Anti-inflammatory analgesics

Several chemically unrelated series of complex organic acids have the ability to relieve mild to moderate pain through actions that reduce inflammation at its source. The prototype of this class of drugs is acetylsalicylic acid, or aspirin. Like aspirin, many of the drugs of this class also reduce fever (antipyretic action), and those that resemble aspirin most closely share what is presumed to be its molecular mechanism of action, namely inhibition of the synthesis of prostaglandins (natural products of inflamed leukocytes, which induce the responses in local tissue that include pain and inflammation). These three properties of anti-inflammatory drugs (i.e., analgesia, anti-inflammation, and antipyretic action) vary among the drugs.

Aspirin, which is now made by total chemical synthesis, is the most widely used mild analgesic, although more potent antipyretic analgesics, such as acetaminophen, are available. Super-aspirins, such as indomethacin, were developed in the 1970s as the mechanisms of critical analgesic action, namely prostaglandin synthesis inhibition, came to be understood.

Research has shown that small doses of certain prostaglandins can mimic almost all of the signs and symptoms of localized inflammation. Prostaglandins are naturally occurring by-products of arachidonic acid synthesis. They are thought to be released at the site of inflammation when leukocytes are attracted to injured or inflamed areas. All mammalian cells except red blood cells can produce prostaglandins, and when injured, the cells release large amounts of these substances. All aspirin-like analgesics inhibit prostaglandin synthesis and release, and their varying potencies depend on the degree to which they can do so.

As might be expected from their common mechanisms of action, many of the non-narcotic analgesic drugs share similar side effects. Hypersensitivity responses to aspirin-like drugs are thought to be due to an accumulation of prostaglandins after the pathways that break down prostaglandins are blocked. These responses can be fatal when very strong anti-inflammatory compounds are given. Inhibition of prostaglandin synthesis may result in other serious side effects, such as gastric ulcers (which may also be due in part to the irritant activity of large doses of aspirin on the lining of the stomach) and the reduced ability of platelets in the blood to aggregate and form clots. The latter effect however, has given aspirin an added use as a prophylactic antithrombotic drug to reduce chances of cardiac or cerebral vascular thrombosis. Some of these aspirin-like analgesics also have specific toxic effects: liver damage occasionally occurs after administration of acetaminophen, and renal toxicity and behavioral symptoms are sometimes seen with use of the super-aspirin anti-inflammatory drugs. Aspirin is thought to be a causative agent of Reye's syndrome, a rare and serious degenerative disease of the brain and fatty tissue of the liver that accompanies certain viral infections in children and young adults.

For treatment of mild pain, two types of analgesics can be used as alternatives to aspirin. The first type comprises the para-aminophenol derivatives such as acetaminophen, which is not a particularly useful anti-inflammatory drug. The term nonsteroidal anti-inflammatory agents is generally reserved for the second type of aspirin-like analgesics, the newer class of highly potent compounds sometimes termed super-aspirins. All these drugs inhibit prostaglandin synthesis. The first of this series, indomethacin, has been largely discarded because of side effects. The most widely used of the super-aspirins are the proprionic acid derivatives, such as ibuprofen, naproxen, and fenoprofen. Although these drugs are widely tolerated and can give significant analgesia in moderate doses, they have also been shown to cause all of the side effects of the other inhibitors of prostaglandin synthesis.