Risk Assessment Of Non Steroidal Anti-Inflammatory Drugs
Non steroidal anti-inflammatory drugs (NSAIDs) have a great history of over 100 years as pain killers. Aspirin is one among the pioneer and long used
NSAID. But now a day it is seldom used as NSAID because of the entry of safer, newer NSAID molecules. All new NSAIDs are not safer than the previous
ones. No NSAID is a safer one which shall not be monitored. The newer generation of cycloxyginase – II (COX – II) specific NSAIDs were thought to be
much safer than the non-specific NSAIDs. And they came to the market and started to rule the NSAID market after 15 to 20 years of premarket research.
But dramatically some studies came up with serious cardiovascular and renal adverse drug reactions of the newer COX – II specific molecules such as
rofecoxib, valedecoxib etc and the pharmaceutical manufacturers withdrawn the drugs from the market. There where around ten coxib molecules in the
market of which only one or two are now being prescribed such as celecoxib and etoricoxib. As the pharmacokinetics is different for these drugs they
vary accordingly in the safety profiles.
Key Words: NSAIDs, coxib, safety, ADR
NSAIDs are commonly used as prescription medicines and over the counter (OTC) medicines in India. Until now we don’t have the national list of OTC
medicines. There is doubt that which drugs to be consumed as non-prescription medicines. NSAIDs are one of the medications which are mostly misused or
self medicated. NSAIDs have been documented as being among the most commonly prescribed drugs in the world, and their use has been associated with
significant gastrointestinal, renal, and hepatic effects. It must be noted that these findings were derived from prescription-strength NSAID use, a
completely safe NSAID is yet to be discovered.1
World Health Organization defines adverse drug reaction (ADR) as any noxious, unintended, and undesired effect of a drug, which occurs at doses used in
humans for prophylaxis, diagnosis, or therapy. But this definition not includes therapeutic failures, overdose, and drug abuse, medication errors or
noncompliance. This definition tries to separate other adverse drug events from the ADR incidences.2
One meta-analysis indicates that nonprescription ibuprofen has an excellent ADR profile in multiple-dose use. There was no evidence of serious adverse
events (AEs) (e.g., GI bleeding, renal failure), which can occur with chronic NSAID use. In addition, non-serious digestive system AEs, which more
typically accompany NSAID use (e.g., dyspepsia, nausea, abdominal pain), occurred with an incidence no greater than the placebo. These results support
the overall safety, particularly the GI safety, of ibuprofen.3
Topical NSAIDs were generally effective and comparatively safe in treating acute painful conditions usually lasts for less than one week.4
COX – II Specificity Conflict
A safe NSAID is yet to be found out. Even though there are variations in the adverse drug profiles, there are no molecules which are remarkably safe.
Generally we classify them based on their specificity to the Cycloxyginase I and II enzymes. Coxibs such as celecoxib and rofecoxibhave been
developed for targeting the COX-2 enzyme more specifically than COX - 1.Celecoxib, demonstrates approximately 375 timeshigher
selectivity for COX-2 compared to COX-1.5
The analgesic property of NSAIDs are due to the inhibition of COX-2 enzymes, where as the GI ADRs are believed to be due to the inhibition of COX-1.
Thus COX-2-specific inhibition was thought to produce effective anti-inflammatory activity and producing lesser GI toxicity. But practically they do produce GI toxicity too. In addition they decrease the production of prostaglandin I2 by
vascular endothelium, and may increase the risk of thrombosis as well as myocardial infarction.
The Adenoma Prevention with Celecoxib (APC) placebo controlled study of celecoxib (200 mg twice daily and 400 mg twice daily) in
2035 patients, resulted in a 2- to 3-fold increase of relative risk of serious CV events. There are no definitive evidence that the nonselective NSAIDs
are not increasing the risk of serious CV events, resulted in the FDA "black box" warning on prescription NSAIDs, that "NSAIDs may cause an increased
risk of serious CV thrombotic events, myocardial infarction, and stroke”.6
Long term use of COX – 2 specific NSAIDs increase in cardiovascular risk when compared with non-specific NSAIDs, especially for 65 years old or older.7
On an average, 1500 patientsmay be exposed to a new drug or chemical under the clinical trials before it comes to the market. So the
clinical monitoring of the new drug continues for a much longer time in the market for its safety and efficacy.8
Approval of regulatory authorities for cyclooxygenase (COX) II inhibitors has drawn attention to the safety profile of all NSAIDs. Safety profile of
COX II inhibitors has not been fully evaluated before marketing since neither of the presently marketed COX II inhibitors has been shown to be safe in
severely compromised renal function or inflammatory bowel disease.9
Impact Of ADRs
Generally ADR may happen in approximately 5% of patients taking a drug. However, little is known about the frequency with which ADRs to newly marketed
medicines are experienced by patients or are reported to doctors. Around 3% of all admissions to geriatric units in the U.K. are due to ADR, and that
in a further 8% of admissions, an adverse drug reaction is a contributory cause.10 In U.K., hospital admissions due to ADRs are much
comparable to the other parts of Europe.11
In one of the study medication errors are found to be the reason for 22% of all deaths happened due to ADRs.Patient safety programs to be
enforced to reduce human errors.8
One study in 1997 states that, the mortality in any patient due to bleeding or perforation is decreased over time. But death due to bleeding or
perforation is high in patients exposed to NSAIDs. Recent knowledge suggest there is an increase of such mortality since 1997.12
Many NSAIDs such as ibuprofen, indomethacin,aspirin,ketorolac, or naproxen,decrease the bone healing. There are some data supporting the evidence that NSAIDs suppress bone formation and healing of bone fracture.5
NSAIDs such as aspirin, ibuprofen, diclofenac and naproxen sodium inhibit cycloxygenase and may inhibit lipoxygenase decreasing the production of
prostaglandins and leukotrienes. Which may account for many NSAID induced renal effects. Prostaglandin inhibition may result in fluid and electrolyte
imbalance and acute renal failure.13
Numerous well documented cases of acute NSAID induced renal disease in patients with prior normal renal function have been documented.14
Drug induced urticaria in most of our patients was due to NSAIDs followed by penicillin group of drugs. Anticonvulsants were the most frequent drugs
implicated for toxic epidermal necrolysis (TEN) in our series, as is reported from Malaysia, whereas antimicrobials were the commonest drugs in other
series, NSAIDs were also implicated in some of the cases of TEN. NSAIDs (salicylates and ibuprofen) were one of the common drugs causing different
types of skin reactions.15
Many NSAIDs are well known for their liver and kidney toxicities.16 One study in Mauritius explaining complications of chikungunya fever
reveals that Six participants had iatrogenic complications due to gastritis induced by NSAIDs out of 68 participants who had been prescribed this drug. 17
Management Of ADRs
Adherence to medication can decrease ADRs. Reduction in patient compliance is not only a problem of drug efficacy. But it can deviate the patient from
the therapeutic plan, even doubling the dose after a missed dose, consumption of over the counter or traditional medicines and its related drug
interactions are other problems. Potentially, higher adherence to the medications prescribed is a good step in management of ADRs.18
To calculate the health reduction outcome of ADRs, Disability adjusted life years (DALYs) could be calculated. DALYs are defined as the sum of the
present value of the future years of lifetime lost through premature mortality and/or present value of the future lifetime adjusted for the average
severity of any morbidity caused by a disease or adverse drug event. In micro economic evaluations DALYs are commonly used as outcome research
Other uses of NSAIDs could be traced to make the best benefit from it. Some studies suggest that regular use of low dose aspirin reduces the risk of
colon cancers. But there are increased bladder cancer risks with phenacetin-containing drugs on long term use.20
Pharmacovigilance In India
Pharmacovigilance is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or
any other possible drug-related problems. In 2004, India's Drugs Control Department within the Ministry of Health & Family Welfare initiate a
nationwide pharmacovigilance network.21 Even though some pharmacovigilance programs were stated in India it was not really effective in
monitoring the medications on a national basis. Phase one of the Pharmacovigilance Programme for India (PvPI) was started on July 2010. But is shall
take long time to be fully functioning in India.22
Spontaneous adverse drug reaction reports from various centers shall provide early signals of ADRs.23 But even though spontaneous reporting
is important in pharmacovigilance, it have many limitations also in giving conclusive evidence.24
After the short life of ‘coxib’ NSAIDs, Diclofenac and Aceclofenac are the most prescribed drugs and drug of choice for different types of pain as well
as higher pain intensity. Last members of the withdrawing ‘coxib’ molecules which are now being prescribed are Celecoxib and Etoricoxib. Rationality of
using NSAIDs for a particular condition is debatable. Even though Aspirin has crossed 100 years of clinical usage, still it’s being questioned and
seldom used for inflammation and pain. The debate continues to the newer selective COX –II inhibitors. And the current evidence disqualifies the
anticipated advantages of COX –II specifics over conventional NSAIDS.
I am thankful for the guidance by the research wing of Karpagam University, Coimbatore, South India on my research on adverse drug profiles of
non-steroidal anti-inflammatory drugs.
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Mr. Dixon Thomas, M.Pharm, M.S. is Associate Professor in Raghavendra Institute of Pharmaceutical Education & Research, Anantapur, A.P. 515721, and a Research Scholar at Karpagam University, Coimbatore. He has more than fifteen research publications and editor of RIPER PDIC bulletin.
Dr. Molly Mathew, M.Pharm, PhD is the Principal of Malik Deenar College of Pharmacy, Bela Post, Kasaragod, Kerala, 671321. She was awarded her PhD in Pharmacology and Pharmacognosy from the University of Kerala. She is research guide in many Universities, having more than 40 research publications to her credit. She is also an editorial team member of International Journal of Green Pharmacy.
Dr. C. Vijaya Raghavan, M.Pharm, PhD is the Vice Principal of PSG College of Pharmacy, Coimbatore, Tamilnadu, 641006. He is a PhD holder in the field of Pharmaceutics and author of many books. He is research guide in many Universities, having more than 30 research publications for his credit. He is the editor of International Journal of Pharma Research (IJPR).