Diclofenac, sold under the brand name Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout.[ It is also available as the fixed-dose combination diclofenac/misoprostol (Arthrotec) to help protect the stomach; however, proton pump inhibitors such as omeprazole are typically first-line since they are at least as effective as misoprostol, but with better tolerability.]
Common side effects include abdominal pain, gastrointestinal bleeding, nausea, dizziness, headache, and swelling.[ Serious side effects may include heart disease, stroke, kidney problems, and stomach ulceration.][ Use is not recommended in the third trimester of pregnancy.][ It is likely safe during breastfeeding.][ Diclofenac is believed to work by decreasing the production of , like other drugs in this class.]
In 2023, it was the 73rd most commonly prescribed medication in the United States, with more than 9million prescriptions.
Medical uses
Diclofenac is used to Pain management pain related to arthritis, dysmenorrhea, rheumatology and other inflammatory disorders,[ and . An additional indication is the treatment of acute .]
Diclofenac ophthalmic is indicated for the treatment of postoperative inflammation in people who have undergone cataract extraction and for the temporary relief of pain and photophobia in people undergoing corneal refractive surgery.
Diclofenac is also available in topical forms and is useful for osteoarthritis but not other types of long-term musculoskeletal pain.
In many countries, eye drops are sold to treat acute and chronic nonbacterial inflammation of the anterior part of the eyes (such as postoperative states).
Diclofenac is often used to treat chronic cancer pain, especially if inflammation is present.
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Contraindications
Diclofenac is contraindicated for pregnant women; for people with active stomach or duodenal Peptic ulcer or gastrointestinal bleeding; and for people undergoing coronary artery bypass surgery.
Adverse effects
Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including COX-2 inhibitors, diclofenac, ibuprofen and naproxen.
In October 2020, the US Food and Drug Administration (FDA) required the prescribing information to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in fetuses that result in low amniotic fluid.[ ][ ]
Heart
In 2013, a study found major vascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.
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 nonsteroidal anti-inflammatory drug 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.
A subsequent large study of 74,838 Danish users of nonsteroidal anti-inflammatory drugs or found no additional cardiovascular risk from diclofenac use.
Diclofenac is similar in COX-2 selectivity to celecoxib.
Gastrointestinal
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Gastrointestinal complaints are most often noted. Most patients receive a gastro-protective drug as prophylaxis during long-term treatment (misoprostol, ranitidine, or omeprazole).
Liver
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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. If used for the short-term treatment of pain or fever, diclofenac has not been found more hepatotoxic than other nonsteroidal anti-inflammatory drugs.
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, 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.
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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.
Kidney
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Nonsteroidal anti-inflammatory drugs "are associated with adverse renal kidney effects caused by the reduction in synthesis of renal "
Mental health
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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.
Pharmacology
As with other nonsteroidal anti-inflammatory drugs, the primary mechanism responsible for its anti-inflammatory, antipyretic and analgesic action is thought to be inhibition of prostaglandin synthesis through Cyclooxygenase-inhibition.
The main target in the inhibition of prostaglandin synthesis appears to be the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2), also known as cycloxygenase-2 (COX-2). That is, diclofenac is partially selective for COX-2. The reported selectivity for COX-2 varies from 1.5 to 30 depending on the source.
The drug may be bacteriostatic via inhibiting bacterial DNA synthesis.
Diclofenac has a relatively high lipid solubility, making it one of the few nonsteroidal anti-inflammatory drugs that are able to enter the brain by crossing the blood-brain barrier.
Diclofenac may be a unique member of the nonsteroidal anti-inflammatory drugs in other aspects. Some evidence indicates it inhibits the lipoxygenase pathways,
Marked differences exist among nonsteroidal anti-inflammatory drugs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1, and COX-2.
Besides the COX-inhibition, several other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:
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Blockage of voltage-dependent (after activation of the channel, diclofenac inhibits its reactivation, also known as phase inhibition)
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Blockage of acid-sensing (ASICs)
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Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)
The duration of action (i.e., duration of pain relief) of a single dose is longer (6 to 8 hour) than the drug's 1.2–2 h half-life. This may be partly due to its persistence for over 11 hours in .
History
Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister in 1973.[ ] It came into medical use in the United States in 1988.[ GSK plc purchased the rights in 2015.][
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Formulations and brand names
Diclofenac formulations are available worldwide under many 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, sold in some other countries, is the potassium salt only. However, Voltarol Emulgel contains diclofenac diethylammonium 1.16%, being equivalent to 1% sodium salt. In 2016, Voltarol was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.3 million.
In the United States, 1% diclofenac gel was approved by the FDA in 2007 as a prescription drug for the temporary relief of the pain of osteoarthritis of joints in the hands, knees, and feet. In 2020, the FDA approved the gel formulation for nonprescription use.[
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In January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are available without a prescription.
Ecological effects
Use of diclofenac in animals has environmental effects: It is toxic to scavenging birds – these consume animal carcases in which the drug is present;
Veterinary use in livestock resulted in a sharp decline in the vulture population in the Indian subcontinent – a 95% decline by 2003
The mechanism of toxicity in vultures is presumed to be kidney failure;
have the same vulnerability to diclofenac as Old World vultures and are therefore at similar risk from its effects.
Despite the vulture crisis, diclofenac remains available in other countries including many in Europe.
Diclofenac is on the European Union's watch list because it pollutes the Baltic Sea. When the substance enters fresh water, it has an environmental impact and is considered more difficult to remove in wastewater treatment plants than, for example, ibuprofen.
Veterinary use
Diclofenac is used for livestock; such use was responsible for the Indian vulture crisis, during which in a few years 95% of the country's vulture population was killed. In many countries, agricultural use is now forbidden.
Diclofenac is approved as a veterinary medication in some countries[ for the treatment of pets as well as in livestock. In some species of birds, diclofenac causes accumulation of uric acid crystals in internal organs—especially the liver and kidneys—resulting in visceral gout, as well as cellular damage and necrosis.]
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