Diclofenac
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Diclofenac (marketed as Voltaren, Voltarol, Diclon, Dicloflex Difen, Difene, Cataflam,
Pennsaid, Rhumalgan, Modifenac, Abitren, Arthrotec and Zolterol, with various drug
dose combinations) is a non-steroidal anti-inflammatory drug (!"#$) taken to reduce
inflammation and an analgesic reducing pain in conditions such as in arthritis or acute
in%ury& #t can also be used to reduce menstrual pain, dysmenorrhea& 'he name is derived
from its chemical name: (-((,)-dichloranilino) phenylacetic acid
#n the *nited +ingdom, #ndia, and the *nited !tates, it may be supplied as either the
sodium or potassium salt, while in some other countries only as the potassium salt&
$iclofenac is available as a generic drug in a number of formulations& ,ver the counter
(,'-) use is approved in some countries for minor aches and pains and fever associated
with common infections&
$iclofenac is well-tolerated after ./ years0 e1perience by the general human population,
but may une1pectedly become intolerated in some of the elderly population of long term
users&
2citation needed3
Mechanism of action
'he action of one single dose is much longer () to 4 hours) than the very short half-life
that the drug indicates& 'his could partly be due to a particular high concentration
achieved in synovial fluids&
'he e1act mechanism of action is not entirely known, but it is thought that the primary
mechanism responsible for its anti-inflammatory5antipyretic5analgesic action is inhibition
of prostaglandin synthesis by inhibition of cycloo1ygenase (-,6)&
#nhibition of -,6 also decreases prostaglandins in the epithelium of the stomach,
making it more sensitive to corrosion by gastric acid& 'his is also the main side effect of
diclofenac& $iclofenac has a low to moderate preference to block the -,6(-isoen7yme
(appro1imately 8/-fold) and is said to have therefore a somewhat lower incidence of
gastrointestinal complaints than noted with indomethacin and aspirin&
$iclofenac may also be a uni9ue member of the !"#$s& 'here is some evidence that
diclofenac inhibits the lipoo1ygenase pathways, thus reducing formation of the
leukotrienes (also pro-inflammatory autacoids)& 'here is also speculation that diclofenac
may inhibit phospholipase "( as part of its mechanism of action& 'hese additional actions
may e1plain the high potency of diclofenac - it is the most potent !"#$ on a broad
basis&
8
'here are marked differences among !"#$s in their selective inhibition of the two
subtypes of cyclo-o1ygenase, -,6-8 and -,6-(& :uch pharmaceutical drug design has
attempted to focus on selective -,6-( inhibition as a way to minimi7e the
gastrointestinal side effects of !"#$s like aspirin& #n practice, use of some -,6-(
inhibitors due to their adverse effects has led to massive numbers of patient family
lawsuits alleging wrongful death by heart attack, yet other significantly -,6-selective
!"#$s like diclofenac have been well-tolerated by most of the population&
Indications
-ombined $iclofenac sodium and misoprostol tablets&
$iclofenac 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& "n additional indication is the
treatment of acute migraines& $iclofenac 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&
$iclofenac suppositories
"s long-term use of diclofenac and similar !"#$s predisposes for peptic ulcer, many
patients at risk for this complication are prescribed a combination ("rthrotec;) of
diclofenac and misoprostol, a synthetic prostaglandin analogue, to protect the gastric
mucosa&
"n e1ternal, gel-based form of diclofenac (!olare7e;) is available for the treatment of
facial actinic keratosis which is caused by over-e1posure to sunlight& !ome countries
have also approved the e1ternal use of diclofenac gel to treat muskoskeletal conditions&
,ver-the-counter use against minor aches and pains and fever associated with common
infections is also licensed in some countries&
#n 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)& " common brand
name is <oltaren-ophta&
Off label/inestigational uses
$iclofenac is often used to treat chronic pain associated with cancer, particularly if
inflammation is also present (!tep # of the World =ealth ,rganisation (W=,) !cheme for
treatment of chronic pain)& >ood results (sometimes better than those with opioids) have
been seen in female breast cancer and in the pain associated with bony metastases&
$iclofenac can be combined with opioids if needed& #n ?urope -ombaren; e1ists, a fi1ed
combination of diclofenac and codeine (@/ mg each) for cancer treatment& -ombinations
(
with psychoactive drugs such as chlorprothi1ene and5or amitriptyline have also been
investigated and found useful in a number of cancer patients&
Fever due to malignant lymphogranulomatosis (=odgkin0s lymphoma) often responds to
diclofenac& 'reatment can be terminated as soon as the usual treatment with radiation
and5or chemotherapy causes remission of fever&
$iclofenac may prevent the development of "l7heimer0s disease if given daily in small
doses during many years& "ll investigations were stopped after it was found that some of
the other investigated !"#$s (napro1en, rofeco1ib) caused a higher incidence of death
cases due to cardiovascular events and stroke compared to placebo&
$iclofenac has been found to increase the blood pressure in patients with !hy-$rager
syndrome (autonomous hypotension) often seen in diabetic patients& -urrently, this use is
highly investigational and cannot be recommended as routine treatment&
$iclofenac has been found to be effective against all strains of multi drug resistant e coli,
with a :#- of (@ microg5mA& 'herefore, it may be suggested that diclofenac has the
capacity to treat *'# (uncomplicated urinary tract infections) caused by ?& coli&
283
Contraindications
=ypersensitivity against diclofenac
=istory of allergic reactions (bronchospasm, shock, rhinitis, urticaria) following
the use of "spirin or another !"#$
'hird-trimester pregnancy
"ctive stomach and5or duodenal ulceration or gastrointestinal bleeding
#nflammative intestinal disorders such as -rohn0s disease or ulcerative colitis
!evere insufficiency of the heart (B=" ###5#<)
Cecently, a warning has been issued by F$" not to treat patients recovering from
heart surgery
!evere liver insufficiency (-hild-Dugh -lass -)
!evere renal insufficiency (creatinine clearance E./ ml5min)
-aution in patients with pree1isting hepatic porphyria, as diclofenac may trigger
attacks
-aution in patients with severe, active bleeding such as cerebral hemorrhage
!ide effects
$iclofenac is among the better tolerated !"#$s& 'hough (/F of patients on
long-term treatment e1perience side effects, only (F have to discontinue the drug,
mostly due to gastrointestinal complaints&
Cardiac
.
Following the identification of increased risks of heart attacks with the selective
-,6-( inhibitor rofeco1ib in (//G, attention has focused on all the other
members of the !"#$s group, including $iclofenac& Cesearch results are mi1ed
with a meta-analysis of papers and reports up to "pril (//) suggesting a relative
increased rate of heart disease of 8&). compared to non users&
2(3
Drofessor Deter
Weissberg, :edical $irector of the Hritish =eart Foundation said, I=owever, 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 symptomsI& ,nly "spirin
was found not to increase the risk of heart disease, however this is known to have
a higher rate of gastric ulceration than $iclofenac&
" subse9uent large study of JG,4.4 users of !"#$s or co1ibs, published in :ay
(//) found no additional cardiovascular risk from $iclofenac use&
2.3
$iclonefac has similar -,6-( selectivity to celeco1ib
2G3
& Derhaps related to this
selectivity, a review of this constantly changing topic by F$" :edical ,fficer
$avid >raham concluded in !eptember, (//) that $iclofenac does increase the
risk of myocardial infarction
2@3
&
"astrointestinal
>astrointestinal complaints are most often noted (see above)& 'he development of
ulceration and5or bleeding re9uires immediate termination of treatment with
diclofenac& :ost patients receive an ulcer-protective drug as prophyla1is during
long-term treatment (misoprostol, ranitidine 8@/mg at bedtime or omepra7ole
(/ mg at bedtime)&
#epatic
Aiver damage occurs infre9uently, but is usually reversible& =epatitis may occur
rarely without any warning symptoms and may be fatal& Datients with
osteoarthritis more often develop symptomatic liver disease than patients with
rheumatoid arthritis& Aiver function should be monitored regularly during long-
term treatment& #f used for the short term treatment of pain or fever, diclofenac
has not been found to be more hepatoto1ic than other !"#$s&
Renal
!tudies in Dakistan 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 ?cological problems)& !pecies and individual humans that are drug
sensitive are initially assumed to lack genes e1pressing specific drug
deto1ification en7ymes& Hecause elderly humans have reduced e1pression levels
of all en7ymes, elderly human metabolisms may gradually approach those of
vultures, thus une1pectedly becoming more diclofenac intolerant&
!"#$s Iare associated with adverse renal 2kidney3 effects caused by the
reduction in synthesis of renal prostaglandinsI
2)3
in sensitive persons or animal
species, and potentially during long term use in non-sensitive persons if resistance
G
to side effects decreases with age& *nfortunately this side effect can0t be avoided
merely by using a -,6-( selective inhibitor because, IHoth isoforms of -,6,
-,6-8 and -,6-(, are e1pressed in the kidney&&& -onse9uently, the same
precautions regarding renal risk that are followed for nonselective !"#$s should
be used when selective -,6-( inhibitors are administered&I
2)3
Other
Hone marrow depression is noted infre9uently (leukopenia, agranulocytosis,
thrombopenia with5without purpura, aplastic anemia)& 'hese conditions may be
life-threatening and5or irreversible, if detected too late& "ll patients should be
monitored closely& $iclofenac is a weak and reversible inhibitor of thrombocytic
aggregation needed for normal coagulation&
$ormulations
?nteric -oated $iclofenac !odium tablets by $e1el-Dharma Atd&
<oltaren and <oltarol contain the sodium salt of diclofenac& #n the *nited +ingdom
<oltarol can be supplied with either the sodium salt or potassium salt, while -ataflam in
some other countries is the potassium salt only&
$iclofenac is available in stomach acid resistant formulations ((@ and @/ mg), fast
disintegrating oral formulations (@/ mg), slow- and controlled-release forms (J@, 8// or
8@/ mg), suppositories (@/ and 8// mg), and in%ectable forms (@/ and J@ mg)&
$iclofenac is also available over the counter (,'-) in some countries: <oltaren dolo
(8(&@ mg diclofenac as potassium salt) in !wit7erland and >ermany, and preparations
containing (@ mg diclofenac in ew Kealand&
%cological problems
*se of diclofenac in animals has been reported to have led to a sharp decline in the
vulture population in the #ndian subcontinent, up to L@F in some areas&
2J3
'he mechanism
is probably renal failure, a known side-effect of diclofenac& <ultures eat the carcasses of
domesticated animals that have been administered veterinary diclofenac, and are
poisoned by the accumulated chemical& "t a meeting of the ational Wildlife Hoard in
:arch (//@, the >overnment of #ndia announced that it intended to phase out the
veterinary use of diclofenac&
243
:elo1icam is a safer (though more e1pensive) candidate
to replace use of diclofenac&
2L3
I'he loss of tens of millions of vultures over the last
@
decade has had ma%or ecological conse9uences across the #ndian subcontinent that pose a
potential threat to human health& #n many places, populations of feral dogs (Canis
familiaris 2sic3) have benefited from the disappearance of Gyps vultures as the main
scavenger of wild and domestic ungulate carcasses& "ssociated with the rise in dog
numbers is an increased risk of human cases of rabies&I
2L3
'he >overnment of #ndia cites one of those ma%or conse9uences as a vulture species
e1tinction&
243
" ma%or 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
#ndia&
'he loss of vultures has had a social impact on the #ndian Koroastrian Darsi community,
who traditionally use vultures to dispose of human corpses in Isky burialsI ('owers of
!ilence), and are now having to seek alternative disposal methods&
2L3
#n Dun%ab it appears that vulture numbers are slowly rising after use of the drug was
discontinued&
References
8& & :a7umdar +, $utta +, $astidar !>, :otohashi , !hirataki B ((//))& I$iclofenac in
the management of ?& coli urinary tract infectionsI& In Vivo '( (@): )8.ML& D:#$
8J/L8J)4&
(& & +earney D, Haigent -, >odwin J, =alls =, ?mberson J, Datrono - ((//))& I$o selective
cyclo-o1ygenase-( inhibitors and traditional non-steroidal anti-inflammatory drugs
increase the risk of atherothrombosisN :eta-analysis of randomised trials&I& BMJ ))'
(J@@.): 8./(-4& D:#$ 8)JG/@@4&
.& & !olomon $, "vorn J, !tOPrmer ', >lynn C, :ogun =, !chneeweiss ! ((//))&
I-ardiovascular outcomes in new users of co1ibs and nonsteroidal antiinflammatory
drugs: high-risk subgroups and time course of risk&I& Arthritis Rheum *+ (@): 8.J4-4L&
D:#$ 8))G@L))&
G& & Fit7>erald >, Datrono - ((//8)& I'he co1ibs, selective inhibitors of cycloo1ygenase-
(I& N Engl J Med )+* ()): G..-G(& D:#$ 88GL)4@@&
@& & >raham $ ((//))& I-,6-( inhibitors, other !"#$s, and cardiovascular risk: the
seduction of common senseI& JAMA ',- (8.): 8)@.-)&
doi:8/&8//85%ama&(L)&8.&%ed)//@4& D:#$ 8)L)44./&
)& Q
a
b
Hrater $- ((//()& ICenal effects of cycloo1ygyenase-(-selective inhibitorsI& J ain
!ymptom Manage ') (G !uppl): !8@-(/R discussion !(8-.& D:#$ 88LL(JG@&
J& & ,aks JA, >ilbert :, <irani :K, Watson C', :eteyer -*, Cideout H", !hivaprasad
=A, "hmed !, -haudhry :J, "rshad :, :ahmood !, "li ", +han "" ((//G)&
I$iclofenac residues as the cause of vulture population decline in DakistanI& Nature +'.
()LJ@): )./-.& D:#$ 8GJG@G@.&
4& Q
a
b
Dress #nformation Hureau, >overnment of #ndia ((//@-/@-8))& I!aving the <ultures
from ?1tictionI& Dress release& Cetrieved on (//)-/@-8(&
L& Q
a
b
c
!wan >, aidoo <, -uthbert C, >reen C?, Dain $J, !warup $, Drakash <, 'aggart
:, Hekker A, $as $, $iekmann J, $iekmann :, +illian ?, :eharg ", Datra C-, !aini
:, Wolter + ((//))& ICemoving the threat of diclofenac to critically endangered "sian
vulturesI& "o! Biol + (.): e))& D:#$ 8)G.@44)&
)
J
