Pain Relief Using Non Steroidal Antiinflammatory Drugs Biology Essay

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Non-steroidal anti-inflammatory drugs are a class of drugs that possess analgesic properties and are the most commonly used drugs in the management of acute and chronic pain. NSAIDs also have anti-inflammatory effects and antipyretic effects (reduction of temperature during fever) (Rang, Dale et al. 2007). Although there are some variations, drugs of this family achieve their effects primarily via inhibition of the enzyme cyclo-oxygenase (COX). COX exists as three isoforms; COX-1, COX-2 (inducible) and COX-3. COX-1, the first isoform to be identified, is constitutively expressed in the body under basal conditions where it functions to maintain gastric mucosa, cause platelet aggregation and produce vascular prostacyclin (a potent vasodilator). Therefore, inhibition of COX-1 is undesirable (Gotlieb, 1999), and is what causes side effects such as prolonged bleeding, gastrointestinal ulcers and compromised renal blood flow (Rang, Dale et al. 2007). COX-2, on the other hand, is expressed only in inflammatory cells, and is responsible for the production of prostanoids (prostaglandin E2, prostacyclin and thromboxane A2) which are involved in mediating the inflammatory-response. Currently, the role of COX-3 in humans is not understood. The physiological effects of COX-1 and COX-2 are summarised in figure 1 (below):


FIGURE 1 An overview of the effects of COX-1 and COX-2, and the drugs

that inhibit their actions (self-produced).

Drugs belonging to the NSAID class are generally non-selective, i.e. they inhibit both COX-1 and COX-2 isoforms, e.g. aspirin and ibuprofen. However, a newer class of NSAIDs that became available in the late 1990s are COX-2 selective (coxibs). The selectivity of NSAIDs for COX-1 and COX-2 is determined by the size of their side groups. COX-1 and COX-2 have very similar structures. In fact, they only differ by a few amino acids - the most important amino acid change being from Ile-523 in COX-1 to Val-523 in COX-2. This single amino acid change allows access to a deeper hydrophobic pocket in COX-2 not accessible in COX-1 (due to bulkiness of isoleucine compared to valine), which causes a 25% increase in size of the active site (Knights et al., 2010). The deep cavity of COX-2 therefore permits entry of NSAIDs with larger side groups in comparison to COX-1 which cannot accommodate larger side groups - this is the basis of COX-2 specificity among various NSAIDs (Rang, Dale et al., 2007). Despite this, once both non-selective and COX-2 selective inhibitors are inside COX-1 or COX-2, they cause inhibition in the same way by forming hydrogen bonds with Arg-120 and blocking entry of the arachidonic acid substrate into the catalytic domain. In general, inhibition of COX-1 is reversible and occurs more rapidly than inhibition of COX-2, which is largely irreversible. Figure 2 (below) shows the critical residues in the structures of the COX isozymes:

FIGURE 2 Comparison of the critical residues in the COX isozymes.

Ile-523 and Val-523 of COX-1 and COX-2 respectively are crucial in determining whether or not an NSAID can enter. COX-2 exposes a deeper cavity in which the substrate can enter; hence COX-2 selective inhibitors (with large side groups) may enter only COX-2.

Isoleucine to valine substitution opens up the hydrophobic 'side' pocket in COX-2 relative to COX-1, 2010. [Online image] Available at: [Accessed February 2nd 2011]

COX-1 and COX-2 produce prostanoids from arachidonic acid or other fatty acid substrates through very similar mechanisms. COX-1 and COX-2 are associated with haem and exist as homodimers in intracellular membranes. They are bifunctional enzymes, and thus catalyse two distinct reactions (Rang, Dale et al., 2007). In the first step, also known as the dioxygenase step, 2 molecules of O2 are added to carbons 15 and 11, to form the cyclised and oxygenated intermediate PGG2 (prostaglandin G2). PGG2 then undergoes a peroxidase reaction in which it is converted to PGH2 (prostaglandin H2), with a hydroxyl group at carbon 15. From here, isomerases, reductases or synthases can convert PGH2 into other prostanoids such as thromboxane A2 (TxA2), PGE2 and PGI2 (Griffin, 2008). Figure 3 (below) summarises the role of COX enzymes in prostanoid synthesis:

FIGURE 3 Mechanisms catalysed by COX in the synthesis of prostanoids. COX enzymes are bifunctional enzymes that catalyse two steps, resulting in production of PGH2. This is then converted to other prostanoids using isomerases, reductases and synthases.

Adapted from: Cyclooxygenase conversion of arachidonic acid into prostaglandin H2 (PGH2), 2008. [Online image] Available at: [Accessed February 2nd 2011]




The rationale for the development of COX-2 selective inhibitors was to avoid gastrointestinal disturbances such as haemorrhages and ulceration associated with COX-1 inhibition (NMIC, 2000), which are debilitating, and in the worst cases can be fatal. It is estimated that 34-46% of patients on long-term NSAID therapy experience some kind of gastrointestinal disturbance (Vinod et al., 2008). COX-1 is responsible for the protection of the gastric mucosa and inhibition of acid secretion, achieved by the production of prostaglandins.

Rofecoxib (trade name = Vioxx) was a COX-2 selective inhibitor, or ‘coxib’, that was developed for the treatment of arthritis in 1999 but was withdrawn from the market in 2004 due to increased risk of myocardial infarction and stroke (Topol et al., 2004). This was the biggest drug recall in history, since as Merck & Co., the drug company that produced Vioxx, generated $2.5billion the preceding year from Vioxx sales alone (Reuters, 2006). The first line of evidence against Rofecoxib that came to light was from the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, conducted in 2000. This study revealed that amongst rheumatoid arthritis patients that were administered either rofecoxib or naproxen; the incidence of myocardial infarction in the rofecoxib patients was five times greater than the naproxen patients (Topol et al., 2004). This is now known to be an underestimate, since as other severe cardiovascular effects such as stroke and thromboses had not been completely reported. In 2001, Dr Eric Topol, the first physician to speak out against Vioxx, published a review article in the Journal of the American Medical Association (JAMA) alongside two other researchers, entitled Risk of cardiovascular events associated with selective COX-2 inhibitors. In this article, they reviewed previous clinical trials of Vioxx and concluded that it caused a three-fold increase in likelihood of blood clots, myocardial infarctions and stroke (Topol et al., 2001). Presented with this new evidence, Merck & Co defended itself by suggesting that previous clinical trials were flawed and that the reason why incidence of myocardial infarction in Vioxx patients was significantly higher than in naproxen patients was because naproxen exhibited cardioprotective properties. This, however, was never proven (Topol et al., 2001). Succeeding the research conducted by Topol et al, a series of additional studies were conducted, all producing further evidence that Vioxx caused increased risk of myocardial infarction in comparison with other NSAIDs or COX-2 specific inhibitors. Despite all this evidence against Vioxx, Merck & Co. still concluded that the studies were flawed. Not only did Merck & Co. fail to respond to the evidence, but the food and drug authority (FDA) also ignored the evidence, and did not demand that Merck & Co. conduct its own investigations in defence. In a 2001 study conducted by Robert S. Bresalier of the Anderson Cancer Centre, University of Texas, Vioxx was tested for its ability to prevent recurrent colon polyps in patients that had pre-cancerous colon polyps removed. This trial, called the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial, was sponsored by Merck & Co., and an independent review was carried out alongside this trial to investigate the incidence of myocardial infarction or stroke among the subjects. After 18 months of Vioxx therapy, it was found that incidence of such thrombotic cardiac events increased by 1.6% (almost doubled). Upon this result (September 30th 2004), Merck & Co. recalled Vioxx from the market voluntarily (NCI, 2005). This recall drew attention to other coxibs being prescribed at the time and led to the drug company Pfizer recalling valdecoxib (trade name = Bextra) from the market in April 2005. This was due to an increased risk of myocardial infarction, stroke and various serious skin conditions, which were acknowledged the previous year (FDA, 2005).



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