Analgesics

Analgesics are drugs that relieve pain selectively, without affecting consciousness or sensory perception. This is the important distinction between analgesics rift gold and anesthetics. Intensive research on the biochemistry of analgesia from the 1970s has shown that there are two main classes of analgesics. The first, opioids, combine chemically with molecular ‘‘receptors’’ in the brain to block pain impulses in the central nervous system. Nonsteroidal anti-inflammatory drugs (NSAIDs) alleviate pain by inhibiting the production of prostaglandins, hormone-like substances that cause local inflammation and pain at the site of an injury or infection. Opioid analgesics can be used for short-term or long-term relief of severe pain; NSAIDs are used to relieve moderate pain, such as headaches, superficial injuries, or muscle strain.

Opium, the dried, powdered sap of unripe poppy seedpods, has been used as an analgesic since antiquity. Over 20 different alkaloids are found in dry opium, of which the most important is morphine. The correct chemical structure of morphine was proposed in 1925 and confirmed by total synthesis in 1955. Morphine, administered by subcutaneous injection, effectively relieves pain, but there are various side-effects such as drowsiness, respiratory depression, nausea, and vomiting. The analgesic effect peaks at about 1 hour after administration and lasts 4–5 hours. Morphine users develop physical dependence on the drug and become tolerant to it. Increasing doses are needed to maintain its effectiveness, and serious withdrawal symptoms accompany the cessation of morphine medication. Codeine, another naturally occurring opium alkaloid, is a less potent analgesic than morphine, but it is also less addictive and produces less nausea than morphine. It can be administered orally and is often used in conjunction with aspirin. Meperidine (Demerol), a synthetic morphine analog identified in 1939, was originally thought to provide short-lasting analgesia without addiction, but this proved false and the drug was widely abused. It is still the most common drug used for pain relief in childbirth and has superseded morphine. The side effects of meperidine are similar to those of morphine but are less severe and are further reduced when given with the antihistamine drug promethazine. In prolonged use meperidine may cross the placental barrier, and the drug has been found in newborn infants. Heroin, introduced in 1898, was also falsely heralded as a nonaddictive alternative to morphine. It is about ten times more potent than morphine when administered intravenously and is still used clinically for its analgesic properties in some countries, though it is not generally available for therapeutic purposes due to its highly addictive propensities. Methadone, a synthetic opioid analgesic discovered in Germany during World War II, has long-lasting analgesic effects when taken orally, and, as it alleviates the euphoriaproducing effects of heroin, it is used to control the withdrawal symptoms of heroin addiction. The opioid analgesics were formally called narcotic drugs as they induce sleep and cause physiological dependence and addiction. The term is less commonly used in medicine because many drugs other than opioids also show these effects. In 1973 complex compounds called opioid receptors, which can combine with opioid molecules, were discovered in the brain, hypothalamus, and spinal cord. At least eight such substances are known, though only four are thought to be important to the central nervous system. The best understood is the m receptor, which affects euphoria, respiratory depression, tolerance, and analgesia. The k receptor is also involved in analgesia as well as diuresis, sedation, and physical dependence. Soon after discovery of these receptors, peptide-like compounds consisting of chains of amino-acid residues and showing opioid properties were found in the pituitary gland. Three groups of endogenous opioid peptides known as endorphins, enkephalins, and dynorphins were discovered around 1975. Found to be neurotransmitters, one of the most important is b-endorphin, consisting of a chain of 30 amino acid residues. It is synthesized, stored, and released from cells in the pituitary gland, and it can also be prepared synthetically. Injected intravenously, b-endorphin is three times more potent than morphine. Interest in these drugs intensified when two potent analgesic pentapeptides, each containing five linked amino acids, were found in extracts of pig brain. Named enkephalins, they are derived from endorphins. They can be prepared synthetically and injected intravenously to induce analgesia by combining with receptors in the brain in the manner of the opioids.

Several chemically unrelated groups of organic compounds also show mild analgesic properties. They include derivatives of salicylic acid, pyrazolone, and phenacetin. These nonopioid drugs are often self-prescribed, though continued use can lead to adverse effects including drug abuse and addiction, allergic reactions, gastrointestinal irritation, and fatal overdose. The oldest and most widely used nonopioid analgesic is acetyl salicylic acid, or aspirin, first developed and marketed in 1899 by the German chemical company, Bayer. In addition to its analgesic properties, aspirin reduces fever and inflammation by inhibiting the synthesis of prostaglandins. The irritant effect of large doses of aspirin on the stomach lining may result in gastric ulcers. Hypersensitivity to aspirin and related drugs is thought to be due to the accumulation of prostaglandins after the pathways that break them down are blocked. All aspirin-like analgesics inhibit prostaglandin synthesis, and their potency depends on the degree to which they do so. Many share similar side effects, some of which can be serious. However, the inhibition of prostaglandins also reduces the ability of blood platelets to form clots and this effect has given aspirin added value as an antithrombotic drug.

As the mechanisms of analgesic action began to be understood, alternatives to aspirin were introduced. Acetaminophen, a derivative of phenacetin introduced in 1956, is a popular alternative drug that avoids severe symptoms of stomach irritation. This mild analgesic and antipyretic however has much weaker anti-inflammatory properties, and overdoses can cause liver rift gold and kidney damage. Pyrazolone analgesics such as phenylbutazone show similar properties to aspirin and have been used to treat rheumatoid arthritis. Recently potent NSAIDs, sometimes called ‘‘super-aspirins,’’ are widely used to replace aspirin itself. These include the propionic acid derivatives, naproxen (first made by Syntex in 1979), ketoprofen (by Wyeth in 1986) and ibuprofen. The latter, manufactured by Upjohn in 1984, is much more potent than aspirin, causes fewer side effects, and is beter tolerated by most individuals. In large doses or prolonged use however, it can cause all the symptoms of other inhibitors of prostaglandin synthesis including gastric irritation and renal toxicity.