Analgesics, Antipyretics, and Antiinflammatory Agents
Authors: Nugent Richard A. , Hall Charles M. 
Published: July 2004

AbstractPain, pyresis, and inflammation are distinct physiological responses which can occur independently; they are often associated as the body mounts a response to an injury or insult. The twentieth century has seen considerable progress in the understanding of pain and inflammation. It is increasingly apparent that the central and peripheral nervous systems are capable of causing the production of mediators which can attract and activate inflammatory cells, thereby initiating or amplifying an inflammatory response. A number of interdependent physiological mechanisms, allowing for the development of new treatments for pain, pyresis, and inflammation, have been discovered. At least eight distinct types of opioid receptors have been identified and the corresponding individual functions are beginning to be understood. A great deal has been learned about the role of lipid mediators in the inflammatory response and how antiinflammatory agents control their production. Morphine effectively relieves pain and increases an individual's ability to tolerate a painful experience. It also produces a broad range of other effects, including drowsiness, mood changes, respiratory depression, nausea, decreased gastrointestinal motility, and vomiting. An important feature of morphine and related drugs is the development of physical dependence on, and tolerance to, some of the effects. Codeine is a significantly less potent analgesic than morphine. However, codeine is orally effective and is less addictive. Introduced in 1898, heroin showed itself to be highly addictive and is preferred by addicts over morphine. Synthetic analogues of morphine have been prepared. The replacement of theN‐methyl group on the nitrogen atom of the piperidine ring of morphine and analogues, by allyl, isopropyl, or methyl cyclopropyl, an isopropyl isostere, results in compounds which antagonize opioid responses, especially respiratory depression. Naloxone, C19H21NO4, and naltrexone, C20H23NO4, when administered with an opioid analgesic, promptly reverse the effects produced by the opioid agonist. The ability to antagonize opioids at all of the different opioid receptors makes naloxone useful for the treatment of opioid overdose. Naltrexone has a similar profile. The quest for compounds that combined the analgesic properties of morphine, were nonaddictive, and lacked side effects, led to the development of the drugs that have both agonist and antagonist activities. Nalbuphine blocks the effects of the morphinelike drugs. Pharmacologically, the effects of these drugs resemble those of opioid agonists. Most of the time, powerful analgesia is not needed. Rather, a mild analgesic, such as aspirin, can be used for the treatment of simple pain. Aspirin, the oldest of the nonsteroidal antiinflammatory drugs (NSAIDs), is a member of the salicylate group. Aspirin's pain relief results through peripheral action. The action of endogenous pyrogens on the hypothalmus produces fever. Salicylates and other NSAIDs achieve their antipyretic effect by controlling the prostaglandin‐induced release of pyrogens. A second class of NSAIDs, the so‐called coal‐tar analgesics, are derived from acetanilide. Although it is no longer used therapeutically, its analogues, phenacetin and the active metabolite, acetaminophen, are effective alternatives to aspirin. They have analgesic and antipyretic effects that do not differ significantly from aspirin, but they do not cause the gastric irritation. A more recently introduced, nonprescription analgesic is the aryl propionic acid, ibuprofen. A cyclooxygenase inhibitor, ibuprofen displays good antiinflammatory activity. It is more potent than aspirin and has a lower incidence of gastrointestinal irritation. The adrenal cortex produces steroidal hormones that are associated with carbohydrate, fat, and protein metabolism, electrolyte balance, and gonadal functions. One of these, cortisone, C21H28O5demonstrated a remarkable ability to relieve the symptoms of inflammatory conditions. Other glucocorticoid steroids, such as dexamethasone, C22H29FO5and prednisolone, C21H28O5, also have antiinflammatory properties. These steroids are capable of preventing or suppressing the development of the swelling, redness, local heat, and tenderness which characterize inflammation. Unfortunately, while steroids merely suppress the inflammation the underlying cause of the disease remains. Another serious concern is that of toxicity. Long‐term use of steroids may induce osteoporosis, peptidic ulcers, the retention of fluid, or an increased susceptibility to infections. Because of these problems, steroids are rarely the first line of treatment for any inflammatory condition, and their use in rheumatoid arthritis begins after more conservative therapies have failed. Analgesics and antiarthritics represent significant worldwide pharmaceutical markets.