It is zoonotic , most commonly by a bite from an infected animal. For a human, rabies is almost invariably fatal if post-exposure prophylaxis is not administered prior to the onset of severe symptoms...

" and casualties of almost 50,000 people. The Government of India cites one of those major consequences as a vulture species extinction. A major shift in transfer of corpse pathogens from vultures to feral dogs and rats can lead to a disease pandemic causing millions of deaths in a crowded country like India; whereas vultures' digestive systems safely destroy many species of such pathogens.

The resulting multiplication of feral dogs in India and Pakistan has caused a multiplication of leopard
Leopard
The leopard , Panthera pardus, is a member of the Felidae family and the smallest of the four "big cats" in the genus Panthera, the other three being the tiger, lion, and jaguar. The leopard was once distributed across eastern and southern Asia and Africa, from Siberia to South Africa, but its...

s feeding on those dogs and invading urban areas looking for dogs to prey on, resulting in occasional attacks on human children.

The loss of vultures has had a social impact on the Indian Zoroastrian
Zoroastrianism
Zoroastrianism is a religion and philosophy based on the teachings of prophet Zoroaster and was formerly among the world's largest religions. It was probably founded some time before the 6th century BCE in Greater Iran.In Zoroastrianism, the Creator Ahura Mazda is all good, and no evil...

 Parsi community, who traditionally use vultures to dispose of human corpses in Towers of Silence, but are now compelled to seek alternate methods of disposal.

Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.

Formulations


Pennsaid is a minimally systemic prescription topical lotion formulation of 1.5% w/w diclofenac sodium, which is approved in the US, Canada and other countries for osteoarthritis of the knee.

Flector Patch is a minimally systemic topical patch formulation of diclofenac. It is indicated for acute pain due to minor sprains, strains, and contusions. The patch has been approved in many other countries outside the U.S.A under different brand names.

Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

 Voltarol can be supplied with either the sodium salt or the 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 (25 and 50 mg), powder for oral solution (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: 12.5 mg diclofenac as potassium salt in Switzerland
Switzerland
Switzerland name of one of the Swiss cantons. ; ; ; or ), in its full name the Swiss Confederation , is a federal republic consisting of 26 cantons, with Bern as the seat of the federal authorities. The country is situated in Western Europe,Or Central Europe depending on the definition....

, Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...

 ("Voltaren dolo"), The Netherlands
Netherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...

 ("Voltaren K"), United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

 (since October 2008 as "Voltarol Pain-eze"), and preparations containing 25 mg diclofenac as the potassium salt in New Zealand
New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...

, Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...

, Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...

, ("Voltaren Rapid"), and Sweden
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....

 ("Voltaren T" and "Diclofenac T"). Diclofenac as potassium salt can be found throughout the Middle East in 25 mg and 50 mg doses ("Cataflam").
Solaraze (3% diclofenac sodium gel) is topically applied, twice a day for three months, to manage the skin condition known as actinic or solar keratosis.
Parazone-DP is combination of Diclofenac potassium and Paracetamol, Mfg. and supplied by Ozone pharmaceuticals and chemicals, Gujarat,India

Trade names


Trade names include:
  • Neofenac (Bangladesh)
  • Anuva
  • Abitren
  • Arthrotec (combination with misoprostol
    Misoprostol
    Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...

    )
  • Artifen (Pakistan Abbott Laboratories LTD)
  • Befol
  • Berifen
  • Betaren
  • Bufenac Forte
  • Cambia
  • Cataflam
  • Catafast
  • Clafen
  • Clofast
  • Clonac
  • Dedolor
  • Deflamat
  • Deflox
  • Diclac
  • Diclo M (India & Myanmar) V.I.P Pharma
  • Dicloberl
  • Diclofenac
  • Diclofenac-Asteria (USA and Korea)
  • Diclofenaco Normon (Spain)
  • Diclofenacum
  • Dicloflex
  • Diclogem
  • Diclogesic (Jordan and Romania)
  • Diclohexal
  • Diclomax
  • Diclowin Plus (India)
  • Diclon
  • Diclopar (Tanzania)
  • Diclotab (Laos)
  • Diklofenak T Actavis (Sweden)
  • Difen
  • Difenac (Venezuela)
  • Difene
  • Dioxaflex (Latin America, Central America)
  • Disflam K (diclofenac potassium, Central America)
  • Dolex
  • Dyloject
  • Feloran
  • Fenac (diclofenac potassium, Australia)
  • Flamrase
  • Flector Patch
  • Flogozan (Mexico)
  • Kemoren (Indonesia)
  • Klodifen
  • Modifenac
  • Morbidic (India)
  • Motifene
  • Naklofen
  • Neopyrazon (United Laboratories, ASIA)
  • Oflam
  • Olfen
  • Ortofen
  • Panamor
  • Parazone-DP (combination of Paracetamol & Diclofenac Potassium
  • Pennsaid
  • Pritaren
  • Rapidus
  • Rapten-K
  • Rhumalgan
  • Rufenal
  • Safeguard (combination with misoprostol
    Misoprostol
    Misoprostol is a drug that is used for the prevention of non steroidal anti inflammatory drug induced gastric ulcers, for early abortion, to treat missed miscarriage, and to induce labor. The latter use is controversial in the United States. Misoprostol was invented and marketed by G.D...

    )
  • Sandoz (diclofenac sodium, Australia)
  • Solaraze
  • Seradic (India)
  • Topac
  • Trabona
  • Uno
  • Veltex CR (South Africa)
  • Vetagesic
  • Voldic
  • Volini (India)
  • Volfenac (Thailand)
  • Voltaflam (India)
  • Voltaren
  • Voltarol
  • Voltarol Pain-eze
  • Voltfast
  • Voren (Taiwan)
  • Voltral (Pakistan)
  • Votrex
  • Vostar
  • Votalin (China)
  • Voveran
  • Vurdon
  • Zipsor
  • Zolterol


External links