Methylxanthines have proved valuable in relieving apnea, or arrested breathing, in premature infants. Traditionally, theophylline has been chosen for this purpose, because a 1921 study demonstrated its greater potency in this respect, but more recently caffeine has been preferred by many physicians because the regimes for dosing (in part resulting from the longer half-life of caffeine in infants) are more easily managed and also because, paradoxically, administering theophylline to infants results in a greater buildup of caffeine in their systems than does the administration of caffeine.
Caffeine and Headaches and Pain Control
Because of its purported value as an analgesic adjuvant, caffeine has been used for decades in both non-narcotic and narcotic painkillers. Are these benefits genuine? Doctors disagree. One study demonstrated that the potency of analgesics compounded with caffeine was 40 percent greater than the same analgesics without caffeine. This means that, if you add caffeine to aspirin, for example, you will only need about two-thirds as much aspirin to achieve the same result as with aspirin alone. However, this does not mean that caffeine together with aspirin can relieve more intense pain than aspirin alone.20
Caffeine has been especially credited with the relief of headache pain, an effect that has been associated with its action as an adenosine antagonist. Caffeine has demonstrated vasoconstrictor effects on cerebral blood vessels, and it is believed that this action may augment its value in treating headaches, such as migraines, in which vasodilatation is a contributing factor. In addition, caffeine has a specific effect that can help migraine sufferers: It enhances the action of ergotamine, used in the treatment of migraine. This discovery was made by migraine patients who noted that strong coffee provided symptomatic relief, especially when combined with ergot alkaloids. The benefit is believed to result from the fact that caffeine increases ergotamine’s oral and rectal absorption.
In at least one instance, caffeine was the cause of a major headache for one of the leading pharmaceutical companies. Excedrin, an over-the-counter Bristol-Myers Squibb analgesic, contains acetaminophen and caffeine. Recently, however, two 1,000bottle lots of Excedrin caplets were accidentally filled with 200 mg of pure caffeine, as much as in a NoDoz caffeine caplet, another Bristol-Myers Squibb product. Evidently the Excedrin gel tabs were being filled on the same processing line as NoDoz, and, despite all the computerized tracking, someone made a mistake. Bristol-Myers Squibb set up an 800 number to answer consumer questions and recalled the pills in question. Although the company feared an avalanche of bad publicity, the story received little news coverage. A company spokeswoman told us, “One adverse event was documented”: a woman who, after taking the pills, was “treated and released,” although what she was treated for was not specified. The company maintains that “untoward reactions to caffeine are not usually observed” at doses of less than 1,000 milligrams, but acknowledged that sensitivity to caffeine varies widely and that some people might have problems at lower doses.
Caffeine and Setting the Circadian Clock
A study by Dr. Margaret Moline of the New York Hospital-Cornell Medical Center, presented to the Boston Sleep Research Society in 1994, suggested that jet lag can be averted with judicious use of caffeine.21 Moline isolated five middle-aged men from clocks, televisions, windows, or any other external indicia of the passage of time. All the men followed their natural sleep schedules and received only a placebo for the first five days. After this, they were allowed to go to sleep at their normal time, but were awakened six hours earlier than usual and given either a pill containing 200 mg of caffeine or a placebo. This sleep displacement simulated the displacement experienced by travelers from New York to London. The results strongly suggested that a subject who took caffeine helped to reset his body’s clock with less intense disturbances and of a shorter duration than a subject who was given the placebo.
Books on jet lag often advise abstaining from caffeine for a week or two before a flight and then drinking several strong cups of coffee or tea at the correct hour to reset your biological clock to daytime after arriving at your destination. We have tried this and found that it works remarkably well.
Caffeine and Weight Control
We do not know enough to say if, or under what conditions, or for which subjects, or in what doses, caffeine can contribute to efforts to lose weight. Because it is evident that it can do so sometimes, for some people, anyone with a weight problem may be well advised to give caffeine a careful try, if he has no problems using caffeine to begin with.
Caffeine and Low Blood Pressure
Caffeine’s therapeutic effects on low blood pressure caused by failure of the autonomic regulatory system, a condition afflicting about fifty thousand Americans, was investigated by researchers at Vanderbilt University Medical School in 1985. They administered two and one-half cups of coffee a day to patients with low blood pressure caused by autonomic failure, a disorder of the blood pressure regulatory mechanism that results in pressure so low that victims often faint when they stand up, especially after eating a meal. The autonomic nervous system controls the motor functions of the heart, lungs, intestines, and other internal organs. When experiencing autonomic failure, the body does not respond properly to conditions in which it needs to raise the blood pressure, such as while standing up or eating.
Caffeine has been shown to raise blood pressure in normal subjects, but only if they have not had any coffee in several days. Usually this effect wears off when coffee is consumed regularly. Nevertheless, as a result of his study, David Robertson, in a report in the New England Journal of Medicine, concluded, “We now advise our patients with autonomic failure to drink two cups of coffee with breakfast and to abstain for the rest of the day.”22
Caffeine and Athletic Performance
The International Olympic Committee, convinced that caffeine has positive ergogenic effects—that is, that an athlete can increase output or endurance by using caffeine—has restricted the urine levels of caffeine that competing athletes may exhibit after a competition. Laboratory studies, however, are not so clear if or when or to what degree these beneficial effects occur, whether they are more or less likely to be observed in trained athletes than in people in average condition, whether they are observed more in relation to certain muscle groups, whether they are observed only when the activity in question is sustained at a very high level for a very long time, and other similar questions.
Caffeine and Skin Problems
Atopic dermatitis may be treatable with topical use of caffeine. Topical treatment with 30 percent caffeine in a hydrophilic base or in a hydrocortisone cream produces improvement in various forms of this skin condition, including pruritus, erythema, scaling, lichenification, oozing, and dermatitis. The improvement may be related to caffeine’s ability to liberate water from epidermal and subcutaneous tissues.23
Caffeine and Parkinson’s Disease
A high intake of caffeine may be associated with a lower incidence and slower pro-gression of Parkinson’s disease. A study reported in the Journal of the American Medical Association (May 24, 2000), led by G.Webster Ross, M.D., staff neurologist at the Department of Veterans Affairs in Honolulu, analyzed thirty years of data from the Honolulu Heart Program, which has followed more than 8,000 Japanese-American men since 1965. Age-adjusted incidence of Parkinson disease dropped dramatically, from 10.4 per 10,000 man-years in men who drank no coffee to 1.9 per 10,000 manyears in men who drank over 28 ounces, or about five 6-ounce cups, a day. A similar decline was observed for caffeine intake from sources other than coffee. Ross concluded that “caffeine has a medicinal effect. It could be treating motor symptoms.”
As reported in an interview in HealthScout (May 23, 2000), Abraham Lieberman, M.D., professor of neurology at the University of Miami and medical director of the National Parkinson Foundation, attributes the possible role of caffeine in preventing Parkinson’s Disease to its ability to block adenosine receptors and increase the levels of dopamine, which are low in people suffe
ring from the disease. However, Lieberman maintains, further long-term studies of the progression of the disease are needed to establish the treatment potential of caffeine in Parkinson’s disease more definitively.
Clinical Actions of the Methylxanthines
Desired Action Preferred Agent
Cerebral Stimulation Caffeine (Coffee)
Coronary Dilation Theophylline (Tea)
Diuresis Theobromine (Chocolate)
Respiratory Stimulant for Premature Infants Caffeine or Theophylline
appendix d
Methodological Pitfalls
Everyone knows that scientists investigate the world by systematically testing hypotheses using carefully designed experiments. The results of their studies are presumably replicable and therefore their conclusions represent objective advances in scientific understanding. Unfortunately, in the area of human health, the complexity of the human body and mind and the inability of investigators to conduct potentially dangerous experiments on human beings as part of their research often make it difficult to make reliable judgments. There are three potential weaknesses of medical studies that pose problems for those seeking to understand caffeine’s health effects: biased sample selection, inaccurately measured exposure, and failure to exclude confounding variables. Because these limitations can be seen most clearly in studies of caffeine’s effects on the outcomes of pregnancy, it is valuable to examine in detail some of the methodological problems that bedevil scientists working on these questions. While reading this section, however, the reader should keep in mind that similar or identical problems attend investigations of every area of caffeine and human health discussed in this book.1
Sample Selection
Studies of the effects of caffeine consumption on reproductive hazards, including the risk of delayed conception, spontaneous abortion, prematurity, low birthweight, and major congenital malformations, multiplied like rabbits throughout the 1980s and 1990s. Although poor design has limited the value of many of them, the larger, more probative studies generally demonstrate no correlation between caffeine use and reproductive hazards of all kinds.2 Yet, as is true for the results of any epidemiological studies, the value and weight of their conclusions depend on whether the people studied were selected in a way that did not prejudice or distort the outcomes.
Unfortunately, defective sample selection is endemic to studies of caffeine and human reproduction, in part because few researchers into reproductive hazards undertake studies with caffeine or coffee as their primary initial interest. Many even inquire about caffeine use only to divert attention from questions about other risk factors such as cigarettes and alcohol. Such casual treatment of caffeine is possible— and especially distressing—only because caffeine is so much a part of life that it is little noticed and then often only as an afterthought.
Exposure
It is evident that an accurate assessment of exposure, that is, the amount of caffeine consumed, is fundamental to any evaluation of a link between caffeine consumption and health. In fact, precision in measuring exposure is essential, because a dose-response relationship—that is, the tendency of increasing doses to elicit increasing responses—strongly suggests a causal relationship and cannot be evaluated without it. If a low exposure is correlated with low risk, moderate exposure with moderate risk, and high exposure with high risk, scientists are more inclined to posit a corresponding cause-and-effect connection. In the matter of adverse effects on pregnancy, such a relationship would exist if those pregnant women who consume more caffeine were at a higher risk for adverse effects than pregnant women who consume less, and it would lead us to think that caffeine exposure is the cause for these untoward outcomes.
Laboratory control studies rely on a number of stratagems, such as using decaffeinated coffee to which varying doses of caffeine have been added, to enable the researchers to record the exact amount of caffeine consumed. For epidemiologists, scientists who study the occurrence and causes of diseases in the field, however, it is rarely a simple matter to determine how much caffeine subjects have used. Tea and coffee cups commonly range from four to sixteen ounces.3 So long as estimates of caffeine consumption are tied to coffee drinking, the wide variability of caffeine content in the beans and of roasting and brewing methods, which reflect regional variations and personal preferences, will limit the ability of epidemiologists to determine the actual levels of caffeine consumption. An additional problem is the unreliability of questionnaire answers, which may underestimate or overestimate intake. For example, in a recent breast cancer study in which records of caffeine consumption were kept and compared with later recollections of that consumption, it was found that the women studied reported an average of 75 mg a day less caffeine than they had actually ingested, while the women serving as controls underreported their consumption by only 40 mg a day.4 In another study, pregnant controls were more likely to underreport consumption than women who had miscarried.5 In any case, serum concentrations of caffeine’s primary metabolites, such as paraxanthine, do not closely correspond with questionnaire answers about caffeine consumption. Discrepancies may reflect errors in recollection, varying methods of preparation, or differences in metabolic degradation rates. It is evident that, to accurately gauge caffeine exposure, future researchers must utilize not only questionnaires and cup counts, but biomarkers—that is, objective measures of caffeine and its metabolites in the body—as well.
Measuring exposure to the fetus is especially difficult because the amount of caffeine consumed and the speed at which it is metabolized vary throughout pregnancy. For example, because of the nausea associated with the first six months of pregnancy, consumption may be lower than usual during that period. Another confusing factor is that it takes longer for the body to get rid of caffeine’s metabolites near the end of pregnancy.6 Therefore, to avoid the unpleasant feelings associated with elevated blood levels of caffeine’s metabolites, some women appear to reduce their consumption of caffeinated drinks during pregnancy.
A different sort of problem arises when exposure to caffeine is measured but effects of exposure to other drugs that may have been consumed along with it are overlooked. Yet another confounding exposure may arise from neglect of non-dietary sources of caffeine, such as over-the-counter and prescription medicines that people may not realize contain caffeinated and so fail to report.
Confounding Variables
We have already noted ways in which hidden variables can baffle attempts to understand the relationship between the use of caffeine and any given health outcome. Epidemiologists call such variables “confounders” that, according to one researcher, “plague the literature” about the link between caffeine and problems in human reproduction. An example is the confounding variable of maternal age. Coffee consumption tends to increase with age throughout the childbearing years and, at the same time, the risk of many reproductive hazards also increases with age past 25 or 30.7
People who drink coffee differ in significant ways—over and beyond their use of coffee—from those who do not, and those who drink a great deal of coffee differ from those who drink less. Comparisons of health effects are particularly problematic between members of these groups and people who do not use caffeine with respect to any health-related variable.8 An example of material confusion results from the fact that people who drink little or no coffee tend to use less tobacco and alcohol than those who are heavy coffee drinkers. This kind of insidious confounder can easily engender false claims of a causal connection between coffee or caffeine and health problems.9
notes
OVERVIEW
1. Henry Watts, ed., Dictionary of Chemistry, vol. I, p. 707.
2. John Evelyn, Works, note, p. 11.
3. Sir Richard Steele, Tatler, April 12, 1709.
PROLOGUE
1. Johann Wolfgang von Goethe, Versuch die Metamorphose der Pflanzen zu erklären (Attempts to Illustrate the Metamorphosis of Plants). In this book Goethe takes his place as a pioneer in the theory of evoluti
on.
2. As P.Walden, in his essay “Goethe and Chemistry,” states, “At Weimar the time had come for Goethe to reexamine his chemical knowledge and concepts, to transfer them into the realm of practice and reality, simultaneously, however, to give them a more solid theoretical foundation” (George Urdang, Goethe and Pharmacy, p. 15).
3. Fielding H.Garrison, History of Medicine, p. 262.
4. The singular distinction of Goethe’s fame is that the paradigm of the widely celebrated writer began with him. Before Goethe, the authors of important books had enjoyed respect, but they had never become personal heroes to a large public. Although their works were honored, the authors themselves were uninteresting to the popular imagination. But from the time his early novel The Sorrows of Young Werther instigated suicides among teenagers across Europe, people everywhere became what we would today call Goethe’s “fans.”
5. Wolfgang von Goethe, The Sorrows of Young Werther, p. ix.
6. Berthold Anft, “Friedlieb Ferdinand Runge,” p. 574.
7. It is the use of “sleepy substance” as an explanatory mechanism for morphine that Molière makes fun of in the Imaginary Invalid and that Nietzsche cites as typifying the silliness of the empiricists’ arbitrary reifications.
The World of Caffeine Page 50