History of NSAID Use in the Treatment of Headaches Pre and Post-industrial Revolution in the United States: the Rise and Fall of Antipyrine, Salicylic Acid, and Acetanilide.

PURPOSE OF REVIEW: Non-steroid anti-inflammatory drugs (NSAIDs) constitute a vital class of medications in today's headache regimen. However, up until the nineteenth century, they were largely unknown to most of the medical community. The purpose of this review is to explore the evolution of NSAIDs in the treatment of headaches spurred on by the Industrial Revolution in the USA. RECENT FINDINGS: The currently available data on the impact of NSAIDs reflects their significant contribution to headache treatment. The emergence of mass production spurred on by the Industrial Revolution, lead to widespread use of antipyrine, salicylic acid, and acetanilide. However, along with it came the growing awareness of consumer safety, leading to their ultimate downfall, and the subsequent birth of the Food and Drug Act.

The evil of the unknown--risk-benefit evaluation of new synthetic drugs in the 19th century.

In the 19th century, synthetic chemistry discovered completely new chemical entities for medicinal use, which dramatically enriched the therapeutic armamentarium. However, no information was available regarding the safety of these new drugs, which were unrelated to most of the medicinal agents formerly known. Therefore, the question arises, if and how far, considerations regarding the relationship between benefit and risks were made. In this study, chloroform, phenazone (antipyrine) and sulfonal, were investigated as examples for drugs newly introduced in the 19th century. The results revealed that these drugs were provided by the manufacturer, tested by the physicians in a multicentre pattern and side effects were published in the medical literature soon after. Within a few years, several hundred cases were reported but the data were rarely summarized statistically. Therefore, physicians needed to stay updated with the medical literature because neither systematic industrial research nor regulatory authorities existed. The number of case reports within the first years were sufficient to detect common (> 1/100 to < 1/10) side effects but rare events were also reported. An extraordinary example is the drug-induced toxic epidermal necrolysis, which is commonly known as the Lyell syndrome or its less severe form, the Stevens-Johnson syndrome. This reaction has been clearly described by Baruch Spitz (1854-1932) as a side effect of antipyrine in 1887, several decades before Stevens, Johnson and particularly Lyell.

[From willow bark to the coxibs. Development of antiphlogistic analgesics]. / Von der Weidenrinde zu den Coxiben. Entwicklung der antiphlogistischen Analgetika.

Antiphlogistic analgesics comprise the most widely used class of drugs worldwide. These compounds derive more or less directly from three prototypes which were discovered about 130 years ago in Central Europe: acetylsalicylic acid (aspirin), acetanilide (the forerunner of acetaminophen), and phenazone. All of them are still available. Attempts to improve their effect/side effect spectrum and enhance their analgesic activity led to the development of animal models of inflammatory pain which allowed for the screening and discovery of the so-called aspirin-like drugs, also termed nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase inhibitors. This group presently dominates the market despite the fact that all these compounds imply the risk of unwanted drug effects, including gastrointestinal ulcers, renal dysfunction, inhibition of blood coagulation, pseudoallergic reactions, and possibly also accelerated development of atherosclerosis. Attempts to reduce these unwanted drug effects on the basis of molecular pharmacological insights resulted in the development of the so-called selective cyclooxygenase-2 inhibitors which are presently discussed ambiguously. These compounds appear to go along with less gastrointestinal toxicity, they do not inhibit blood coagulation, and have a reduced propensity for causing pseudoallergic asthmatic attacks. They may, on the other hand, cause more unwanted cardiovascular effects than the traditional NSAIDs. Hope for further reduction of unwanted drug effects comes from the recently discovered role of glycinergic spinal pain control. It is hoped that new classes of analgesic compounds may result from these new glycinergic mechanisms.