Diclofenac is a nonsteroidal anti-inflammatory drug taken or applied to reduce inflammation
and as an analgesic reducing pain in certain conditions. It is supplied as or contained
in medications under a variety of trade names. The name "diclofenac" derives from its chemical
name: 2-(2,6-dichloranilino) phenylacetic acid. Diclofenac was originally developed
by Ciba-Geigy in 1973. It was first introduced in the UK in 1979.
In the United Kingdom, India, and Brazil diclofenac may be supplied as either the sodium or potassium
salt; in China, it is most often supplied as the sodium salt, while in some other countries
it is only available as the potassium salt. Diclofenac is available as a generic drug
in a number of formulations, including diclofenac diethylamine, which is applied topically.
Over-the-counter use is approved in some countries for minor aches and pains and fever associated
with common infections. In the United States it is available as both the sodium and potassium
salt.
Medical uses Diclofenac is used to treat pain, inflammatory
disorders, and dysmenorrhea.
Inflammatory disorders may include musculoskeletal complaints, especially arthritis, rheumatoid
arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, TMJ pain, spondylarthritis,
ankylosing spondylitis, gout attacks, and pain management in cases of kidney stones
and gallstones. An additional indication is the treatment of acute migraines. Diclofenac
is used commonly to treat mild to moderate postoperative or post-traumatic pain, in particular
when inflammation is also present, and is effective against menstrual pain and endometriosis.
As long-term use of diclofenac and similar NSAIDs predisposes for peptic ulcer, many
patients at risk for this complication are prescribed Arthrotec - a combination of diclofenac
and misoprostol, a synthetic prostaglandin analogue, to protect the gastric mucosa.
Diclofenac is also available in topical forms under the brand names Iodex UltraGel, Flector,
Pennsaid, Solaraze, and Voltaren for the treatment of conditions such as osteoarthritis, actinic
keratosis, and acute pain caused by minor strains, sprains, and contusions.
In many countries, eye drops are sold to treat acute and chronic nonbacterial inflammations
of the anterior part of the eyes. A common brand name is Voltaren-ophtha.
Investigational uses Diclofenac is often used to treat chronic
pain associated with cancer, in particular if inflammation is also present scheme for
treatment of chronic pain). Good results have been seen in the pain associated with bony
metastases.
Diclofenac can be combined with opioids if needed. Under trade names such as Combaren
and Voltaren Plus, a fixed combination of diclofenac and codeine is available in Europe.
Combinations with psychoactive drugs such as chlorprothixene and/or amitriptyline have
also been investigated and found useful in a number of cancer patients.
Fever due to malignant lymphogranulomatosis 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. Currently, this use is highly investigative and cannot
be recommended as routine treatment. Diclofenac has been found effective against
all strains of multidrug-resistant E. coli, with a MIC of 25 micrograms/ml. Therefore,
it may have the capacity to treat uncomplicated urinary tract infections caused by E. coli.
It has also shown effectiveness 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 following the use of aspirin or another NSAID
Third-trimester pregnancy Active stomach and/or duodenal ulceration
or gastrointestinal bleeding Inflammatory bowel disease such as Crohn's
disease or ulcerative colitis Severe insufficiency of the heart
Pain management in the setting of coronary artery bypass graft surgery
Severe liver insufficiency Severe renal insufficiency
Caution in patients with pre-existing hepatic 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, as it induces capillary leakage
and subsequent heart failure. 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 nonusers. 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 found no additional cardiovascular risk from diclofenac use. A very large study
of 1,028,437 Danish users of various NSAIDs or coxibs found the "Use of the nonselective
NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an
increased risk of cardiovascular death, with a dose-dependent increase in risk." In Britain
the Medicines and Healthcare Products Regulatory Agency said in June 2013 that the drug should
not be used by people with serious underlying heart conditions—people who had suffered
heart failure, heart disease or a stroke were advised to stop using it completely.
Diclofenac has similar COX-2 selectivity to celecoxib. A review by FDA Medical Officer
David Graham concluded diclofenac does increase the risk of myocardial infarction.
Gastrointestinal Gastrointestinal complaints are most often
noted. The development of ulceration and/or bleeding requires immediate termination of
treatment with diclofenac. Most patients receive a gastro-protective drug as prophylaxis during
long-term treatment. Hepatic
Liver damage occurs infrequently, and 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 more hepatotoxic than other NSAIDs.
As of December 2009, Endo, Novartis, and the US 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 wk after initiating
treatment with diclofenac. Renal
Studies in Pakistan showed diclofenac caused acute kidney failure in vultures when they
ate the carcasses of animals that had recently been treated with it. Drug-sensitive species
and individual humans 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 nonsensitive 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." Mental health
Mental health side effects have been reported. These symptoms are rare, but exist in significant
enough numbers to include as potential side effects. These include depression, anxiety,
irritability, nightmares, and psychotic reactions. Other
Bone marrow depression is noted infrequently. 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.
It induces warm antibody hemolytic anemia by inducing antibodies to Rh antigens; ibuprofen
also does this. Diclofenac may disrupt the normal menstrual
cycle. Research has linked use of diclofenac to an
increased risk of stroke. Mechanism of action
The exact mechanism of action is not entirely known, but the primary mechanism responsible
for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition
of prostaglandin synthesis by inhibition of cyclooxygenase. It also appears to exhibit
bacteriostatic activity by inhibiting bacterial DNA synthesis.
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 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 much longer
than the very short half-life of the drug indicates. This could be partly because it
persists for over 11 hours in synovial fluids. Diclofenac may also be a unique member of
the NSAIDs. Some evidence indicates it inhibits the lipoxygenase pathways, thus reducing formation
of the leukotrienes. It also may inhibit phospholipase A2 as part of its mechanism of action. These
additional actions may explain its high potency - it is the most potent NSAID on a broad basis.
Marked differences exist among NSAIDs in their selective inhibition of the two subtypes of
cyclooxygenase, 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 such
as aspirin. In practice, use of some COX-2 inhibitors with their adverse effects 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 possibly contributing to its pain-relieving
actions have recently been identified. These include:
Blockage of voltage-dependent sodium channels Blockage of acid-sensing ion channels
Positive allosteric modulation of KCNQ- and BK-potassium channels
Ecological effects Use of diclofenac in animals has been reported
to have led to a sharp decline in the vulture population in the Indian Subcontinent, a 95%
decline in 2003, 99.9% decline as of 2008. The mechanism is, it is presumed, renal failure,
a known side effect of diclofenac. Vultures eat the carcasses of livestock that have been
administered veterinary diclofenac, and are poisoned by the accumulated chemical, as vultures
do not have a particular enzyme to break down diclofenac. At a meeting of the National Wildlife
Board in March 2005, the Government of India announced it intended to phase out the veterinary
use of diclofenac. Meloxicam 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 paper based on joint research conducted by the Bombay Natural History Society, Royal
Society for the Protection of Birds and Indian Veterinary Research Institute, published in
May 2014 in the journal of the Cambridge University Press, highlighted that Steppe Eagles have
same signs to that of vultures due to diclofenac and may fall prey to 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 dogs have increased sharply from the disappearance
of Gyps vultures as the main scavenger of wild and domestic ungulate carcasses. Associated
with the rise in dog numbers is an increased risk of rabies" and casualties of almost 50,000
people. The Government of India cites this as one of those major consequences of 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 leopards feeding on those dogs and invading urban areas looking for dogs as prey, resulting
in occasional attacks on human children. The loss of vultures has had a social impact
on the Indian Zoroastrian Parsi community, who traditionally use vultures to dispose
of human corpses in Towers of Silence, but are now compelled to seek alternative methods
of disposal. Diclofenac has been recently authorised for
use on cattle and pigs in Italy, and, since 2013, in Spain where 90% of European vultures
live, and this product is now becoming widely available in other EU countries. BirdLife
partnership, namely SEO/BirdLife, and VCF are leading campaigns to avoid an ecological
and economical disaster. Just in Spain, vultures reduce the emission of almost 200.000 tonnes
of greenhouse effect gases per year consuming carcases that should be, otherwise, incinerated.
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, a minimally systemic topical patch formulation of diclofenac, is indicated
for acute pain due to minor sprains, strains, and contusions. The patch has been approved
in many other countries outside the US under different brand names.
Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom, Voltarol
can be supplied with either the sodium salt or the potassium salt, while Cataflam in some
other countries is the potassium salt only. However, Voltarol Emulgel contains it as dichlofenac
diethylammonium where 1.16% is equivalent to 1% of the sodium variety.
Diclofenac is available in stomach acid-resistant formulations, fast-disintegrating oral formulations,
powder for oral solution, slow- and controlled-release forms, suppositories, and injectable forms.
Diclofenac is also available over-the-counter in some countries: 12.5 mg diclofenac as
potassium salt in Switzerland, the Netherlands, United Kingdom, and preparations containing
25 mg diclofenac as the potassium salt in Germany, New Zealand, Australia, Japan,, and
Sweden. Diclofenac as potassium salt can be found throughout the Middle East in 25-mg
and 50-mg doses. Solaraze 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, manufactured and supplied by Ozone Pharmaceuticals and Chemicals, Gujarat,India
Trade names Trade names include:
References
External links Diclofenac: Drug Information Provided by Lexi-Comp:
Merck Manual Professional