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370 Libby Ha Yun LEE
Clinical Application
Acute pain management
Opioid-sparing eect
Both non-selective NSAIDs and COX-2 inhibitors
have the same efficacy in postoperative analgesia.
Non-steroidal anti-inflammatory drugs have shown
an opioid-sparing effect in acute postoperative pain
relief and have demonstrated up to 40% reduction
in opioid consumption [50]
Role in day surgery
is opioid-sparing effect thus makes NSAIDs
suitable analgesics in ambulatory surgery. ere
is less reported nausea and vomiting and superior
analgesia when compared with hydrocodone/
acetaminophen [28]. ese properties have
encouraged the use of NSAIDs as the analgesic
regimen for day surgery procedures.
Chronic pain management
Non-steroidal anti-inflammatory drugs can prevent
acute pain from the transition to chronic pain
syndrome. Peripheral anti-hyperalgesic actions
against mechanical and heat stimulation have been
demonstrated in human models [38, 60]. Also,
NSAIDs have been shown to have a preventive
analgesic effect, with their duration of analgesia
lasting beyond their pharmacokinetic half-life even
after a single dose [71]. is preventive analgesic
effect is supported by the evidence of the role of
COX-2 in central pain sensitisation [63]. Even a
single dose of COX-2 inhibitor before mastectomy
can significantly reduce hyperesthesia and pain
one year after surgery [65]. Additionally, NSAIDs
are commonly used in a number of chronic pain
situations as adjuvant analgesia as described below.
Please refer to other Chapters of this textbook for
details in treating various chronic pain conditions.
Neuropathic pain
Although there have been large numbers of
animal studies showing the analgesic efficacy of
NSAIDs in neuropathic pain [78] and many
proposed mechanisms of involvement of COX
in the generation of neuropathic pain [48], there
has been no clinical evidence of the usefulness of
NSAIDs in this condition. Despite this, around
40% of patients with peripheral neuropathy in the
USA were given NSAIDs [31]. Such ineffective
and unnecessary treatment exposes patients to the
potential adverse effects of NSAIDs.
Headache
Non-steroidal anti-inflammatory drugs are
commonly used in migraine, tension-type headache
and cluster headache. Naproxen has been used to
prevent and reduce menstruation-related migraine
[2]. ere was a 50% reduction of duration of attack
after 6 months and a 50% reduction of intensity
of headache after 3 months of taking naproxen 7
days before and after onset of menstruation. e
number of attacks was also significantly reduced.
A combination of NSAIDs, prochlorperazine
and caffeine was significantly more effective than
sumatriptan in the acute treatment of migraine
attacks [18]. Of note, is that the combination was
less expensive than sumatriptan per unit dose.
Musculoskeletal and rheumatoid pain
Both non-selective NSAIDs and COX-2 inhibitors
are shown to have the same analgesic efficacy in
osteoarthritis [5, 12, 21, 49, 54, 64] and rheumatoid
arthritis [5].
Rheumatoid arthritis is a lifelong progressive
disease for which NSAIDs are often included in the
multimodal treatment. ey are used to manage
pain and inflammation, while disease-modifying
anti-rheumatic drugs are used as the first-line
therapy for all newly diagnosed cases of rheumatoid
arthritis; biological-response modifiers are given to
selectively inhibit specific molecules of the immune
system [26].
Most clinical trials in osteoarthritis have involved
only a short course of NSAID treatment. Hence,
evidence of efficacy in long-term NSAID use in
osteoarthritis is lacking [81]. Please refer to Chapter
16 for more details.
Non-steroidal anti-inflammatory drugs are effective
in treating acute low back pain, but the evidence
of their efficacy in chronic back pain is lacking
[83]. Fifty-one trials were included in a Cochrane
study in 2007 and showed that NSAIDs were only
effective in providing short-term symptomatic relief
for acute low back pain. ere was strong evidence
(level 1) that various types of NSAIDs were equally
effective for acute low back pain.
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NSAIDs, COX-2 Inhibitors and Paracetamol 371
However, non-selective NSAIDs have a detrimental
effect on bone healing as they affect bone
osteogenesis during bone repair [54]. Glassman
demonstrated a five-fold increase in the non-union
rate in patients who had undergone spinal fusion
and who had received ketorolac after surgery [29].
e effect of COX-2 inhibitors on bone healing is
still controversial. In Long’s rabbit study, celecoxib
did not have any significant deleterious effects
on the healing of intertransverse process fusions
[47]. However, recent studies suggested that bone
healing was significantly affected after receiving a
course of celecoxib [32, 46]. ese findings cannot
be extrapolated to the short-term perioperative
use of COX-2 inhibitors in humans and further
prospective randomised trials in humans are
needed.
Gynaecological pain
Although NSAIDs have been the most commonly
used first-line treatment for endometriosis, there
is inconclusive evidence to show that they are
effective. Instead, women using NSAIDs need to be
aware of the possibility that these drugs may cause
unintended side effects [3]. Also, NSAIDs are also
commonly used in treating primary dysmenorrhoea.
However, most studies only compared NSAIDs to
placebo and a conclusion of the superior efficacy
and analgesic effect of NSAIDs in this condition
could not be drawn [52].
Cancer pain management
Non-steroidal anti-inflammatory drugs are
commonly used in cancer patients. ey are given
to treat cancer pain and also used to reduce the
risk of colorectal cancers [14, 37, 86]. Different
NSAIDs are widely prescribed to treat cancer
pain and are frequently given with opioids in
combination preparations for this purpose. Local
data have suggested that 72% of cancer patients
regularly take NSAIDs as supplements to other
analgesia [82]. However, recent literature has only
demonstrated an efficacy of NSAIDs over placebo;
there was no clear evidence to support the superior
safety or efficacy of one NSAID compared with
another. Also, combinations of NSAIDs and
opioids did not show a strong clinically significant
effect [55, 56]. Please refer to Chapter 9 for more
details.
Side Eects
Eect on platelets
Platelets generate thromboxane A2 from PGH2
in order to aggregate and achieve satisfactory
haemostasis in the presence of COX-1. As platelets
do not possess COX-2, non-selective NSAIDs but
not COX-2 inhibitors are able to prevent platelet
aggregation. Non-selective NSAIDs are hence
believed to increase postoperative haemorrhage,
especially in surgery such as tonsillectomy.
However, the evidence is still controversial. A
recent Cochrane meta-analysis did not show any
significant increased risk of bleeding for non-
aspirin NSAIDs after tonsillectomy [40]. Only
aspirin was shown to generate an increased risk of
post-tonsillectomy bleeding.
Cardiovascular eect
Recently, rofecoxib was withdrawn from the market
because of an increase in thrombotic cardiovascular
events in two large clinical trials [7, 8]. e
APPROVE trial found that there was twice the risk
of heart attack and an increased risk of stroke with
rofecoxib compared with placebo. e increased risk
was evident in those who had been on rofecoxib for
longer than 18 months [8]. In the VIGOR study,
the incidence of myocardial infarction was 0.1% in
the naproxen group and 0.4% in rofecoxib group
[7]. e relative risk of thrombotic cardiovascular
events in patients who took rofecoxib was 2.38
higher than in those on naproxen. In another
study on patients undergoing coronary bypass
surgery, patients treated with parecoxib/valdecoxib
were significantly (p=0.03) more likely to suffer a
cardiovascular thromboembolic event (2.0%) than
patients receiving placebo/placebo (0.5%) [57].
Placebo/valdecoxib treatment was also associated
with a higher incidence (1.1%) of cardiovascular
thromboembolic events versus placebo treatment,
but this difference did not reach statistical
significance. Subsequently, valdecoxib was also
withdrawn from the market by its manufacturer.
In other retrospective studies, the incidence of
cardiovascular events was similar between non-
selective and COX-2 inhibitors [11]. Whether
this pro-thrombotic effect could be identified in
both non-selective and COX-2 inhibitors is still
controversial [41]. e COX-2 enzyme is found
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372 Libby Ha Yun LEE
constitutively in vascular endothelium and plays a
significant role in maintenance of vascular integrity
via the production of prostacyclin. e latter has
both vasodilatory and antiplatelet properties.
e production of prostacyclin is reduced to less
than half of normal when a COX-2 inhibitor is
used [41]. is may account for the increase in
thrombotic tendency and hence cardiovascular
events with the use of COX-2 inhibitors. e
other recent postulation is the shift of substrate to
5-lipoxygenase pathway by inhibiting the COX.
e increase in 5-lipoxygenase activity may lead to
coronary vasoconstriction.
Current literature and advice from the Food and
Drug Administration and the European Agency for
the Evaluation of Medicinal Products recommends
that selective COX-2 inhibitors should not
be used in patients with active cardiovascular
disease and a known thrombotic condition. e
recommendation is to use COX-2 only in short
courses perioperatively in selected patients who do
not have any cardiac risk factors.
Gastrointestinal eect
In an earlier report, more than 100,000 patients
taking non-selective NSAIDs were admitted for
gastrointestinal (GI) perforation, ulceration and
bleeding and 15,000 died in intensive care in the
United States [42]. Another study found that 15–
30% of patients who were newly diagnosed with
peptic ulcer regularly took NSAIDs [23]. e risk
of serious GI complications in NSAID users was
approximately 2.5 to 4.5 times that of non-users
[44].
e COX-2 inhibitors have been proven to be
more advantageous than non-selective NSAIDs in
reducing the incidence of peptic ulcer complication
[20]. In the VIGOR trial comprising 8,076 patients,
a 54% relative risk reduction was demonstrated in
the rofecoxib group in perforation, obstruction,
symptomatic ulcers and upper GI bleeding when
compared with the naproxen group. e Successive
Celecoxib Efficacy and Safety Studies trial in
osteoarthritis, which involved 13,274 subjects,
showed a similar beneficial effect in the celecoxib
group when compared with the naproxen and
diclofenac groups [73].
However, when coxibs are used concomitantly with
aspirin, their GI-sparing effect is reduced. In the
CLASS study in which 21% of 8,059 patients were
taking aspirin as cardiovascular prophylaxis, the
incidence of perforation, obstruction and bleeding
in the celecoxib group and the non-selective
NSAIDs group were the same [72].
Among the non-selective NSAIDs, azapropazone
has been associated with the highest risk, while
ibuprofen has the lowest. Medical co-therapy
with histamine-2 receptor blockers, proton pump
inhibitors, or misoprostol has been found to be
useful in reducing of the incidence of endoscopic
duodenal and gastric ulcers [66]. Of these three
therapies, use of histamine-2 receptor blockers
was the least effective. Omeprazole significantly
reduced the incidence of NSAID-induced ulcers
compared with ranitidine [35, 90]. In Brown’s
recent systematic review, histamine-2 receptor
blockers were less effective in the prevention of
endoscopic ulcers than proton pump inhibitors
and misoprostol [9]. However, misoprostol may
be less cost-effective given its price and the side
effect of diarrhoea, which may occur at all doses
[67]. e American College of Rheumatology has
recommended the use of misoprostol or a proton
pump inhibitor with traditional NSAIDs in high-
risk patients if a traditional NSAID is given in
small doses, otherwise a COX-2 inhibitor should
be considered [62].
Renal eect
It is not uncommon for hypertension and
oedema to occur after the use of non-selective
NSAIDs [24]. Inhibition of COX-1 and COX-2
enzymes will also cause a decrease in intra-renal
vasodilator prostaglandins, which can destabilise
blood pressure control and lead to hypertension
and oedema [34]. Nineteen trials (n=1,204) were
included in Lee’s meta-analysis of the effect of
NSAIDs on postoperative renal function [45].
It was shown that NSAIDs reduced creatinine
clearance by 16 ml/minute and potassium output
by 38 mmol/day on the first day after surgery
compared with placebo. Otherwise, there was no
significant reduction in urine volume or reports
of postoperative renal failure requiring dialysis
during the early postoperative period. Although
NSAIDs can also cause a transient reduction in
renal function in the early postoperative period in
patients with normal preoperative renal function,
this change is clinically unimportant.
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NSAIDs, COX-2 Inhibitors and Paracetamol 373
Eect on asthma
Although there is cross-sensitivity of aspirin to
non-selective NSAIDs, selective COX-2 inhibitors
such as celecoxib and rofecoxib are well tolerated by
almost all aspirin-sensitive asthmatic patients [39,
70]. In a number of trials, COX-2 inhibitors were
given to NSAID-intolerant and asthmatic patients;
no precipitation of asthma or hypersensitive airway
was shown [13].
Szczeklik has suggested that the intolerance to
NSAIDs is likely due to the inhibition of COX-
1 instead of COX-2 [33, 79]. e smooth muscle
of airways can act as a source of inflammation in
asthmatic attacks because there is an increased
COX-2 expression during an attack and a resultant
exacerbation of the release of prostanoids [79]. Using
COX-2 inhibitors can inhibit the inflammatory
reaction in aspirin-sensitive patients.
Drug interactions
Concomitant use of NSAIDs diminishes the effect
of angiotension converting enzyme inhibitors
and beta blockers to stimulate the production of
renal vasodilator prostaglandins with a resultant
anti-hypertensive effect. e natriuretic effect of
furosemide and thiazides is also reduced with the
use of NSAIDs. Aspirin taken with coxibs reduces
their beneficial effect on the GI tract.
Future of Non-steroidal Anti-
inammatory Drugs
Non-steroidal anti-inflammatory drugs inhibit
both COX-1 and COX-2 enzymes, which can
divert alternative processing of arachidonic acid via
the 5-lipoxygenase (5-LX) pathway (leukotrienes),
resulting in increased production of pro-
inflammatory and gastrotoxic LTs. is will tend to
further perpetuate inflammation and complicates
the whole picture. Recent studies now focus on dual
inhibitors, which can block both the 5-lipoxygenase
and cyclo-oxygenase-1 and -2 simultaneously, in
order to limit inflammation and relieve pain.
Licofelone is such an agent and is already in use
to treat osteoarthritis; it has been shown to exert
a profound controlling effect on inflammation
and hyperalgesia in the rat model [74, 75]. It also
inhibits LTB4 generation in neutrophils, prevents
platelet thromboxane B2 production, and
reduces neotimal formation and inflammation
in atherosclerosis [85]. Most importantly, it has
a low gastrotoxicity. Unlike selective COX-2
inhibitors, co-administration of licofelone and
aspirin does not appear to be associated with an
increase in GI adverse events in experimental
models [10].
Paracetamol Overview
Paracetamol is a commonly used drug and easily
available over the counter without a prescription.
For centuries, an extract from cinchona bark, of
which quinine is the active ingredient, was used
as an antipyretic agent. When in the 1880s the
cinchona tree became scarce, people began to look
for alternatives. Paracetamol was discovered in 1893
but it was not until the late 19th century that the
analgesic effect of paracetamol was fully explored.
Since then, paracetamol has gained popularity as
both an antipyretic and analgesic.
Now paracetamol is available in various formulae
that allow different routes of administration.
It can be administered orally, intramuscularly,
intravenously and by suppository. Paracetamol does
not have any anti-inflammatory effect. It had once
been proposed that paracetamol acted on COX-3
[15], a variant of COX which is found in the spinal
cord and brain of animals. However, the existence
of COX-3 in humans and the exact mechanism of
action of paracetamol are still poorly understood.
Future research may provide further insight.
Acute and chronic pain
management
Paracetamol is frequently used in postoperative
analgesia with high efficacy, both in adults
and children [36]. Its safety profile makes it a
commonly chosen analgesic for chronic pain such
as osteoarthritis [4].
Adverse eects
Paracetamol is considered to be a safe drug, provided
that it is used within its recommended dose of less
than 90 mg/kg. www.ncbi.nlm.nih.gov/entrez/
query.fcgi?db=pubmed&cmd=Search&itool=pub
https://t.me/medicina_free
374 Libby Ha Yun LEE
med_AbstractPlus&term=%22Kuffner+EK%22%
5BAuthor%5D. Kuffner demonstrated a low-level,
transient alanine aminotransferase elevation in long-
term osteoarthritic users [43]. is enzyme elevation
usually resolved or decreased with continued
acetaminophen treatment and was unaccompanied
by any signs or symptoms of liver injury.
Toxicity from overdose
In view of its ready availability and accessibility,
as well as potential overdose toxicity, many
countries have imposed regulations in purchasing
paracetamol. In the UK, sales of over-the-counter
paracetamol in pharmacies are restricted to packs
of 32 tablets per customer per occasion (only 16
tablets in non-pharmacy stores). In Ireland, the
limits are 24 and 12 tablets respectively. However,
there are no such regulations or recommendations
in Hong Kong.
Some 60–90% of paracetamol is metabolised
in the liver, where it is converted to inactive
compounds by conjugation with sulphate and
glucuronide, and then excreted by the kidneys.
Another 5–10% is metabolised via the hepatic
cytochrome P450 enzyme system (specifically
CYP2E1). A minor alkylating metabolite (N-
acetyl-p-benzo-quinone imine) is produced
through this pathway. Normally, it will be
removed from the body by conjugation with
glutathione. In paracetamol overdose, the
saturation of conjugation with sulphate and
glucuronide and subsequent over-production
of N-acetyl-p-benzo-quinone imine will cause
death of hepatocytes and liver failure.
Conclusion
Although there is a long medical history of the
use of NSAIDs and paracetamol, these drugs are
not without adverse effects. Great care needs to be
exercised when managing patients taking or self-
prescribing them.
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378 Libby Ha Yun LEE
Thromboxane Prostagladins Leukotrienes
Thromboxane B2
Thromboxane A2
LTA2
LTB4
LTC4
LTD4
LTE4
PGH2
PGG2 5-HPETE EETs
Arachidonic acid
Phospholipid from cell
membrane
Cyclo-oxygenase Cytochrome-450Lipoxygenase
Phospholipase A2
Figure 22.01
Arachidonic acid cascade
PGD2
PGE2
PGF2α
PGI2
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Antidepressants
Introduction
Antidepressants are now widely used to treat various types of
chronic pain syndromes independent of their mechanisms on
patients’ depression. e three main groups of antidepressants
that have been well investigated for their analgesic properties are
tricyclic antidepressants (TCAs), selective serotonin re-uptake
inhibitors (SSRIs) and serotonin norepinephrine re-uptake
inhibitors (SNRIs). e role of TCAs and, recently, SNRIs
in the management of chronic pain (especially in neuropathic
pain) is well established [23, 36]. However, the analgesic role
of SSRIs is not as convincing [50]. Both monoamine oxidase
inhibitors and selective norepinephrine re-uptake inhibitors
have insignificant analgesic effects.
Brief history
e analgesic properties of TCAs were first suggested three
decades ago following the observation of pain relief in patients
with diabetic neuropathy [18]. Five years later, the first
controlled trial of the analgesic effect of amitriptyline in non-
depressed patients with postherpetic neuralgia was published,
supporting the analgesic effect of amitriptyline [103]. Since
then, more than 20 randomised controlled trials have been
published examining the role of TCAs in the management of
patients with neuropathic pain [28]. e SSRI antidepressants
are generally used as the first-line treatment in depression due
to a lower side-effect profile. However, the evidence of their
role in neuropathic pain and headache is conflicting [49]. A
number of SNRI medications have been evaluated in several
controlled trials which have supported their analgesic roles
in various neuropathic pain syndromes, fibromyalgia and
headache [2, 3, 9, 10, 38, 43, 62, 70, 90, 101, 105, 108].
ANTIDEPRESSANTS
Introduction
Brief history
Mechanisms of action
Indications
Pharmaceutical preparations
Side effects
Efficacy
Clinical applications
ANTICONVULSANTS
Introduction
Brief history
Mechanisms of action
Indications
Pharmaceutical preparations
Side effects
Efficacy
Clinical applications
REFERENCES
Antidepressants and Anticonvulsants
23
Philip Wenn Hsin PENG,
Geoff Alexander BELLINGHAM
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