The early history of non-opioid analgesics

The late 19th century gave rise to the discovery of the three prototypes of modern non-opioid antipyretic analgesics: acetaminophen (acetanilide), aspirin and salicylic acid, and phenazone. At three different sites at almost the same time in Germany the zest for finding substitutes for quinine, ie antipyretic drugs, led to synthetic efforts culminating at Erlangen in the synthesis of phenazone (antipyrine), at Strasbourg of acetanilide (antifebrin), and at Wuppertal of aspirin (acetylsalicylic acid). The rationales for synthesising these drugs were not stringent, but proved, nonetheless, successful. Thereafter chemists concentrated their attempts merely on modifying the drugs discovered with the help of the rapidly expanding and improving organic chemistry. Although no new principles were discovered, the ‘relatives’ of the originals, namely aspirin and its modifications, acetaminophen and propyphenazone, as well as dipyrone, still make up for about 50% of the market of the antipyretic analgesics worldwide. Some of these compounds have attracted new interest recently. This is particularly the case with dipyrone (metamizole, Novalgin). After more than 50 years of clinical use (without major research efforts) state of the art investigation was commenced, and at its 75th birthday this compound is now thoroughly investigated. The side effect profile and risks, as well as the pharmacokinetic parameters, are defined and the mode of action has been elucidated. Although several clinical studies show effectiveness, probably due to the 75 year-long worldwide experience, modern therapy orientated studies proving usefulness in specific indications, claimed by many physicians and patients (eg after bone marrow transplantation, against migraine, and in osteoarthrosis), are still unavailable. In this respect, further research efforts and extension of knowledge is required, since this drug lacks gastrointestinal and renal toxicity, blood coagulation is only marginally influenced, and the widely discussed agranulocytosis is extremely rare and nearly never fatal.