PAIN RELIEF USING NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS): MECHANISMS OF ACTION AND THE RISE AND FALL OF VIOXX.
Pain is an unpleasant feeling which signals to an injury. Pain can be of different forms. It can be acute or chronic pain. Acute pain starts suddenly and does not last for a long period whereas chronic pain lasts for a prolonged period. this type of pain can be due to a prevailing chronic disease .acute pain has few minor side effects like increased heart rate, high blood presure,rapid breathing. Chronic pain might have side effects such as depression, low energy levels, loss of interest in activities, disturbed sleep, etc. Each and every person has a different tolerance level towards pain. Pain can be treated in different ways, but the relief from the pain differs from person to person.
Pain can be due to some underlying disorder. Treatment directed towards the disorder can be a great relief from pain. Sometimes even after the treating the disorder some pain relievers such as analgesic may be needed to reduce the intensity of the pain temporarily.
Pain which is caused due to an injury is transmitted through an electrical signal through the peripheral afferent nerves in the spinal cord to the brain. These afferent fibers have some sensory nerve endings which is capable of sensing the signal. This signal is then sent to the central nervous system. Finally the signal is received by the b rain for further processing. This whole process is known as nociception.since the nociceptor neurons are nonmylinated they transmit the stimuli in a very slow pace to the brain.
There are three types of nociceptor neurons:
1) A δ mechanosensitive receptors: these are the neurons which are lightly mylienated and are capable of responding to the mechanical stimulus (pressure and touch) and can conduct in a faster rate.
2) A δ mechanothermal receptors: they have the same property as the mechanosensitive receptors but they can respond to mechanical stimulus as well as heat.
3) Polymodal nociceptors (C fibers): these are the class of neurons which are unmylienated and they respond to a variety of stimulus and conduct in a slow manner.
When we suffer from a sudden pain the signal produced by the sensory nerve fibers reaches the brain. Then this signal gets processed in the brain and it is sent to the motor cortex then down to the spinal cord and to the motor nerves. The impulse produced by these nerves leads to the muscle contraction so as to move away from the source which is causing the pain.
Pain management can be carried out through several methods like medication, surgery, hypnosis, acupuncture; etc.each medicine has its own way of interaction with the pain pathway. The pain medication prescribed depends solely upon the site and the source of the pain. The pain medication (analgesics) is chosen based on the duration and the type of the pain.
Analgesics can be classified into three main types:
1) Opioid analgesics: they act by binding to the natural opioid receptors of the central nervous system in turn they inhibit the ascending pain pathway and activate the descending pain pathway. These analgesics are usually administered in the case of high levels of pain. Prolonged usage of opioid analgesics may lead to the addiction of the drug. Drugs such as morphine, meripidine (Demerol), codeine, and oxycodone fall under the category of opioid analgesics.
2) Non - opioid analgesics. they are administered in the case of a mild moderate pain. These drugs usually act directly on the site of the pain. The tissue which is damaged due to an injury releases a particular enzyme to activate the local pain receptors. The non opioid analgesic hinders the enzyme and thus reduces the inflammation and pain. Drugs such as aspirin, acetaminophen, ibuprofen, and naproxen come under this category of analgesics.
3) Adjuvant analgesics: these analgesics are used to treat pain usually related to the central nervous system and other kind of pains. The antidepressants, antiepileptic, anticonvolusants, etc come under this category of pain medications.
Non steroidal anti inflammatory drugs (NSAIDs): most of the NSAIDs come under the category of the non opioid analgesics. An NSAID does not only reduce pain but also the inflammation caused due to the pain. Sometimes the NSAIDs are combined with the opioid analgesics for the treatment of pain. The most commonly used NSAID s is Aspirin.
Mechanism of action of NSAIDs:
Most NSAIDs act by reducing the production of prostaglandins and thromboxane from arachidonic acid.this id carried out by the selective inhibition of the cyclooxygenase enzyme COX-1 and COX-2.the production of prostaglandin is responsible for the cause of inflammation as a result of the pain. Mostly all NSAIDs block both the COX enzymes, but in exceptional case of the coxibs which inhibits only the COX-2 enzyme, which relieves pain and inflammation.
Although the NSAIDs help in the reduction of pain they have many side effects. Prolonged usage of the drug may cause damage to the stomach lining, excess bleeding, peptic ulcers, etc.except aspirin all other NSAIDs constitute to the increased occurrence of heart attack and blood clot. Doctors usually prescribe NSAID s along with an antacid so as to decrease the chances of the gastro intestinal lining. It is shown that the coxibs (COX-2 inhibitors) have lesser effect on the stomach but may cause more bleeding.
Previously Aspirin was known as the drug which had only anti-inflammatory effects, analgesic effects. Initially Aspirin was used to treat migraines and it was widely used s a pain killer and an antipyretic to treat fever. But the recent research has shown many more advantages of aspirin.
Low dose aspirin is effective in cardiovascular disorders because of its low platelet action. It creates a patch to cover the damage of the walls of the blood vessels, thus blocking the blood flow. Low doses of aspirin can be administered after a heart attack to prevent the occurrence of a blood clot or a second heart attack.
Prolonged usage of aspirin reduces the chances of colon cancer and rectal cancer. Evidence also proves that aspirin reduces the risk of Alzheimer's disease.
Aspirin carries out all these effects by the decrease in the production of prostaglandins and thromboxane.this is done through an irreversible inactivation of the COX enzyme. Aspirin acts as an acetylating agent where an acetylating group is covalently attached to the serine residue in the active site of the COX enzyme.
Aspirin irreversibly inhibits the COX -1 enzyme and thus alters the activity of COX-2.new drugs have been invented which selectively inhibits only the COX-2, and this may have a decreased effect on the gastro intestinal damage. The COX-2 inhibitor which was produced in the name of VIOXX was recently withdrawn because of the increase in the rate of heart attack.
Rofecoxib an non steroidal anti inflammatory drug which was marketed under the trade name Vioxx by Merck & co. This drug was used to treat osteoarthritis, acute pain, Dysmenorrhoea and menstrual cramps. Vioxx was widely accepted by the physicians and initially it was prescribed to 80 million people for the treatment of pain.
In the year 2004, Merck withdrew Vioxx from the market. They stated that when Vioxx was consumed in a high dose continuously for a long time it increased the risk of heart attack. Although short time usage of the drug causes stomach ulcers, they occur less frequently when compared to other NSAIDs.Some major side effects of rofecoxib were headache, abdominal pain, dyspepsia, diarrhea, nausea, heartburn, insomnia, urinary tract infection, etc.
As mentioned before the action of the NSAIDs is mediated by non selective inhibition of the two COX enzymes.COX-1 mediates the production of prostaglandins which plays a major role in the protection of the stomach lining.COX-2 mediates the production of the prostaglandins which controls the pain and inflammation. Vioxx which was a selective inhibitor of the COX-2 enzyme had the side effect of heart attack.
An comparative study of efficacy and the adverse effects between naproxen and rofecoxib was carried out by VIGOR(Vioxx GI Outcomes Research) , conducted by Bombardier, et al.VIGOR over a time span of 12 months indicated an 4 fold increase risk of acute myocardial infarction (heart attack) in patients prescribed with rofecoxib than naproxen.
In the year 2001, Merck commenced another study APPROVe (Adenomatous Polyp Prevention on Vioxx).this was a three year trial which was started to evaluate the cardiovascular safety of rofecoxib. The results of the study showed that there was an increased risk of thrombotic cardiovascular events .this occurred after 18 months of administration of the drug to the patient. This suggested that the prolonged usage of rofecoxib resulted in twice the risk of heart attack when compared to the placebo patients.
After the APPROVe study conducted by merck, they officially withdrew Vioxx from the market worldwide. After its own study in the year 2004 FDA reported that Vioxx caused 88,000 to 136000 heart attacks, out of which 40% was fatal.