FROM ANTIQUITY, it has been appreciated that beverages constituted of aqueous extracts of a wide variety of coffee, cola, and cocoa beans have significant stimulant properties(Gilbert, 1981; Rall, 1985). It was, however, not until the turn of the century, when the natural product, caffeine, was isolated and its structure identified in 1875 (Arnaud, 1987), that it was appreciated that a significant proportion ofthe behavioral and physiological effects produced by these organic extracts was exerted by the alkaloid caffeine. Beverages prepared from these products can contain significant quantities of caffeine. Thus, in a modest 5-oz quantity of coffee, 50 to 150 mg caffeine may be found(Osol and Pratt, 1967). In North America, estimates of daily per capita consumption indicate that approximately 90% of the population consumes an average of approximately 200 mg/day caffeine (Gilbert et al., 1976). Random measurement of plasma caffeine in a clinical outpatient population revealed that 5% of the population had levels greater than approximately 6 jzg/ml (Smith et al., 1982). The ready availability of caffeine extracts and their appreciated stimulant properties led to their incorporation into a variety ofpopular medicinal products. As with many widely available over-the-counter products, the relative contribution of such agents to the efficacy of the treatment failed to be properly evaluated. In the late 1950s, clinical studies were carried out to examine the effects of caffeine in conjunction with various mildly active analgesics; limited subject populations were used in these studies and appropriate controls were often lacking. Such early investigations led to controversial findings that made it difficult to interpret the contribution, if any, of caffeine to the therapeutic efficacy of these agents (Beaver, 1966, 1981; AMA Drug Evaluations, 1983), a fact reflected by the official position of the United States Food and Drug Advisory review panel on over-the-counter analgesics(Over the Counter Drugs, 1977, 1988).

In the past 10 years, however, an increasing number of controlled clinical trials have produced evidence that caffeine, as a drug, may, indeed, contribute to an amelioration of at least certain pain states. Of equal importance, these clinical observations occur in concert with (a) an expanding literature concerning the complex pharmacol-