Safety Profile of Nonsteroidal Antiflammatory Drugs (NSAID) Safety Profile of NSAID

Safety Profile of NSAID
Safety Profile of Nonsteroidal
Antiflammatory Drugs (NSAID)
R. Stoilov: University Hospital St Ivan Rilski, Clinic of Rheumatology
Contact: Rumen Stoilov, Clinic of Rheumatology, University Hospital St Ivan
Rilski, 15 Acad. Ivan Geshov Blvd, 1431 Sofia, e-mail: [email protected]
Key words: Nonsteroidal Anti-Inflammatory Drugs, Gastrointestinal toxicity, Cardiovascular toxicity, COX 2 inhibitors
Abstract: NSAIDs are among the most frequently used medicinal products in medical practice. They are in great use for
managing pain and other symptoms of inflammation, but they can also cause a number of adverse effects on gastrointestinal tract,
cardiovascular or kidney and urinary systems, etc. The leading mechanism which defines their efficiency as well as their toxicity is the
suppression of cyclooxigenesis. COX-1 inhibition is related with the manifestation of adverse drug reaction. COX-2 inhibitors have
smaller gastrointestinal toxicity, though some researches suggest that long-term treatment with coxibs in high doses can increase the
risk from cardiovascular incidents. This review article shows that the efficiency of coxibs is comparable to that of nonselective NSAIDs,
though considerably more sparing to gastrointestinal tract, while some of them can increase the risk from cardiovascular incidents.
Review Article
The rheumatic diseases are characteristic with high
frequency. Every 7th inhabitant on the Earth has some
rheumatic disorders, in every 3rd family there is a member
with a rheumatic problem. More than 200 rheumatic diseases are known. About 300 million in the world are only
those suffering from arthritis and osteoporosis. In Europe
their number is about 100 million. Most of these diseases
are chronic. The rheumatic diseases are one of the most
frequent causes for temporal working incapacity as well as
permanent disability.
The ageing of the population and the changes of the
way of life of the contemporary people will increase the
relative part of these chronic diseases such as osteoarthritis, osteoporosis, and various types of arthritis etc, which
become more frequent in the late decades of people’s lives
(see Graph 1).
The demographic prognosis show definite increase of
the number of people of over 60 and over 80 years of age in
the forthcoming decades. In Europe only the joint diseases
constitute about 50% of all chronic diseases of people over
65 years of age (4).
The chronic course of these diseases requires constant or
intermittent treatment as well as periodical medical and
laboratory control. This is connected with considerable financial funds for drugs, consumables, medical equipment,
doctors’ labour etc.
In Europe the economic burden for only rheumatic diseases is more that 200 billion euro a year (4). In many cases
the working capacity may be preserved but the discomfort
caused by them has influence on the quality of the professional activity of the sufferers and their quality of life in the
leisure time.
(Graph 1)
Frequency of most common
rheumatic diseases by age
The most widely used medicines for the treatment of
rheumatic diseases are the Nonsteroidal antiflammatory
They combine antiflammatory, analgetic and antipyretic
effect. Daily more than 30 million people all over the world
use nonsteroidal antiflammatory drugs. 10% of the total
population in most of the European countries take nonselective NSAID, whereas this percentage reaches 25 with the
adults (14). With this kind of drugs symptomatic influence
can be achieved on the joint pains, on the stiffness and the
swelling as well as on the functional capacity of the loco-
Safety Profile of NSAID
motory system i.e. a considerable clinical improvement of
the sick people.
In clinical application of NSAID it is necessary to observe
the following principles: adequate dosage; sufficient duration of the course of treatment; taking into consideration
the individual sensitivity to NSAID; correct distribution of
the prescribed dose in the twenty-four-hour period; usage
of alternative forms of application (rectal, parenteral,
percutanic) etc. Regardless of the fact that NSAID are extremely useful for supressing the inflammation and pain,
their usage is often accompanied by adverse drug reactions. In the recent years, more and more attention is paid
to the correlation benefit/risk in the clinical application
of NSAID. Particular attention is worth paying to gastrointestinal adverse events (1), and recently the cardiovascular, too (8). According to the data of the Spanish system of
Pharmacovigilance (SSPV) for the period 1983–1991,
18 348 reports of adverse drug reactions were made and
8.8% out of them were caused by NSAID, thus taking
the second place after the antibiotics (15.1%). The most
frequently quoted NSAID are: Diclofenac (364 reports),
Piroxicam (282), Indometacin (197), Naproxen (155) and
Ketoprofen (137).
The nonselective NSAID exert their effects by blocking,
approximately to the same extent, the two isoenzymes of
cyclooxygenase - COX-1 and COX-2. The suppression of the
inducible COX-2 is connected with the therapeutic effects
of NSAID – antiflammatory, analgetic and antipyretic.
The inhibition of the constitutive COX-1 which supports
the homeostasis leads to adverse drug reactions from the
gastro-intestinal tract, the kidneys and the cardio-vascular
system.(Fig. 1)
The adverse effects of NSAID on the GIT are a significant
cause for morbidity and mortality (11). About 60% of the
patients on chronic treatment with NSAID have dyspeptic
complaints: abdominal pain, sickness, vomiting, burning
behind the sternum; whereas 15–30% have gastroduodenal
ulcers proven by endoscopy. Most clinically significant
ADR, connected with the usage of NSAID, are ulcer complications – perforation, obstruction or bleeding (POB). The
clinical studies show that about 1.5% of the patients with
RA and OA, treated with NSAID have POB (1, 13, 14).
(Fig. 2).
The NSAID suppress the synthesis of the cytoprotective
prostaglandines, reduce the mucous and bicarbonate
secretion in the stomach, injure the surface phospholipids’
layer, reduce the blood circulation in the mucous membranes, and increase the acid secretion. All this upsets the
balance between the protective and aggressive factors in
the stomach and the duodenum
The basic factors, associated with the higher risk of
gastro-intestinal adverse drug reactions are:
- high dose or combination of NSAID;
- age over 65;
- anamnesis data of the ulcer in the past;
- continuous usage of NSAID;
- simultaneous application of other drugs
(anticoagulants, glucocorticosteroid and others);
- serious concomitant illnesses;
- others: presence of infection with Helicobacter Pylori,
smoking, alcohol abuse and others;
We must particularly be vigilant at the presence of one
or several of the above factors.
People using NSAID have three times higher relative risk
of development of serious gastro-intestinal adverse drug
reactions and two times higher relative risk of bleeding
compared to those who do not use NSAID.
Patients who are treated with NSAID at an older age are
exposed to three times higher risk of developing gastro-intestinal complications compared to those who use NSAID
at an earlier age. The serious gastro-intestinal complications due to the usage of NSAID in a number of cases can
have a lethal issue. Graph 2 shows that the mortality cause
due to usage of NSAID in the USA for a year is juxtaposable
to that of the sufferers from AIDS.
(Graph 2)
Safety Profile of NSAID
Conventional NSAIDs
mechanism of action
of plateles
pain, fever
Figure 1.
Nonselective NSAID mechanism of action
Figure 2
Adverse NSAID effects on gastric mucous membrane.
Safety Profile of NSAID
In Great Britain, about 20% of the emergency cases with
complication of the upper parts of the gastro-intestinal
tract were due to nonselective NSAID in only one year
(about 12 000 people). Seventy one percent of those using
nonselective NSAID were with injured small intestines
which was determined by capsule endoscopy. Only 10% of
the people, who do not use this type of medicinal products, have similar injuries (7). The treatment of serious
adverse drug events by GIT is connected with considerable
economic losses. The total price of the treatment of one
patient is from US$1800 in Switzerland to US$6500 in the
Netherlands (3). (Graph 3)
Graph 2.
Mortality caused by gastrointestinal complications
related to NSAIDs in comparison to other diseases in the USA
Safety Profile of NSAID
COX-2 conception gave rise to real hopes for optimisation of the balance between the therapeutic effectiveness
and the adverse drug reactions of NSAID, i.e. between the
benefit and the risk. This conception revealed the possibilities to create new generation of NSAID, called selective
inhibitors of cyclooxigenase-2 (6). Today we have considerable experience in their application. The mechanism of
the effect of the selective COX-2 inhibitors is presented
in Figure 3. They block the inducible COX-2 and keep the
constitutive COX-1. (Fig. 3)
Graph 3.
Direct costs associated with serious gastrointestinal adverse events
(Chevat, C. et al Pharmacoeconomics, 2002 19, /Suppl.1/, 17-32).
Safety Profile of NSAID
Molecular basis of COX-2 inhibition
Side pocket
Figure 3.
Mechanism of action of selective COX-2 inhibitors
A number of studies showed, that the selective COX-2
inhibitors have anaesthetizing and antiflammatory effect,
juxtaposed to that of the non-selective NSAID, but to a considerably larger extent protect the gastroduodenal mucous
membrane (10, 13, 15, 16). Recently it has been found out
that some representatives of COX-2 inhibitors with continuous usage lead to cardiovascular complications. This
gave rise to prerequisites to shake the positive attitude to
highly selective COX-2 inhibitors, called coxibis.
Safety Profile of NSAID
Prothrombotic hypothesis
Specific inhibitors
Vasodilation and
endothelial function
No block of TXA2
Platelet aggregation
and vasoconstriction
Misbalance can lead to prothrombotic
state and can increase the cardiovascular risk
Figure 4.
Prothrombotic hypothesis
It is admitted that COX-2 inhibition leads to increase of
the potential risk of the thromboembolic cardiovascular
events, as it was found out in the study VIGOR (9). The
presumptive mechanism for this is connected with the
suppression of the synthesis of the vascular prostacyclin
(PgI2), without suppressing the synthesis of thromboxane
A2 (TXA2) of the thrombocytes. COX-2 inhibitors do not
influence the thrombocyte aggregation (12, 18). Fig. 4
presents the prothrombotic hypothesis (Fig. 4).
Safety Profile of NSAID
Figure 5.
First and second generation coxibs – chemical formulae of structure
We have to underline that the patients participating
in the study VIGOR are treated with Vioxx (rofecoxib), 50
mg/daily, in the course of one year (2). For the time being,
there are no data that other COX-2 selective inhibitors
bring to a higher risk of cardiovascular complications (9).
Having in mind that COX-2 selective inhibitors are different chemical compounds, it seems more likely that the
matter is about specific effect of a drug and not a class specific effect. Fig. 5 presents the chemical structural formulae
of different coxibs in two basic groups – sulfonamides and
sulfonyls (Fig. 5).
Safety Profile of NSAID
Graph 4.
Risk from acute MI related with COX-2 selective inhibitors and
nonselective NSAIDs (~1.4 million patients)
At present, we can consider that the clinical data causing
the withdrawal of Vioxx (rofecoxib) are specifically connected with it and they should not be referred “implicitly”
to the rest of the COX-2 selective inhibitors. With about
1.4 million patients in the USA, who use COX-2 selective
and non-selective NSAID, the risk of acute myocardial
infarction has been studied. It has been found out that
with patients using celecoxib, the risk of acute myocardial
infarction is commensurable with the control group, in
contrast to those treated with rofecoxib, 50 mg/daily, and
some other nonselective NSAID (8, 17). Graph 4 presents
the data of Nested Case-Control Study published in Lancet
2005 (8) (Graph 4)
The American Agency of Food and Drugs (FDA) recommends to the pharmaceutical companies to revise the
medical indications of nonselective NSAID, as well as of
COX-2 inhibitors. These should include special warning
for higher risk of cardiovascular adverse events and life
threatening gastro-intestinal hemorrhages (5). In the
USA and Canada COX-2 inhibitors are counter-indicative
in coronary-arterial bypass surgery and perioperative
application in cardiac-surgery. In Europe (EMEA recommendation) COX-2 selective inhibitors and nonselective
NSAID have different medical information. The contraindications about the application of COX-2 selective inhibitors
are: cardiac insufficiency II-IV class by NYHA, determined
ischemic heart disease peripheral artery diseases, cerebral
artery diseases, uncontrolled hypertonia (only for Arcoxia
Safety Profile of NSAID
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GIT – gastrointestinal tract
CVS – cardiovascular system
NSAID – nonsteroid anatiflammatory drugs
ADR – adverse drug reactions
COX-1 - cyclooxygenaseisoenzyme 1
COX-2 - cyclooxygenaseisoenzyme 2
POB - perforation, obstruction, bleeding
R A – rheumatoid arthritis
OA - osteoartrosis
AMI – acute myocardial infarction