Fixing the pain

Fixing the pain

Though COX II inhibitors were regarded a viable option to non steroidal anti inflammatory drugs (NSAID), this claim was soon shot down by controversies surrounding it. Sachin Jagdale looks into various aspects surrounding COX II inhibitors

The last decade saw many conventional forms of medicines getting replaced with new ones that were thought to be more effective than their predecessors. One such class of drugs, non steroidal anti inflammatory drugs (NSAIDs), have carried the legacy of treating inflammation and pain quite successfully. However, they were soon challenged by COX II inhibitors, though with a mixed success ratio.

The COX II enzyme was discovered in I988 by Dr Daniel Simmons, a Brigham Young University researcher, formerly of Harvard University. Simmons was quick to sense the importance of this discovery and the same day the enzyme was sequenced. Prostaglandins (a kind of chemical messenger) are divided in to two parts depending on their function. The ones that are synthesised with the help of cyclooxygenase-I (COX I) enzyme are responsible for the safety of the gastrointestinal track, while on the other hand, those synthesised by using cyclooxygenase- II (COX II) enzyme lead to inflammation and pain. Efforts to discover COX II inhibitors led to some promising candidates like rofecoxib, celecoxib and valdecoxib that were marketed under the brand names Vioxx, Celebrex and Bextra. Each of these drugs had different levels of effectiveness against inflammation and pain.

Potent remedy

“Conventional Non Steroidal Anti Inflammatory Drugs ( NSAIDs) are very effective for pain control. They act on both COX I and COX II enzymes. Newer COX II inhibitors do not act on COX I and block COX II enzyme”

– Dr Milind Ghare Consultant rheumatologist

L H Hiranandani Hospital, Mumbai

The COX II enzyme is present in the body at areas responsible for inflammation, and not in the stomach like COX I. So, blockage of COX II would reduce inflammation and will not affect the stomach lining or intestinal tract. Medicines blocking COX II never induce the same risk as compared to the COX I enzyme. So those specific blockers of COX II enzyme are known as COX II inhibitors. Rheumatologists have their own justifications in terming COX II inhibitors as one of the most promising anti inflammatory agents. Dr Milind Ghare, Consultant Rheumatologist, L H Hiranandani Hospital, Mumbai, said, “Conventional NSAIDs are very effective for pain control. They act on both COX I and COX II enzymes. Newer COX II inhibitors do not act on COX I and block only the COX II enzyme, which is induced during inflammation and is responsible for increased pain during inflammation. Therefore, COX II drugs are potentially the most promising anti-inflammatory and analgesic drugs.” Dr Kaushik Bhojani, Rheumatologist, Wockhardt Hospitals, Mumbai, gives mixed opinion on the potential that COX II inhibitors might hold. He says, “These were touted to have lesser side effects, particularly lesser gastro intestinal side effects. Also initially, they were expected to have lesser harmful effects on the kidney. However, this theory was later disapproved.”

Better than competitor

COX II inhibitors outweigh conventional NSAIDs to some extent, though not up to the level where market will abandon conventional NSAIDs. COX II gets the priority treatment. “COX I enzyme is essential for normal function of many organ cells in the body. Conventional NSAIDs block both COX I and COX II. Blockage of COX I enzyme is responsible for potential serious side effects associated with NSAIDs such as acid peptic disease and gastrointestinal bleeding, kidney toxicity,” opines Ghare. However, on the other hand, Bhojani does not find any significant benefit of COX II other than lesser gastro intestinal side effects. According to Dr Shashank Akerkar, Consulting Rheumatologist, Godrej Memorial Hospital, COX I is thought to be the housekeeping enzyme, is present in the gastric mucosa and is responsible for its protection. The discovery of COX II blockers was hence thought to be a major breakthrough as they block inflammation without causing gastritis.

Side effects

“COX II inhibitors were touted to have lesser side effects particularly lesser gastro intestinal side effects. Also initially they were expected to have lesser harmful effects on the kidney. However this theory was later disapproved”

– Dr Kaushik Bhojani Rheumatologist

Wockhardt Hospitals, Mumbai

But all is not well even with COX II inhibitors. Due to some of the life threatening side effects of COX II inhibitors, they have become more of an option rather than the definite treatment. Voluntary withdrawal of Vioxx on September 27, 2004 due to the possible risk of myocardial infarction and stroke was one such example. Post their introduction in I999, Celebrex and Vioxx climbed the popularity charts very rapidly. Moreover, they became the most common prescription on prescription pads in the United States. Within a year by October 2000, their US sales exceeded 100 million prescriptions per year for $3 billion, and were still rising, sales of Celebrex alone reaching $3.1 billion in 2001.

Ghare elaborates, “Each drug has side effects. Even excess vitamins and excess water intake is harmful. Similarly COX II drugs are not magic bullets. They block COX I as well to some extent and do have side effects (selective COX II blockade degree of selectivity varies from drug to drug). Therefore, all these drugs should be used judiciously selecting the patient appropriately.”

Cardiovascular side effects, thrombosis and Stevens Johnson Syndrome (a serious allergic skin reaction) are the most severe side effects of COX II inhibitors. Side effects vary according to the patient and his/her dosage. Cardiovascular conditions, accompanied by occurrence of Stevens Johnson Syndrome, forced regulators to closely scrutinise all COX II inhibitors, and finally, led to the recall of two of them. The list of notorious COX II inhibitors is big and researchers have been compelled to take notice of them due to their severe side effects. Forbes magazine had quoted a Cleveland Clinic cardiologist as saying that to properly examine the cardiovascular risk issue, researchers need to specifically study arthritis patients who already have coronary heart disease, or are at a very high risk of getting it soon.

Opining on the ethico-legal aspect of COX II inhibitors use, Ghare says, “After Vioxx was marketed and was very successful, it was gradually noted in its post marketing surveillance that there was an increased morbidity and mortality from cardiovascular diseases. Although, the toxicity was limited in specific age group with underlying cardiovascular conditions; Merck decided to withdraw the drug as a result.”

Studies have shown that besides being anti-inflammatory in nature, COX II inhibitors have some other useful effects as well. Most prominent is their possible role in the treatment of cancer. Bhojani informs, “There have been encouraging results in colonic polyps and the inhibitors have also been used in Alzheimer’s disease where they tend to retard the progression of disease.” The right use of COX II reaps more benefits. These drugs are generally safe when used appropriately. “They are very good analgesics and anti inflammatory. They are used preoperatively as these drugs do not have significant anti platelet effect and do not increase risk of bleeding,” says Ghare. These drugs also do not have any significant interaction with commonly used anaesthetics, muscle relaxants, do not cause respiratory depression and are a safe and effective choice before and after surgery.


COX II inhibitors have been looked upon as the potential treatment of neuroblastoma. If Akerkar is to be believed, research on the possible use of COX II blockers in prevention and treatment of various malignancies will be high on the wish list of researchers.

Research in this direction will definitely be productive for researchers. With time, it is being realised that many more conditions and diseases in humans are inflammatory in nature.

“Inflammation is either the central cause or is contributing to acceleration of the disease. This is mostly seen in atherosclerosis (with resultant coronary artery disease, strokes etc.) Alzheimers disease etc,” says Ghare. There is more interest in using anti inflammatory drugs, including COX II drugs in treatment and prevention of such conditions. COX II inhibitors have received a mixed response over the last one decade. However, to survive on the shelf, COX II inhibitors should first inhibit the clouds of suspicion hovering over it.