Rational Medicine

Non steroidal anti inflammatory drugs (NSAIDs) are the most used and abused drugs in the world today (annually about 20,000 tonnes of Aspirin is consumed in United States alone). Pain and fever being the most common complaints, these drugs naturally are in great demand and doctors have no hesitation to cater to this. And the Indian drug industry, always ready to cater to the 'needs' of medical professionals and always in the forefront of developing mixtures and combinations of various kinds, has responded very well to this 'demand'. Today if the market share of 'NSAID combination pills', the great invention of the Indian drug industry, is much bigger than that of individual drugs, it speaks volumes of our irrational prescribing habits. (The 'combined pills' of Ibuprofen+Paracetamol now have a much bigger market share than ibuprofen alone, which was once the No. 1 NSAID sold in India)

Pain, inflammation and fever are to a large extent caused by prostaglandins, products of arachidonic acid metabolism. The membrane phospholipids are cleaved to produce arachidonic acid that is in turn metabolised via the cyclooxygenase and/or lipooxygenase pathway to produce prostaglandins and/or leukotrienes respectively.

		Phospholipid
	Phospholipase A₂		Glucocorticoids
		Arachidonic Acid
NSAID	Cyclooxygenase COX-1, COX-2		Lipooxygenase
Cyclic Endoperoxides			Hydroperoxy Eicosatetranoic acid (HPETE)

Prostaglandins PGD₂, PGE₂, PGF_{2 α}, PGI₂	Thromboxane TXA₂		Hydroxyeicosa tetranoic acid(HETE)	Leukotrienes LTA₄, LTB₄, LTC₄, LTD₄, LTE₄

Three isoforms of cyclooxygenase have been identified, cyclooxygenase 1, cyclooxygenase 2 (COX - 1 and COX - 2) and cyclooxygenase 3 (or cyclooxygenase 1b). COX-1 is normally present in all tissues while COX-2 is induced by cytokines and certain serum factors.

Glucocorticoids inhibit phospholipase A₂ and thus block the production of both prostaglandins and leukotrienes, exerting a potent anti-inflammatory effect. Glucocorticoids also block the actions of cyclooxygenase -2.

Pain Inflammation, injury etc. Bradykinin, IL-1, IL-8, TNFα etc.	Cyclo-oxygenase/ lipo-oxygenase Prostaglandins	Pain Lower the threshold of pain receptors/C fibres
Fever Infection, tissue damage, inflammation, graft rejection, etc. IL-1, IL-6, TNFα	Cyclo-oxygenase/ lipo-oxygenase Prostaglandins	Fever PGE2 triggers the hypothalamus to elevate body temperature.
Inflammation Infectious agents, ischemia, antigen-antibody reactions, thermal or physical injury IL-1 and TNF etc.	[NSAIDs Block Here]	Inflammation Vasodilation, increased capillary permeability; infiltration of leukocytes and phagocytes; tissue degeneration, fibrosis etc.

Non-steroidal anti-inflammatory drugs like aspirin and indomethacin block cyclooxygenase (both COX 1 and COX 2 isoforms) and thereby block the synthesis of prostaglandins. They also block the synthesis of thromboxane A₂and thereby also exert anti-platelet effects. These drugs do not block lipooxygenase and as a result of blockade of cyclooxygenase, availability of substrate for the lipooxygenase pathway may increase, resulting in increased levels of leukotrienes, one of the important mediators of bronchial asthma. Inhibition of COX-1 results in blockade of prostaglandin synthesis in the gastric mucosa and in the kidneys, leading to drug induced gastritis and compromised renal blood flow.

Inhibition of COX-2 is theoretically enough for the treatment of inflammation. It has also been claimed that selective inhibition of COX-2 can protect the gastric mucosa and the renal blood flow. Many selective COX 2 inhibitors have been developed (celecoxib, rofecoxib, valdecoxib, eterocoxib, parecoxib and meloxicam) with claims of equal efficacy as non selective COX inhibitors, but lesser adverse effects on the gut and the kidneys. However, post marketing experience has been disastrous for some of these drugs (rofecoxib and valdecoxib in particular), forcing them out of the market. (See reports below)

Using NSAIDs: NSAIDs are used in the treatment of pain, fever and inflammation, occurring alone or in any combination. All NSAIDs act on the same cyclooxygenase enzyme and hence all have analgesic, antipyretic and anti-inflammatory effect. However the potency of the various NSAIDs vary.

Aspirin (acetyl salicylic acid) irreversibly acetylates cyclooxygenase, while other NSAIDs are reversible inhibitors by competing with arachidonic acid at the active site on cyclooxygense. Indomethacin is a more potent NSAID than others. More the potency, more are the adverse effects.

Paracetamol (Acetaminophen) acts only as analgesic and does not have any anti-inflammatory action (because it is inactivated by peroxides in the inflamed tissue).

Therefore, whenever a patient has inflammation, pain and/or fever, any NSAID can be used alone and whenever patient has pain and/or fever, without inflammation, paracetamol can be used alone.

Inflammation and fever being the natural response to injury or insult, these are necessary evils that help to combat the injury or infection. Use of anti inflammatory or antipyretic drugs would therefore be an interference in the nature's defense mechanism, with a potential risk of aggravating the underlying illness. Therefore, these drugs should be used sparingly in the symptomatic treatment of fever, pain and inflammation. Use of NSAIDs for the management of post operative pain may increase the risk of bleeding and delay wound healing and therefore are not ideal for managing post operative/post partum pain.

All NSAIDs have significant adverse effects on the gastrointestinal tract (gastritis, ulcers and bleeding), kidneys (compromise in renal blood flow; may precipitate acute renal failure in patients with pre-existing renal disease, dehydration or receiving drugs like ACE inhibitors or angiotensin blockers) and the heart. Therefore, NSAIDs should not be used recklessly and the benefits of their use should outweigh these potential risks.

Are NSAID combinations more effective? In India, a variety of NSAID combinations are available, often as Over-The-Counter products. These combinations are the easiest way of selling two drugs when one (or even none) may be needed for the patient. These 'combined' pills are marketed with slogans like "Ibuprofen for pain and Paracetamol for fever" and "Ibuprofen for peripheral action and paracetamol for central action"! Recently, combinations of NSAIDs with rantidine, omeprazole and other proton pump inhibitors are also being marketed with the ostensible reason that the gastric adverse effects of NSAIDs can be prevented by using these combinations. It is indeed very unfortunate that the medical fraternity in India have fallen prey to such gimmicks. The gullible patient then has to pay for the doctors' complacence in terms of extra cost and extra adverse effects.

The 'Special' NSAID combinations available in India
Ibuprofen 400 mg +Paracetamol 325 mg or 500 mg tablet Ibuprofen 100mg + Paracetamol 125mg or 162.5 mg per 5 ml syrup for children	Diclofenac 50 mg +Paracetamol 325 mg or 500 mg tablet
Ibuprofen 400 mg + Methocarbamol 750 mg tablet	Diclofenac 50 mg +Paracetamol 325 or 500 mg + Chlormezanon 100 mg tablet
Indomethacin 25 mg + Paracetamol 325 or 500 mg tablet	Diclofenac 50 mg +Paracetamol 325 or 500 mg + Chlorzoxazone 250 mg or 500 mg tablet
Nimesulide 100 mg + Paracetamol 500 mg	Diclofenac 50 mg +Paracetamol 250 mg + Dextropropoxyphene 32.5 mg tablet

These combination pills have now become the largest selling 'brands' of antiinflammatory/analgesic/antipyretic products. The 'single' drugs have almost become redundant and 'old fashioned'. The pharmaceutical companies are vying with one another to churn out such 'innovative' combinations and the latest in this list are combinations of paracetamol + nimesulide and paracetamol + tizanidine, a muscle relaxant.

There is no synergism when two drugs acting on the same enzyme are combined. Thus combining two NSAIDs or NSAID with analgesics like paracetamol does not and cannot improve the efficacy or potency of treatment. If at all, it only adds to the cost of therapy and more important, to the adverse effects. And the 'muscle relaxants' in some of these combinations are of questionable efficacy.

Product	Price (in Rupee per tablet)	Cost of drugs when given as separate tablets
Paracetamol 500 mg	0.40
Ibuprofen 400 mg	0.67
Diclofenac 50 mg	0.45
Nimesulide 100 mg	1.00 - 3.50
Methocarbomol 500 mg	2.65
Chlorzoxazone 500 mg	3.70
Ibuprofen 400 + Paracetamol 500	1.20 - 1.30	1.07
Diclofenac 50 + Paracetamol 500	0.70-1.60	0.85
Diclofenac 50 + Paracetamol 500 + Chlorzoxazone 500	4.50 - 5.00	4.55
Nimesulide 100 + Paracetamol 500	2.40	1.40

It is clear then, the pharmaceutical companies in India are selling (dumping) their stocks of NSAIDs by shrewd marketing ploys and at a premium price. Even if these drugs are to be administered together, it would be cheaper to give them as individual tablets than as the combined pills. Doctors are misled and patients are robbed in the day light!

Combinations of NSAID/analgesics with antispasmodic agents are also available. These are not only irrational but also could be dangerous. The antipyretic drug promotes sweating and thereby helps in heat dissipation. On the other hand, the anticholinergic antispasmodic drug inhibits sweating. Combining these two can result in dangerous elevation of the core temperature. Some such fixed drug combinations are now banned in India.