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Selective COX-2 Inhibitors: Road from Success to Controversy and the Quest for Repurposing

The introduction of selective COX-2 inhibitors (so-called ‘coxibs’) has demonstrated tremendous commercial success due to their claimed lower potential of serious gastrointestinal adverse effects than traditional NSAIDs. However, following the repeated questioning on safety concerns, the coxibs ‘controversial me-too’ saga increased substantially, inferring to the risk of cardiovascular complications, subsequently leading to the voluntary withdrawal of coxibs (e.g., rofecoxib and valdecoxib) from the market. For instance, the makers (Pfizer and Merck) had to allegedly settle individual claims of cardiovascular hazards from celecoxib and valdecoxib. Undoubtedly, the lessons drawn from this saga…

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 COX-2 inhibitors: a story of greed, deception and death

In 1999, drug manufacturers introduced a class of NSAIDs called COX-2 inhibitors or coxibs. The drugs were avidly promoted directly to the consumers and became bestsellers from the start. Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain, bleeding and other side-effects. In the year after their introduction, doctors wrote over 100 million prescriptions for celecoxib (Celebrex) and rofecoxib (Vioxx). Celebrex is the sixth best-selling drug, with sales of more than US$ 4 billion since its debut in 1999. Vioxx had sales of US$ 2.6 billion in 2001. However, the coxibs increase the risk of heart attacks and strokes, and their price, in the USA, is obscene. The manufacturers faced a possibly complicit, toothless and bloodless FDA, and used every maneuvering to fleece the patients. We must now reflect on attitudes that we thought only belong to the tobacco industry. Fortunately, safe and active alternatives exist.

Articles of Interest

Cardiovascular issues of COX-2 inhibitors and NSAIDs

The selective cyclooxygenase-2 (COX2) inhibitors gained widespread popularity, having equivalent analgesic and antiinflammatory effect as the traditional nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), yet with reduced gastrointestinal (GI) side effects.1–5 However, rofecoxib (Vioxx) was shown to increase the risk of certain cardiovascular (CV) events: myocardial infarct (MI) and ischaemic stroke.6 Cardiovascular safety of all COX-2 inhibitors, and indeed traditional NSAIDs, have since been under intense investigation.

Celecoxib: the “need to know” for safe prescribing

A significant benefit of celecoxib is that it is associated with less risk of gastrointestinal bleeding compared to non-selective NSAIDs. Use of celecoxib is associated with an increase in cardiovascular risk, but this risk is similar to that associated with non-selective NSAIDs.

COX-2 chronology

The role of selective cyclooxygenase (COX)-2 inhibitors in medical practice has become controversial since evidence emerged that their use is associated with an increased risk of myocardial infarction. Selective COX-2 inhibitors were seen as successor to non-selective non-steroidal anti-inflammatory drugs, in turn successors to aspirin. The importance of pain relief means that such drugs have always attracted attention. The fact that they work through inhibition of cyclooxygenase, are widespread, and have multiple effects also means that adverse effects that were unanticipated (even though predictable) have always emerged.

COX-2 inhibitors

COX-2 inhibitors differ from traditional NSAIDs by targeting only the pain-signaling prostaglandins. They do not affect cyclo-oxygenase 1 (COX-1), a chemical associated with protecting the stomach lining.

COX-2 Inhibitors and Cardiovascular Risk

Placebo-controlled trials of nonsteroidal antiinflammatory drugs (NSAIDs) selective for COX-2 have revealed an enhanced risk for cardiovascular events. COX-2 inhibitors (coxibs) selectively reduce vascular prostacyclin synthesis without disrupting COX-1-derived thromboxane synthesis in platelets. Removal of prostacyclin's capacity to restrain all known endogenous compounds contributing to platelet activation and vasoconstriction is a well-recognized mechanism for coxib action in the cardiovascular system which can pre-dispose to thrombosis, hypertension and atherosclerosis.

Cyclooxygenase-2 Enzyme Inhibitors: Place in Therapy

Studies suggest that COX-2 inhibitors are as efficacious as traditional NSAIDs in treating inflammatory disease.20–26 COX-2 inhibitors also have a theoretically more favorable side effect profile than traditional NSAIDs. However, the differences between traditional NSAIDs and COX-2 inhibitors have been small and clinically modest.26 The decision to use the more expensive COX-2 inhibitors should be based on the individual patient's risk of gastrointestinal tract hemorrhage.

Don’t Take These Pain Killers That Slow Down Bone Healing – Do This Instead

We all hope it will never happen. But if it does, you might be surprised to discover that when it comes to fracture healing, the “don’ts” may be just as important as the “do’s”.

Lessons from 20 years with COX-2 inhibitors: Importance of dose–response considerations and fair play in comparative trials

The cardiovascular risks with COX-2 inhibitor or high-dose NSAID treatment that were already noted two decades ago are undisputable today. A growing body of evidence also shows that the risk is increased already during the first weeks of treatment. Of particular importance is the realization that diclofenac carries a similar risk as the COX-2 inhibitors, as suspected early on but very convincingly shown by now. Diclofenac should not be sold OTC.

Lessons to learn from the COX-2 saga

The bad news for the COX-2 pain relievers started in September 2004. Rofecoxib (Vioxx) was pulled from the market after a study testing whether the pain reliever could prevent colon polyps instead showed that it doubled heart attack and stroke risk. In December 2004, it went from bad to worse. The FDA put its strongest "black box" warning on valdecoxib (Bextra), another COX-2 inhibitor. One study of celecoxib (Celebrex), the best seller in the class, showed that it, too, increased cardiovascular risk, although a smaller study gave it a clean bill of health. Pfizer kept Celebrex on the market, but the FDA forced the company to stop advertising it to the public.

NSAIDs between past and present; a long journey towards an ideal COX-2 inhibitor lead

The detection of COX-2 role in inflammation process launched a new era in its management. Several trials have been established to proceed towards selectivity of well-defined anti-inflammatory members. COX-2 selective inhibitors are evidently safer on the gastrointestinal tract than non-selective NSAIDs. Nevertheless, their unexpected cardiovascular risks cannot be ignored.

Potential Risks and Complications of Celecoxib

It is recommended that patients consider the increased risk of major cardiovascular, gastrointestinal, kidney, and liver complications before taking celecoxib. Celecoxib is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

The Coxibs, Selective Inhibitors of Cyclooxygenase-2

In less than a decade after the discovery of cyclooxygenase-2, clinical trials have demonstrated that treatment with highly selective cyclooxygenase-2 inhibitors causes significantly fewer serious gastrointestinal adverse events than does treatment with nonselective NSAIDs. More selective coxibs are already being developed.

The “Aspirin” of the New Millennium: Cyclooxygenase-2 Inhibitors

COX-2 inhibitors are the “next-generation” NSAIDs that may selectively block the COX-2 isoenzyme without affecting COX-1 function. This function. This may result in control of pain and inflammation with a lower rate of adverse effects compared with older nonselective NSAIDs. Rapidly evolving evidence suggests that COX-2 enzyme has a diverse physiologic and pathologic role.

Resources

5 Reasons to Take Astaxanthin Every Day

Even though it’s 100 percent natural, astaxanthin works like some prescription analgesics, but without the risk of addiction, GI bleeds or heartburn. More specifically, astaxanthin blocks COX 2 enzymes just like Celebrex, the blockbuster drug prescribed for osteoarthritis,