ABSTRACT

Analgesic substances from plants that were known from ancient time include salicylates from willow bark and opiates from the poppy Papaver somniferum. The analgesic properties of morphine and cocaine (from Erythroxylon coca) were used medically from the middle of the 19th century. Purification of the active components occurred in the 19th century and structures were determined by the 1920s. The addictive properties of opiates and cocaine led to their banning by the Harrison Narcotics Act in 1912. The first synthetic analgesics were made in the late 1800s and included antipyrine, aspirin, and phenacetin. Systematic searches for improved analgesics began after WWII and led to the NSAIDS (nonsteroidal anti-inflammatory drugs) including ibuprofen and naproxen. Investigation of the metabolism of phenacetin identified acetaminophen as the active metabolite and led to its introduction in the United States as Tylenol in 1955. Many analogs of morphine were synthesized and shown to have both the analgesic and addictive characteristics of morphine. Some have specific medical application such as short-term analgesics in diagnostic procedures. Investigation of the mechanism of action of aspirin and the NSAIDS identified prostaglandin formation by cyclooxygenase as the target enzyme. Recognition that two forms of the enzyme existed led to the synthesis of selective inhibitors of cyclooxygenase-2, known as coxibs. They showed reduced gastrointestinal side effects but increased the risk of cardiovascular events. Use of cocaine as a topical anesthetic began in the 1800s and was followed by the introduction of synthetic analogs including benzocaine and procaine (Novocain) and several others used widely in dentistry. The use of chloroform and ether as inhaled anesthetics began in the mid-1800s. They have been replaced by safer halogenated hydrocarbons such as halothane and isoflurane. Intravenous general anesthetics such as propofol and etomidate were also introduced.