Next generation of everyday analgesics.

Pain is the leading symptom of most diseases. Humans have always tried to overcome pain using physical and chemical means, and it is believed that opioids and salicylates present in natural products have been used since prehistoric times. The development of the sciences, in particular chemistry and medicine, in the 19th century led to the discovery of the active ingredients of poppy and willow bark (morphine and salicylic acid). Shortly after, synthetic chemistry provided substitutes produced from coal tar (ie, acetaminophen, aspirin, phenazone, and pethidine). These represent the two main types of analgesics commonly used to treat mild and serious pain: the opioids (pethidine) and the antipyretic analgesics, which may be further divided into the aspirin-derived (acidic) nonsteroidal anti-inflammatory drugs (eg, ibuprofen) and the phenazone and acetaminophen-like (nonacidic) antipyretic analgesics (which have little anti-inflammatory activity). Chemical modifications and broad-spectrum screening provided medicine with thousands of pharmacologic analogs that broadened the therapeutic spectrum but did not supplant the original compounds developed in the 19th and early 20th century. Recently, molecular biology and genomics have led to the development of new target-selective chemical entities for use in pain relief. These include selective cyclooxygenase (COX)-2 inhibitors, substance P, blockers or agonists of cannabinoid and vanilloid receptors, inhibitors of tetradotoxin-resistant Na channels, and many more. Most of these selective compounds did not succeed in everyday pain treatment. Some look promising, including the COX-2 selective inhibitors, but doubts remain about the superiority of these new compounds in everyday use. This is particularly the case with the generation of selective COX-2 inhibitors currently in clinical use.