NSAIDs armamentarium in clinical management of pain

Dr Balvinder Arora

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are drugs with analgesic, antipyretic and anti-inflammatory activities that help reduce pain, fever and inflammation.

The term "non-steroidal" is used to distinguish these drugs from steroids viz. mineralocorticoids and glucocorticoids – the glucocorticoids that also possess anti-inflammatory action. Aspirin and ibuprofen along with paracetamol (acetaminophen) are important NSAIDS but acetaminophen has little or negligible anti-inflammatory activity. These drugs are considered together because they are used for similar problems and may have similar mechanism of action. All these compounds inhibit cyclooxygenase.

History of NSAIDS started with the isolation of salicylic acid in 1829 from the folk remedy willow bark. Since then NSAIDs have become an important part of the clinical management of mild to moderate pain and help reduce the intensity of inflammation at higher doses.

What is important and interesting about NSAIDS?

NSAIDs unlike opioids (and its analogues) do not produce sedation, respiratory depression, or addiction. This is precisely the reason that certain NSAIDs, including ibuprofen and aspirin, are commonly available over-the-counter without a physician’s prescription that most individuals undertake for self management of mild to moderate pain ( a dangerous proposition in the long run !!! ). NSAIDs, albeit, do possess some problems especially with chronic use viz gastric irritation among many others that limits its use and dosage.

What is more safe NSAIDS or the STEROIDS?

NSAIDS, undoubtedly, provide the mainstay therapy for the management of many painful musculoskeletal diseases where inflammation is the underlying pathology with or without alteration of the immune functions. Although STEROIDS ESPECIALLY -GLUCOCORTICOIDS are also used to manage such inflammatory conditions especially seronegative spondylo arthropathies, rheumatoid arthritis, gout and other types of crystal arthritis but unless the dose of glucocorticoids is carefully gauged these are not without their serious side effects especially bone loss (a long term concern), cartilage destruction, Cushing’s syndrome, ‘bruising and skin thinning’, GIT ulcerations, and not invariably introduction of multiple infections. All these side effects are too difficult to manage and prove very costly as for as the maintenance costs are concerned. Above all –‘Are these side effects not an incessant source of agony to the patient who becomes more concerned towards these grave side effects rather than the underlying primary disease for which he/she sought the clinician’s advice’? NSAIDS are indeed a safe bet.

Mode of action

The mechanism of action was first elucidated by John Vane who received Nobel Prize for his work. Principal action of NSAIDs includes non-selective inhibition of the enzyme cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. Cyclooxygenase catalyses the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipids bilayer by phospholipase A2). Prostaglandins, among other molecules in the process of inflammation serve as ‘messenger molecules’ in the process of inflammation. From a clinicians viewpoint and application of NSAIDS in medical practice there is little difference in clinical efficacy between the NSAIDs when used at equivalent doses. Any such differences between compounds tend to be dose selected and are an integral function of the half-life of the compound, route of administration, and tolerability profile of the NSAID selected for pain therapy.

Classification of NSAIDS

I Salicylates

-Aspirin
-Methyl Salicylates
-Diflunisal

II Arylalkanoic acids

-Indomethacin
-Sulindac
-Diclofenac

III2-Arylpropionic acids (profens)

-Ibuprofen
-Ketoprofen
-Naproxen
-Ketorolac
-Carprofen
-Fenoprofen

IV N-Arylanthranilic acids (fenamic acids)

-Mefenamic acid

Oxicams

-Piroxicam
-Meloxicam

V Coxibs

-Celecoxib
-Rofecoxib (withdrawn from market)
-Valdecoxib
-Parecoxib
-Etoricoxib

VI Sulphonanilides

-Nimesulide

NSAIDS in Clinical Practice

NSAIDs are usually indicated for the treatment of acute or chronic painful inflammatory conditions.

The conditions that commonly invite use of NSAIDS include

Inflammatory arthropathies (e.g. ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome)
Rheumatoid arthritis
Osteoarthritis
Acute gout and other types of crystal arthritis.
Metastatic bone pain
Postoperative pain
Dysmenorrhoea
Headache and migraine
Inflammatory conditions and tissue injuries producing mild-to-moderate pain.
Pyrexia
Renal colic
Aspirin is the NSAID that irreversibly inhibits COX-1 is also indicated in clinical situations where inhibition of platelet aggregation is an important indication, for example in the management of cerebrovascualr accidents. Aspirin, however, irreversibly acetylates platelets and interferes with the coagulation of blood thereby increases the risk of GIT bleeding.

Adverse effects

NSAIDs have become the mainstay of the management of mild to moderate pain. Some of these are very popular in general population and are available without prescription – the potential source of profits for the pharmacists. Easy access to some of these NSAIDS, therefore, is also one of the reasons for higher incidence of the adverse effects that often remain oblivious to the physician as well as the user when taken for long periods. Although there are many adverse effects but the two most significant adverse drug reactions that have been well documented - because if its very high occurrence rates - are gastrointestinal (GI) adverse effects and renal damage especially when used over longer periods of time (chronic use).These effects are a direct function of dose-intake, and when used in higher doses pose the serious risks of gastric/peptic ulcer perforation, upper gastrointestinal bleeding, and not invariably death.

Gastrointestinal Tract Adverse Effects

NSAIDS cause direct and indirect irritation of the gastrointestinal tract (GIT) - the acidic molecules irritate the gastric mucosa (direct); and indirectly inhibit COX-1 leading to marked reduction in the levels of protective prostaglandins. Nausea, dyspepsia – indigestion, ulceration / bleeding and diarrhea are the other common side effects.
Some NSAIDS viz. Indomethacin, Ketoprofen and Piroxicam appear to have the highest prevalence of gastric adverse effects, while ibuprofen (lower doses) and Diclofenac appear to have lower rates.

Certain NSAIDs, such as enteric-coated formulations of aspirin have become very popular with clinicians who believe that these reduce the incidence of gastrointestinal ADRs but do these formulations reduced risk of GI ulceration is still a matter of ambiguity. Most clinicians also believe that gastrointestinal adverse effects can be reduced through suppressing acid production by concomitant use of a proton pump inhibitors e.g. omeprazole; or the prostaglandin analogue misoprostol but rebound acidity is a serious problem. Further, one needs to know that Misoprostol is in itself associated with a high incidence of gastrointestinal adverse effects, especially diarrhea.

Renal or Urinary Tract Adverse Effects

NSAIDs are notorious for causing relatively high incidence of analgesics induced nephropathies. The mechanism of these renal adverse effects is whether due to changes in renal haemodynamics (blood flow), or alterations in the levels of prostaglandins productions, which are affected by NSAIDs, is a matter of interest to research scholars.

Acute renal failure develops as a result of acute tubular necrosis in about 2% of patients who take an overdose of acetaminophen. Renal dysfunction is usually accompanied by severe hepatic failure, but in few cases there is acute renal failure without hepatic damage. Acute renal failure arises several days after ingestion and is mainly oliguric in type

Altered renal functions due to chronic intake of NSAIDS include salt and fluid retention and hypertension. NSAIDS may also cause renal damage, especially when employed in combination with other nephrotoxic agents. Serious alterations in pathophysiology of renal functions may culminate into renal failure especially if the patient is also concomitantly taking an ACE inhibitor and a diuretic - the "triple whammy" effect. Occasionally NSAIDs may also cause more severe renal conditions: interstitial nephritis, nephrotic syndrome, and acute renal failure.

NSAIDS and Photosensitivity

Photosensitivity reactions associated with the use of prescription or over-the-counter drugs are either phototoxic i.e. caused by potentiation of solar energy by a drug or photo allergic in which the combination of a photosensitizing agent and light evokes a true cell-mediated hypersensitivity response. The 2-arylpropionic acids class of NSAIDS have proven to be the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including Piroxicam, Diclofenac and benzydamine. Benoxaprofen, since withdrawn due to its hepatotoxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photo activity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. Ibuprofen is a weak photosensitizing agent probably due to weak absorption

The degree of photosensitivity is a subjective constitutional phenomenon. Not everyone using NSAID medications containing photo reactive agents will develop a photoreaction. In fact, a person who has a photoreaction after a single exposure to an agent may not react to the same agent after repeated exposures. On the other hand, people who are allergic to one chemical may develop photosensitivity to another related chemical to which they would normally not be photosensitive. In such cross-reaction, photosensitivity to one chemical increases a person's tendency for photosensitivity to a second.

NSAIDS usage in Pregnancy

NSAIDs are best avoided during pregnancy. NSAIDS can alter renal cortical functions in adults and also decrease fetal urine output causing ologohydroamnios. Cox 2 inhibitors have been associated with renal failure. Although not directly teratogenic, NSAIDS have been implicated in premature closure of the fetal ductus arteriosus (especially with indomethacin when used as tocolytic during pregnancy), increased risk of interventricular hemorrhage, necrotizing enterocolitis and renal adverse drug effects in the fetus. NSAIDS are also linked with premature birth.

NSAIDS if used at very low doses during pregnancy may be safe e.g. aspirin, when used with heparin, may be beneficial in pregnancy for women with antiphospholipid antibodies. Paracetamol (acetaminophen) however is regarded as being well-tolerated during pregnancy. Clinicians must be careful while prescribing the doses of acetaminophen due to risk of hepatotoxicity with overdoses. Other adverse effects of NSAIDS include raised liver enzymes, headache, and dizziness. Relatively uncommon adverse effects include: cardiac failure, hyperkalaemia, confusion, bronchospasm, rash etc.

Newer NSAIDs:

Selective COX inhibitors

I. COX-2 inhibitors

COX-2 was first discovered in 1991 by Daniel L. Simmons. COX-2 is an enzyme facultatively expressed in inflammation, and it is the inhibition of COX-2 that produces the desirable effects of NSAIDs. The relatively selective COX-2 inhibiting Oxicams, Meloxicam, was the first step towards developing a true COX-2 selective inhibitor. Coxibs, the newest class of NSAIDs include Celecoxib, Rofecoxib, Valdecoxib, Parecoxib and Etoricoxib.

Controversies associated with the use of COX-2 inhibitors

Currently Rofecoxib has been globally withdrawn from the market since October 2004 due to its association with increased risk of cardiovascular complications including MI.

II. COX-3 inhibitors

COX-3 was discovered by Simmons in 2002 who critically analyzed this new isozyme's relation to acetaminophen. Most research scholars engaged in studies of pathophysiology of pain believe that inhibition of COX-3 could be due to a primary central mechanism by which these drugs decrease pain and possibly fever. Currently, a vast degree of research is being carried out to advance the knowledge of COX isozymes with the hope it may provide answer to safe newer class of NSAIDS for treatment of pain, inflammation, and fever in near future.

In conclusion, a large number of NSAIDS available in the market today - with relentless research efforts to improve the existing ones and develop newer ones – no doubt provide a huge armamentarium for the management of mild to moderate pain including metastatic bone pains but their judicious use demands a high degree of diligence, rationale and continuing education on the part of clinicians advocating their use.

About Authors

Dr Balvinder Arora, (M.D.) Professor – Clinical Microbiology is currently pursuing CRA with KRC. Inc., Toronto,Ontario, Canada. Dr. Balvinder is well known for his exceptional abilities and an outstanding teacher with a strong commitment to improving undergraduate and post graduate education. Dr. Arora is voracious reader and an outstanding prolific writer in many areas of Medicine, Microbiology and Clinical trials. He has done extensive work in the field of infectious diseases and during his more than 10 years of research and teaching in general biology, microbiology and medicine – most frequently as a sole lecturer – Dr. Balvinder has instructed over 5000 students. His teaching skills and style have been honed in both large lecture and small class room environments and with diverse groups of students. Dr. Balvinder is not only a very good academician but also very social and enterprising personality with a great sense of humor. His role in the improvement of medical education remains as his most significant contribution to the development of society at large.
Email: dr_arorabalvinder007@yahoo.com

Dr. Sandeep Bagga is a Certified Bioinformatics Specialist, Cert. in SAS Programming and associated with Pharmaceutical Research and Clinical Trials, PRACT Advisory Service, Sterling, Virginia (USA). Email: sbagga@practadvisors.com